GB2162845A - Phenethanolamine derivatives - Google Patents

Abstract

Compounds of the general formula (I> <IMAGE> (wherein R represents a hydrogen atom or a straight chain C1-3 alkyl group and n is 1 or 2, and physiologically acceptable acid addition salts, solvates and metabolically labile esters thereof) of use in the treatment of heart failure, cardiogenic shock or ischaemic heart disease. Also disclosed are compounds of general formula (XV> <IMAGE> (wherein n is 1 or 2, R<2>, R<3>, R<4> and R<5> each represent a hydrogen atom or a protecting group and R<8> represents a carboxyl group, or a salt or C1-5 alkyl ester thereof) which are of value as intermediates.

Description

SPECIFICATION Phenethanolamine derivatives This invention relates to phenethanolamine derivatives having cardiotonic and vasodilator activity, to processes for their preparation, to pharmaceutical compositions containing them and to their use in med icine, particularly in the treatment of heart failure.

Heart failure is characterised by the inability of the heart to pump blood in sufficient quantities for the needs of the body. As a result, there is a reflex increase in sympathetic drive to the heart and vascular system, leading to elevated heart rate and contractile force and to increased vascular resistance. The increased resistance further opposes an already compromised heart and an interaction is established whereby the increase in resistance (brought about to maintain cerebral blood flow) progressively exacerbates the condition.

Therapy of heart failure generally involves increasing the contractile force of the heart or reducing resistance in the peripheral vascular system. Hitherto, the most commonly used agents for the treatment of heart failure have been the digitalis glycosides, which increase the contractile force of the heart, i.e. they improve its pumping action. However, these cardiotonic agents suffer from the disadvantage of being undesirably toxic. Other agents, such as dopamine and dobutamine, suffer from the disadvantage that they, like isoprenaline, adrenaline and noradrenaline, have a short duration of action and are inactive following oral administration or cause undesirable side effects.

More recently it has been found that the use of vasodilators to reduce peripheral vascular resistance (i.e., to reduce the resistance of the blood vessels to the pumping action of the heart) is of value in the treatment of heart failure. However, a common side effect of vasodilator agents such as nitroprusside and hydralazine is that they cause undesirable side effects such as headache and reflex tachycardia.

The combination of a cardiotonic agent and a vasodilator is of particular value in the treatment of heart failure.When administering such a combination of agents it is desirable that they possess similar pharmacokinetic profiles such that both agents are active over similar periods. This is often very difficult to achieve in compounds of differing structures.

Thus, compounds of low toxicity which increases the force of contraction of the heart and decrease peripheral vascular resistance without unduly affecting heart rate and which have a long duration of action would be of great value in the treatment of heart failure. Activity following oral administration would also be desirable.

Phenethanolamines having a wide range of substituents on the phenyl ring and on the amino group are known. A number of different activities have been ascribed to such compounds, for example, p-adrenoreceptor blocking, vasodilating, bronchodilating and local anaesthetic activity. Uses have been found for a number of these agents in the treatment of conditions such as hypertension, cardiac arrhythmias, cardiac insufficiency, angina, asthma and glaucoma.

We have now found a small group of phenethanolamines having a particular combination of substituents in the phenyl ring and on the amino group, which compounds increase the contractile force of the heart and reduce peripheral vascular resistance. This particular group of phenethanolamines has not been disclosed in the prior literature and we have found that these compounds are cardiotonic agents and act as vasodilators and may be used in the treatment of heart failure.

Thus, the invention provides compounds of the general formula (I):

wherein R represents a hydrogen atom or a straight chain C13 alkyl group and n is 1 or 2, and physiologically acceptable acid addition salts, solvates and metabolically labile esters thereof.

It will be appreciated that the compounds according to the invention possess an asymmetric carbon atom, namely the -CH(OH)- group and there are thus two optically active enantiomers of the general formula (I). It is to be understood that the present invention encompasses both the individual isomeric forms of the compounds of formula (I) and all mixtures of such enantiomers.

The physiologically acceptable acid addition salts of the compounds of formula (I) may be derived from inorganic or organic acids. Examples of such salts include hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, p-toluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, citrates, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates, acetates or tricarballylates. Preferred acid addition salts are the hydrochlorides, fumarates and phosphates.

Physiologically acceptable metabolically labile ester derivatives may be formed by acylation of any of the hydroxyl groups in the parent compound of general formula (I). Examples of such esters include lower alkanoates such as acetates or pivaloates. In addition to the above ester derivatives, the present invention includes within its scope compounds of general formula (I) in the form of other physiologically acceptable equivalents, i.e. physiologically acceptable compounds which, like the metabolically labile esters, are converted in vivo into the parent compounds of general formula (I). The invention also includes within its scope the solvates, especially the hydrates, of compounds of general formula (I).

Tests in animals have shown that compounds of general formula (I) at low dosages increase the force of contraction of cardiac muscle and decrease total peripheral resistance.The compounds according to the invention are potent stimulants of myocardial function and act as vasodilators. Furthermore, compounds according to the invention have particular advantages over known cardiotonic agents such as isoprenaline and dobutamine in that they have a longer duration of action, and in addition they are absorbed from the gastrointestinal tract, as evidenced by their activity following oral administration. We have found that compounds of general formula (I) selectively block vascular aI-adrenoceptors and stimulate myocardial ,-adrenoceptors.The compounds show no signs of toxicity at the highest doses tested.

One aspect of the present invention provides for compounds of formula (I) wherein R represents a hydrogen atom, a methyl group or an ethyl group, and n is 1 or 2, and physiologically acceptable acid addition salts, solvates and metabolically labile esters thereof.

A preferred group of compounds of formula (I) is that wherein n is 1.

Another preferred group of compounds of formula (I) is that where R represents a hydrogen atom.

A particularly preferred compound is 2-[2-[[2-(3,5-dihydroxyphenyl)-2-hydroxy- ethyl]amino]ethoxy]benzene-acetamide and its physiologically acceptable acid addition salts, e.g. the fumarate or phosphate conveniently in the form of a racemic mixture of its (R) and (S) isomers.

Compounds according to the invention may be used in the treatment of heart failure, cardiogenic shock, or ischaemic heart disease.

The invention accordingly further provides compounds of general formula (I) and their physiologically acceptable acid addition salts and metabolically labile esters for use in the therapy or prophylaxis of heart failure in a human or animal subject.

The compounds of formula (I) and their physiologically acceptable acid addition salts and metabolically labile esters may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions comprising at least one compound of formula (I) or a physiologically acceptable salt, solvate or metabolically labile ester thereof adapted for use in human or veterinary medicine. Such compositions may be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.

Thus, the compounds according to the invention may be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate; or-wetting agents such as sodium lauryl sulphate.The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. The compounds or their salts or esters may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

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

The compounds of formula (I) and their physiologically acceptable acid addition salts and metabolically labile esters may also be formulated for parenteral administration by injection or continuous infusion.

Formulations for injection may be presented in unit dose 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 constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

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, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from a nebuliser. In the case of a pressurised aerosol the dosage unit may be determined by providing a value to deliver a metered amount.

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

When the compositions comprise dosage units, each unit will preferably contain 5mg to 500mg, advantageously where the compounds are to be administered orally 25mg to 400mg of the active compound.

The daily dosage as employed for adult human treatment will preferably range from 5mg to 39, most preferably from 25mg to ig which may be administered in 1 to 4 daily doses, for example, depending on the route of administration and on the condition of the patient.

The compounds of formula (I) and their physiologically acceptable acid addition salts and metabolically labile esters may be administered in combination with other therapeutic agents.

The compounds of the invention may be prepared by a number of processes as described in the following.

According to one general process (1), the compounds of general formula (I) may be prepared by an alkylation reaction between a compound of formula (II)

(wherein -NA represents a group -NHRS, -NR5CH2CH2X,

R2, R3, R4 and R5 are each a hydrogen atom or a protecting group and X is a readily displaceable atom or group) and a compound of formula (III)

(where R and n are as defined in formula I, B is a hydrogen atom or a protecting group, and Y represents hydrogen when -NA represents -NR5CH2CH2X,

or Y represents the group CH2CH2X where X is as previously defined when -NA represents -NHRS) followed by removal of any protecting groups where present as described hereinafter.

Examples of X include a halogen atom such as a chlorine, bromine or iodine atom or a hydrocarbylsulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy. Where X is chloro or bromo the reaction may be facilitated by addition of an iodide such as sodium iodide.

In one particular embodiment of the process, the compounds of general formula (I) may be prepared by alkylation of an amine of formula (IV)

with an alkylating agent of formula (V)

followed by removal of any protecting groups where present as described hereinafter.

The reaction is preferably carried out in the presence of a base such as an alkali metal bicarbonate or carbonate e.g. sodium bicarbonate or potassium carbonate or an amine e.g. diisopropylethylamine or silver oxide, and in solution at any temperature in the range -20" to +100"C. Suitable reaction solvents include ethers, e.g. dioxan, acetonitrile, substituted amides, e.g. N,N-dimethylformamide and hydrocarbons, e.g. benzene.

In a further embodiment of the process, the compounds of formula (I) may be prepared by alkylation of a phenol of formula (Vl)

with an alkylating agent of formula (Vli)

followed by removal of any protecting groups where present as described hereinafter.

Alternatively, compounds of formula (VII) may be in the form of an aziridine:

or an aziridinium salt:

where A- represents an anion such as a halide ion.

The reaction is preferably effected in the presence of a base. Suitable bases include inorganic bases such as sodium hydroxide, sodium hydride, potassium carbonate or potassium t-butoxide, organic bases such as diisopropylethylamine and basic ion exchange resins such as Amberlite (RTM). Alternatively the compound of formula (VI) may be used in the form of a phenolate salt e.g. sodium salt. The reaction is conveniently effected in a medium such as water; acetonitrile; an alcohol, e.g. methanol; or a ketone, e.g. acetone or methyl isobutyl ketone, and at a temperature in the range -20" to 150"C preferably 20" to 100"C.

According to another general process (2), the compounds of formula (I) may be prepared by reacting a compound of formula (VIII)

(wherein R2 and R3 are as previously defined in general process (1) and Re represents a group

in which R4 and X are as previously defined in general process (1)) with an amine of formula (IX)

(where R, Ri, R5 and n are as previously defined in general process (1)) followed by removal of any protecting groups, where present, as described hereinafter.

This reaction may be effected either in the presence or absence of a solvent at a temperature of 0 to 150", preferably 20" to 100 C. Suitable solvents include alcohols, e.g. methanol or ethanol; halogenated hydrocarbons,e.g. chloroform or dichloromethane; substituted amides, e.g. N,N-dimethylformamide; ethers, e.g. diethyl ether or tetrahydrofuran; acetonitrile; esters, e.g. ethyl acetate; and water and mixtures of such solvents.

When Re represents a group

the reaction may be carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide or as an organic base such as pyridine. Alternatively an excess of the amine of formula (IX) may be used.

According to another general process (3), the compounds of formula (I) may be prepared by reductive alkylation. Thus a compound of formula (X)

(wherein R7 represents the group -COCHO or

and R2,R3,R4 and Rye are as previously defined in general process (1)) may be reacted with a compound of formula (Xl)

(wherein Z represents the group CHO when R7 is or

or Z represents the group CH2NHR5 when R7 is -COCHO and R, RI, R and n are as previously defined in general process (1)) in the presence of a reducing agent followed by removal of any protecting groups, where present, as described hereinafter.

In one particular embodiment of general process (3) a compound of formula (X) in which R7 is CH(OR4)CH2NHR5 is reacted with a compound of formula (Xl) in which Z is CHO in the presence of a reducing agent. Examples of suitable reducing agents include an alkali metal or alkaline earth metal borohydride or cyanoborohydride, such as sodium borohydride or cyanoborohydride, using an alcohol such as ethanol or propanol as solvent, or hydrogen in the presence of a catalyst, such as Raney nickel, platinum, platinum oxide, palladium or rhodium, using an alcohol e.g. ethanol; an ether, e.g. dioxan or an ester, e.g. ethyl acetate as reaction solvent. The catalyst may be supported on for example charcoal or a homogenous catalyst such as tristriphenylphosphine rhodium chloride may be used.The reduction may conveniently be carried out at any temperature from -20" to 100"C, preferably 0" to 50"C.

The reaction may proceed via the imine (XII)

(where R,R5R2,R3,R4 and n are as previously defined in general process (1)) and it may be possible to isolate this intermediate. Reduction of the imine using the conditions described above followed where necessary by removal of any protecting groups gives a compound of general formula (I).

In a further embodiment of general process (3) a compound of formula (X) in which R7 is COCHO is reacted with a compound of formula (Xl) in which Z is CH,NHRS in the presence of a reducing agent.

Suitable reducing agents are those previously described in the first embodiment of the reductive alkylation process.

This reaction may proceed via the imine of formula (XIII)

(wherein R,R',R2,R3, and n are as previously defined in general process (1)) and it may be possible to isolate this intermediate. This compound may also be reduced using the reagents previously described in the first embodiment of the reductive alkylation process followed by removal where necessary of any protecting groups to give a compound of formula (I).

According to another general process (4), the compounds of formula (I) may be prepared by reduction of a compound of formula (XIV)

(where B,R1,B2,R3,Rs and n are a previously defined in general process (1)) followed by removal of any protecting groups, where present, as described hereinafter. Reduction may be effected using an alkali metal or alkaline earth metal borohydride, such as sodium borohydride or hydrogen in the presence of a catalyst such as palladium or platinum, which may be supported, for example on charcoal. Stereoselective reduction may be achieved using an optically active boran such as alpine-borane (9-(2,6,6-trimethyl bicyclo[3.1 .1 .]hept-3-yl)-9-borabicyclo- [3.3.1 ]nonane).

The reaction is conveniently effected in an organic solvent such as an ether, e.g. tetrahydrofuran, or an alcohol, e.g. methanol or ethanol, at a temperature of, for example 20" to 80"C.

According to another general process (5) the compounds of the invention may be prepared by amina tioh of a compound of formula (XV)

(where R > ,R3,R4,R5 and n are as previously defined in general process (1) and Rs represents a carboxyl group or a salt or reactive derivative thereof, for example an acid halide e.g. acid chloride, an acid anhydride formed with for example an acid chloride e.g. pivaloyl chloride or chloroformate, or an ester e.g. a C, 5 alkyl ester) followed by removal of any protecting groups where present as described hereinafter.

The reactive derivative may also be formed in situ by treatment of the acid or salt thereof with a con densing agent such as N,N'-dicyclohexylcarbodiimide or N,N'-carbonyldiimidazole.

The amination will generally be effected using an amine RHN2, (where R is previously defined in formula 1). The reaction is conveniently carried out in an organic solvent such as an alcohol, e.g. methanol or ethanol; an ether, e.g. tetrahydrofuran; an amide, e.g. N,N'- dimethylformamide; or a halogenated hydrocarbon, e.g. methylene chloride, optionally in the presence of a catalyst such as silica or rhodium trichloride and at a temperature of, for example 0 to 150"C preferably 50" to 100"C. when ammonia is used for the reaction (ie R is hydrogen) it may be desirable to carry out the reaction at high pressure, preferably using water or an alcohol such as methanol or ethanol as solvent.

Compounds of formula (XV) where R5 is a carboxyl group and salts and esters (e.g. C, 5 alkyl esters) thereof are novel compounds which are valuable intermediates, and constitute a further feature of the invention.

An interesting class of compounds of formula (XV) are those wherein R2,R3,R4 and R5 are hydrogen atoms.

A particularly interesting class of compounds of formula (XV) are those wherein R2,R3,R4 and R5 are hydrogen atoms and R5 represents a carboxyl group or a C,.5 alkyl ester thereof (eg a methyl or isopropyl ester).

Compounds of formula (XV) wherein R2,R3,R4 and Rs are hydrogen atoms and R8 represents a carboxyl group are especially interesting, more particularly when n is 1.

According to another general process (6) the compounds of the invention in which R represents hydrogen may be prepared by hydrolysis of a compound of formula (XVI)

(where R2,R3,R4,R5,,d n are as previously defined in general process (1)) followed by removal of any protecting groups, where present, as described hereinafter. The hydrolysis may be effected under acidic or basic conditions using an aqueous acid e.g. polyphosphoric, hydrochloric or sulphuric acid, or a base such as an alkali metal hydroxide e.g. potassium hydroxide and at a temperature of 0-100"C. The reaction may conveniently be effected in a water miscible solvent such as an alcohol, e.g. t-butanol or methanol, a ketone, e.g. acetone or using acetic acid, preferably in the presence of water.

According to another general process (7), the compounds of formula (I) may be prepared by deprotection of a compound of formula (XVII)

where R,R',R2,R3,R4,R5 and n are as previously defined in general process (1), or R4 and R5 together represent a protecting group, providing that at least one of R',R2,R3,R4 and R5 represents a protecting group.

Where R1,R2,R3,R4 or R5is a protecting group it may be any conventional protecting group, for example, as described in 'Protective Groups in Organic Chemistry', Ed. J.F.W. McOmie (Plenum Press, 1973). Examples of suitable hydroxyl protecting groups represented by R2,R3 and R4 are alkyl groups such as tbutyl or methoxymethyl, aralkyl groups such as benzyl, diphenylmethyl ortriphenylmethyl, heterocyclic groups such as tetrahydropyranyl and acyl groups such as acetyl.Examples of suitable amino protecting groups represented by R5 are aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl and acyl groups such as dichloroacetyl. Examples of suitable amide protecting groups R' are t-butoxycarbonyl and 2,2,2-trichloroethoxycarbonyl groups.

The protecting groups R',R2,R3,R4 and/or R5 may be removed using conventional techniques to yieid a compound of formula (I). Thus, for example an aralkyl group such as benzyl may be cleaved by hydrogenolysis in the presence of a noble metal catalyst (e.g. palladium or palladium oxide on charcoal); an acyl group such as dichloroacetyl may be removed by reduction using for example zinc and acetic acid; and alkyl or heterocyclic group protecting a hydroxyl group may be cleaved by hydrolysis under acidic conditions. An amide protecting group, for example a t-butoxycarbonyl group, may be removed by acid hydrolysis.

In a particular embodiment of this process the groups R4 and R5 together may represent a protecting group as in a compound of formula (XVIII)

(where R,Rq,R2,R3 and n are as previously defined in general process (1) and yi represent a carbonyl or thiocarbonyl radical or a bivalent radical formed from an aldehyde or ketone such as acetaldehyde or acetone. A compound of formula (XVIII) may be converted into a compound of formula (I) by hydrolysis under acidic or basic conditions using for example aqueous hydrochloric or sulphuric acid or sodium hydroxide and where necessary, removal of any other protecting groups present using the methods described above.

Alternatively, the substituent on the amino group may act as an internal protecting group for the hydroxyl group in the ethylene moiety as in a compound of formula (XIX)

where R,RI,R2,R3,RS and n are as previously defined in general process (1). The compound of formula (XIX) may be converted into a compound of formula (I) by reduction using the reagents previously described in general process (3), and, where necessary, removal of any other protecting groups present using the methods described above.

When it is desired to prepare an acid addition salt of a compound of formula (I), the product of any of the above procedures may be converted into a salt by treatment of the resulting free base with a suitable acid using conventional methods.

Physiologically acceptable salts of the compounds of general formula (I) may be prepared by reacting a compound of general formula (I) in the form of the free base with an appropriate acid in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol, e.g. methanol, ethanol or isopropanol.

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

Optically active enantiomers of the compounds of the invention may be obtained from intermediates having the required chirality. Alternatively such enantiomers may also be obtained by resolution of the corresponding racemic compound using conventional means, such as an optically active resolving acid; see for example 'Stereochemistry of Carbon Compounds' by E L Eliel (McGraw Hill 1962) and 'Tables of Resolving Agents' by S H Wilen.

Examples of optically active resolving acids that may be used to form salts with the racemic compounds include the (R) and (S) forms of organic carboxylic and sulphonic acids such as tartaric acid, di-ptoluoyltartaric acid, camphorsulphonic acid and lactic acid.The resulting mixture of isomeric salts may be separated, for example, by fractional crystallisation, into the diastereoisomers and if desired, the required optically active isomer may be converted into the free base.

In another method the optically active enantiomers of the invention may be obtained by separation of optically active derivatives of the compounds. Thus, for example, derivatives of compounds of the invention can be prepared in which one of the groups Ri, R2, R3, R4 and R5 in the compounds of formula (XVII) represents a chiral protecting group.R2, R3 or R4 may, for example, represent an optically active sugar residue such as a - D-glucopyrano-sidyl group. An example of a suitable optically active amine protecting group R5 is an a-methylbenzyl group. These optically active protecting groups may be removed, after separation of the enantiomers, using the methods previously described in general process (7).

The methods just described for preparing the compounds of the invention can each be used as the last main step in a preparative sequence. The same general methods can be used for the introduction of the desired groups at an intermediate stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multi-stage processes.

The compounds of formula (VIII) in which R6 represents a group

may be prepared from a compound of formula (XX)

(where Ra and R3 are as defined above and Xis a halogen atom) by treatment with for example, sodium borohydride to form the halohydrin followed by treatment with a base such as potassium carbonate or sodium hydroxide. The reaction is conveniently effected in a solvent such as dimethylformamide, an alcohol such as methanol or ethanol or-water at a temperature of from room temperature to reflux.

The compounds of formula (VIII) in which R6 represent a group -CH(OR4)CH2X (where R4 and X are as previously defined in general formula (I)), may be prepared from the corresponding epoxides by treatment with the appropriate reagent such as hydrogen halide or p-toluenesulphonic acid followed by introduction of a protecting group if desired.

The compounds of formula (X) in which R7 is COCHO may be prepared from compounds of formula (XXI)

(where R2, R3 and XI are as previously defined) by reaction with an alkoxide such as sodium methoxide in methanol followed by treatment with an acid such as hydrochloric acid.

The compounds of formula (XX) are known compounds.

Compounds of formula (XXI) may be prepared by halogenation of a compound of formula (XXII):

(where R2 and R3 are as previously defined) using for example a halogen (e.g. chlorine) or a N-halosuccinimide (e.g. N-bromosuccinimide).

The compounds of formula (X) in which R7 is COCHO may also be prepared directly from a compound of formula (XXII) by oxidation using a suitable oxidising agent such as selenium dioxide.

The compounds of formula (XIV) may be prepared by reaction of a compound of formula (XX)withan amine of formula (IX) using the reaction conditions previously described in general process (2).

Compounds of formula (XVII) may be prepared using any of processes 1-4 as described previously.

The compounds of formula (VII) may be prepared by reacting a compound of formula (VIII) with an amine of formula

(where R5 and X are as previously defined) or when compounds of formula (Vll) are in the form of an aziridine or aziridinium salt, by reaction of a compound of formula (VIII) with an amine of formula

(wherein R5 is as previously defined) using the conditions described in general process (1).

Compounds of formula (IX) may be prepared from compounds of formula (V) by reaction with an amine of formula R 5 NH 2 (where R5 is as previously defined) following the reaction conditions of general process 1.

The compounds of formula (V) may be prepared from compounds of formula (Vi) by reaction with a compound XCH2CH2X (where X is as previously defined).

The compounds of formula (XI) where Z is CHO may be prepared by alkylation of the phenol of formula (VI) with an alkylating agent of'formula HCOCH2X (wherein X is as previously defined) or, particularly a protected derivative thereof, e.g. an acetal such as a diethylacetal.

Compounds of formula (XVI) can be prepared by reaction of a compound of formula (XX) with a nitrile of formula (XXIII)

(where R5 and n are as defined previously) followed by treatment with a reducing agent such as sodium borohydride.

Compounds of formula (XV) where -Rs is a carboxyl group or a salt or ester thereof can be prepared by reaction of compounds of formula (XXIV)

(where R5, Ba and n are as defined previously) with compounds of formula (XX) followed by treatment with a reducing agent such as sodium borohydride followed, where necessary, by removal of any protecting groups as described previously.

Compounds of formula (XV) where Ra is a carboxyl group can be prepared by hydrolysing a corresponding ester followed by removal of any protecting groups, where present, as described hereinafter.

The hydrolysis may be effected under acidic or basic conditions using an aqueous acid eg polyphosphoric, hydrochloric or sulphuric acid, or a base such as an alkali metal hydroxide eg sodium hydroxide and at a temperature of 0-100 C. The reaction may conveniently be effected in a water miscible solvent such as an alcohol eg methanol.

Compounds of formula (XV) where R5 is a reactive derivative of a carboxylic acid, for example an acid chloride or acid anhydride, may be prepared in a conventional manner for example by formation of an acid chloride or acid an hydride.

Compounds of formula (XV) where R6 is a carboxyl group or a salt or ester thereof and n is 2 can be prepared by reduction of the corresponding a-p-ethylene-carboxylic acid or acid salt or ester using suitable hydrogenation methods as described previously.The unsaturated precursor can be made by methods analogous to those described herein for the preparation of the compounds of the invention, for example by alkylation as described in general process (I) and illustrated in the Examples.

Compounds of formula (XXIII) and (XXIV) can be prepared by reaction of a compound of formula (XXV)

(where n is as previously defined and Ba represents the group C8N, CO2H or a carboxylic acid ester as defined previously for R8) with a compound of formula XCH2CH2Br (where X is as defined previously) followed by amination with a compound of formula RSNH, (where R5 is as defined pr viously).

Compounds of formula (XVIII) can be prepared from a compound of formula (XVII) where R,R'R2,R3 and n are as defined in general process (1) and R4 and R5 are hydrogen atoms by reaction with 1,11-carbonyldiimidazole or 1,11-thiocarbonyldiimidazole.

Compounds of formula (XIX) can be prepared by reaction between a compound of formula (IV) and a compound of formula (XI) in which Z represents a group CHO.

The following Examples illustrate the invention.

Temperatures are in "C. 'Dried' refers to drying using magnesium sulphate unless otherwise stated. Thin layer chromatography (t.l.c.) was carried out on silica plates. FCC - Flash Column Chromatography was carried out on silica (Merck (RTM) 9385).

The following abbreviations are used: EA-ethyl acetate; ER-diethyl ether; PE-petroleum ether; ME -methanol; MC-methylene chloride; T-toluene; ET-ethanol; A-0.88 ammonia solution; H-hexane; DMF-dimethylformamide; THF-tetrahydrofuran; 9-BBN 9-borabicyclo [3:3:1]nonane; Pd-C Palladium on carbon;PdO-C Palladium oxide on carbon Intermediate I Methyl 2-(2-bromoethoxy)benzeneacetate A mixture of methyl 2-hydroxybenzeneacetate (50.0g), anhydrous potassium carbonate (84.09), and dibromoethane (500my) in dry ME (2t) was refluxed for lllh. The resulting mixture was evaporated and the residue was dissolved in chloroform (500ml), washed with water (2x250ml) and brine (250ml), dried (NaaSO4), and evaporated. The resulting oil (82g) was purified by FCC eluting with T to give the title compound as a yellow oil (32.59).

Analysis Found: C,48.5; H,4.8.

C,,H,,BrO, requires C,48.4; H,4.8% Intermediate 2 Methyl 2-/2-/'phenylmethyi)aminoiethoxy/benzeneacetate A mixture of Intermediate 1 (15g), benzylamine (58.7g) and sodium iodide (16.4g) in dry acetonitrile (400ml) was heated under reflux for 4h. The inorganic solid was filtered off and the filtrate evaporated. A solution of the residue in EA (200ml) was washed with water (50ml) and brine (50ml), dried and evaporated. The residue was purified by FCC, eluting with EA to give the title compound as an orange oil (13.2g).

Analysis Found: C,72.4; H,7.2; N,4.8.

CiaHaiNOa requires C,72.2; H,7.1.; N,4.7% Intermediate 3 2-(2-Bromoethoxy)benzeneacetamide A solution of 2-hydroxybenzeneacetamide (1.069), potassium carbonate (1.9g) and tris [2-(2-methoxyethoxy)ethyllamine (0.11g) in dibromoethane (50ml) was refluxed for 21h and evaporated. The resulting solid was dissolved in EA (75ml), washed with water, dried and evaporated. The residue was purified by FCC eluting with ER and then EA to give the title compound as a white solid (0.99) m.p. 84-86"C.

Intermediate 4 2-[2-[(Phenylmethyl)amino]ethoxy]benzeneacetamide A solution of Intermediate 2 (5.0g) in ME (10ml) was heated in an autoclave with liquid ammonia (15ml) at 75" for 45h. The solvent was evaporated and the residue purified by FCC eluting with EA-ME (9:1) to give the title compound as an off-white solid (2.609) m.p. 89-90".

Intermediate 4 (Alternative preparation) A solution of Intermediate 3 (52g), benzylamine (218ml) and sodium iodide (60g) in acetonitrile was refluxed for 18h, filtered and evaporated. The residue was dissolved in EA (300ml), washed with aqueous sodium carbonate (2M) and water, dried and evaporated. The resulting brown oil was purified twice by FCC eluting with ER and then EA to give the title compound as a white solid (12g) m.p. 85-87"C.

Intermediate 5 Meth y/2-[2-2-[3, 5-bis lp hen ylm eth oxylp hen y-2-h ydroxyeth yll(phen ylmeth yllamin o/ethoxy]benzenacetate A solution of 1-L3,5-bis(phenylmethoxy)phenyl]-2-bromoethanone' (1.379) in dry DMF (25ml) was added over 5 mins to a stirred solution of Intermediate 2 (1.0g) and diisopropylethylamine (0.4329) in dry DMF (25ml). The mixture was stirred at room temperature for 3.5h under nitrogen and evaporated. Sodium borohydride (0.5g) was added over l0min to a solution of the residue in absolute ET (130ml). The mixture was stirred at room temperature for 18h and concentrated in vacuo.Water (5ml) and ME (100ml) were added and the solution was evaporated.A solution of the residue in EA (50ml) was washed with water (25ml) and brine (25ml), dried and evaporated to give the title compound as a yellow oil (2.13g).

T.l.c. (EA) Rf 0.7.

S.N. Quessy and L.B. Williams AustJ.Chem. 32, 1317, (1979).

Intermediate 6 2-/2-AminoethoxyJbenzeneacetamide A solution of the Intermediate 4 (2.59) in absolute ET (25ml) was hydrogenated over 10% PdO-C until uptake had ceased. The catalyst was removed by filtration and the filtrate evaporated under reduced pressure to give a pale yellow oil which was purified by FCC eluting with dichloromethane-ET-A 100:8:1 to give the title compound as a colourless oil which crystallised on standing (1.3g) m.p. 92-94".

Intermediate 7 a-(Aminometh yll-3, & islphen ylmethoxylbenzenemethanol A mixture of 3,5-bis(phenylmethoxy)benzaldehyde (31.8g), trimethylsilylcyanide (9.929) and zinc iodine (0.49) in dry benzene (50ml) was stirred for 4h under nitrogen. The resulting solution was added to an ice-cooled solution of lithium aluminium hydride (7.69) in dry THF (500ml) and the mixture was stirred for 18h at room temperature.The reaction mixture was cooled in an ice-bath and water (7.6ml) was added dropwise followed by 2N sodium hydroxide solution (15.2ml) and water (22.8ml). The inorganic solid was filtered off and the filtrate evaporated to give a red gum which was purified by FCC eluting with EA-ME 7:1 to give the title compound as a colourless solid (21.8mg) m.p. 89-90".

Intermediate 8 2-(2-Bromoethoxy)benzeneacetonitrile A mixture of 2-hydroxybenzeneacetonitrile (1.6g) and potassium carbonate (3.3g) in dibromoethane (15.5ml) was heated at 120" for 2 days. The solvent was evaporated, EA was added to the residue, the inorganic solid was filtered off, and the filtrate was evaporated to give a brown gum.The gum was purified by FCC eluting with ER-PE (1:1) to give the title compound as an orange oil (2.29). T.l.c. (ER-PE 2:1) Rf 0.4 Intermediate 9 2-[2-[(Phenylemethoxy)amino]ethoxy]benzeneacetonitrile A mixture of Intermediate 8 (5.0g), benzylamine (11g), potassium carbonate (5.89) and sodium iodide (4.79) in acetonitrile (100ml) was heated under reflux for 3h. The inorganic solid was filtered off and the filtrate was evaporated. The residue was purified by FCC eluting with EA to give the title compound as a yellow oil (4.89). T.l.c. (EA) Rf 0.25.

Intermediate 10 2-2[2-[[2[3,5-Bis(phenylmethoxy)phenyl]-2-hydroxy]-ethyl]amino]eth oxylbenzeneacetonitrile A solution of 1-[3,5-bis(phenylmethoxy)phenyl] -2-bromoethanone (5.969), Intermediate 9 (4.00g) and diisopropylethylamine (2.61 ml) in DMF (30ml) was stirred at room temperature for 2.5h and evaporated.

The residual: gum was dissolved in ME (30ml) and treated with sodium borohydride (1.9g) for 16h at room temperature. The reaction mixture was evaporated, treated with ME (50ml), re-evaporated, and partitioned between chloroform (2x100ml) and water (100ml). The organic phase was dried and evaporated to leave a yellow gum which was purified by FCC eluting with T-ER (19:1) to give the title compound (5.60g) as a yellow gum. Tic. (T-ER 19:1) Rf 0.24.

Intermediate 11 1-Methylethyl 2-hydroxybenzeneacetate A solution of o-hydroxyphenylacetic acid (3.04g) in isopropanol (20ml) was treated with sulphuric acid (18M; 0.1 ml) at room temperature for 66h, refluxed for 3h, and evaporated. The residue was partitioned between EA (50ml) and aqueous sodium bicarbonate (1M; 2x20ml). The organic phase was dried and evaporated to leave the title compound (3.459) as a yellow oil which later solidified. T.l.c. (ER) Rf 0.52.

Intermediate 12 1-Methylethyl 2-F2-bromoethoxyJbenzeneacetate A mixture of Intermediate 11 (1.949), potassium carbonate (2.8g), dibromoethane (20ml), and isopropanol (50ml) was refluxed for 16h, filtered, and evaporated to leave a pale brown oil (3.009). T.l.c. (PE-20% ER) Rf 0.26.

Intermediate 13 (iii) 1-Methylethyl 2-[2-[(phenylmethyl)amino]ethoxy]-benzeneacetate A mixture of Intermediate 12 (809), benzylamine (300ml), potassium carbonate (74g) and sodium iodide (809) in acetonitrile (1e) was heated under reflux for 20h. The inorganic solid was filtered off and the filtrate was evaporated. The residue was purified by FCC eluting with ER to give the title compound as a pale yellow oil (709). T.l.c. (ER) Rf 0.4.

Intermediate 14 1-Meth ylethy/ 2-[2-[[2-[3,5-bis(phenylmethoxy)phenyl]-2-hydroxyethyl](phenylmethyl)amino]ethoxy] benzene-acetate A solution of 1-[3,5-bis(phenylmethoxy)phenyl]-2-bromoethanone (5.0g) in dry DMF (15ml) was added to a solution of Intermediate 13 (4.09) and diisopropylethylamine (4.5ml) in DMF (50ml), and the solution was stirred at room temperature for 3h. The solvent was evaporated and the residue was redissolved in ET (80ml) and treated with sodium borohydride (2.5g). The mixture was stirred for 2h, water (20ml) was added and the mixture stirred for a further 0.5h. The ET was evaporated, the residue was acidified with 2N hydrochloric acid and the mixture was heated on a steam bath for 20min.The solution was then neutralised with 8% sodium bicarbonate and extracted with EA (3x80ml). The combined extracts were washed with brine (50ml), dried and evaporated. The residue was purified by FCC eluting with ER-PE (1 :1) to give the title compound as a pale yellow oil (5.6g). T.l.c. (ER-PE 1:1) Rf 0.35.

Intermediate 15 2-[2-[[2-[3,5-Bis(phenylmethoxy)phenyl]-2-hydroxy-ethyl]phenylmethyl)amino] jethoxylbenzeneacetic acid A solution of Intermediate 14 (56.1g) and 2N sodium hydroxide (223ml) in ME (400ml) was heated under reflux for 16h. ME was evaporated and the aqueous phase was acidified to pH6 with glacial acetic acid (20ml) and extracted with EA (3x100ml). The combined extracts were washed with water and brine, dried and evaporated. The residue was purified by FCC eluting with EA-PE (7:3) to give the title compound as a white foam (32.89). T.l.c. (EA-PE 7:3) Rf 0.25.

Intermediate 16 2-f2-[[2- (3, 5-Dih ydroxyph en yl)-2-h ydroxyeth yl]amin o]-eth oxyib enzen eacetic acid A solution of Intermediate 15 (2.0g) in a mixture of ET (50ml) and ME (50ml) was hydrogenated over 10% Pd-C (0.29). When uptake had ceased the catalyst was filtered off and the filtrate evaporated to give the title compound as a colourless solid (0.96g) m.p. 225". T.l.c. (Dichloromethane-ET-water-acetic acid, 5:5:1:1) Rf 0.74.

Analysis Found: C,60.5; H,6.3; N,3.8.

C,8H2,NO6.H2O requires C,60.7; H,6.2; N, 3.9% Example 1 (i) 2-[2-fJ2-f3, 5-Bis(phenylmethoxy)phenyl]-2-hydroxyethyl](phenylmethyl)amino]ethoxy] benzeneacetamide A solution of Intermediate 5 (2.029) in ME (25ml) and liquid ammonia (25ml) was heated in an autoclave at 65-70 for 65h. The solvent was evaporated and the residue purified by FCC, eluting with EA-PE (3:2) to give the title compound as an off-while solid (1.239) m.p. 123-5"C.

(ii) 2-[2-[[2-(3,5-Dihydroxyphenyl)-2-hydroxyethyl]amino]ethoxy]benzeneacetamide hydrochloride.

Product from stage (i) (1.089) in absolute ET (150ml) was hydrogenated over Pd-C (350mg). The catalyst was filtered off and the filtrate evaporated. The residue was purified by FCC, eluting with T-ET-A (78:20:2 and 68:30:2). The product was treated with ethereal hydrogen chloride to give the title compound as a buff hygroscopic solid (190mg) m.p. 86-88"C (dec).

Analysis Found: C,55.2; H,6.6; N,6.5 - C,8H22N2Os.HCI 0.33 -CH3CQ2C2H50.5H2O requires C,55.1; H,6.4; N,6.65% T(D4 Methanol) 2.66-2.77 (2H,m), 2.92-3.06 (2H,m), 3.60 (2H,d), 3.77 (1H,t), 5.04 (1H,m), 5.60 (2H,t), 6.38 (2H,s), 6.44 (2H,t), 6.60-6.90 (2H,ABX).

Example 2 (i) 2-[[2-[3,5-Bis(phenylmethoxy)phenyl]-2-hydroxyethyl](phenylmethyl)amino]ethoxy] benzeneacetamide A solution of 1-[3,5-bis(phenylmethoxy)phenyl1-2-bromoethanone (7.239) in dry DMF (80ml) was added dropwise to a solution of Intermediate 4 (5.0g) and diisopropylethylamine (2.279) in dry DMF (80ml)un- der nitrogen and the mixture was stirred at room temperature for 23h. The solvent was evaporated and a solution of the residue in absolute ET (400ml) was treated with sodium borohydride (2,649) and the mixture stirred at room temperature for 18h. Water (40ml) and ME (200ml) were added and the mixture was concentrated. Water was added and the suspension extracted with EA (3x100ml).The combined extracts were washed with water (50ml), brine (50ml), dried and evaporated. The residue was crystallised from EA-PE to give the title compound as a white solid (8.379) m.p. 121-3".

(i) 2-[2-[[2-(3,5-Dihydroxyphenyl)-2-hydroxyethyl] amino]ethoxylbenzeneacetamide hemffumarate Product from stage (i) (8.13g) in absolute ET (850ml) was hydrogenated over Pd-C (2.09). The catalyst was filtered off and the filtrate evaporated. The residue (4.0g) was dissolved in absolute ET (30ml) and a solution of fumaric acid (670mg) in absolute ET (30ml) added. The precipitated solid was filtered off, crystallised from ETand recrystallised from ME/EAto give an off-white solid (2.399) m.p.- 110-115 (dec).

A portion (1g) was slurried in absolute ET, filtered off and dried in vacuo at 70" to give the title compound as an off-while solid (650mg) m.p. 212-213" (dec).

Analysis Found: C,59.1; H,5.9; N,6.6 (C,8H22N2Os)2C4H404 requires C,59.4, H,6.0-; N,6.9% Example 3 2-12- ff2-f3, 5-B is (phen ylmethoxy)phenylj-2-hydroxyethylj (phenylmethyl)aminojethoxyjbenzeneacetamide A stirred solution of Intermediate 10 (0.1g) in t-butanol (2ml) was treated with finely powdered potassium hydroxide (0.2g) and the mixture was stirred at reflux for 30 min.The mixture was diluted with saturated sodium chloride solution (15ml) and extracted with EA (3x5m1). The combined extracts were dried and evaporated under reduced pressure to give a pale yellow gum which was purified by FCC eluting with T-ET-A 79:19:2 to give a pale yellow glass which was triturated under ER to give the title compound as a white powder (20mg) m.p. 120-121". T.l.c. (T-ET-A 79:20:1) Rf 0.5.

Example 4 R(-)2-[2-[[2-(3,5-Dihydroxyphenyl)-2-hydroxyethyl]amino]-ethoxy]benzeneacetamide hemifumarate (i) R(-)&alpha;-(Bromomethyl)-3,5-bis(phenylmethoxy)benzene methanol A solution of 1-[3,5-bis(phenylmethoxy)phenyl]-2-bromo-ethanone (89) in THF (6ml) was added to freshly prepared alpine borane (from 9-BBN (4.99) and (+)-(x-pinene (7ml)) at 60" under nitrogen. The solution was stirred overnight and then kept at room temperature over the weekend. Acetaldehyde (4ml) was added and solvent evaporated. The residue was dissolved in ER (50ml) and ethanolamine (2.6ml) added. The mixture was stirred at 0" for 15 min and the solid filtered off.The filtrate was washed with brine, dried and evaporated to leave a pale yellow gum (10g). This was purified by FCC eluting with T, crystallised from ER and recrystallised from ER-H to give the title compound as colourless needles (3.49) m.p. 81".

(ii) R(-)[3,5-Bis(phenylmethoxy)phenyl]oxirane A mixture of the product from stage (i) (3.39), potassium carbonate (1.5g), ME (40ml) and water (30ml) was stirred and refluxed for lh. The ME was evaporated and the residue extracted with Er (2x40ml). The extracts were washed with brine, dried and evaporated to leave the title compound as a colourless gum (2.6g).

(iii R(-)2-[2-[[2-[3, 5-Bis R(-)2-[2-[[2-[3,5-Bis(phenylmethoxy)phenyl]-2-hydroxyethyl](phenylmethyl)amino]ethoxy] benzeneacetamide A solution of the product from stage (ii) (2.59) and Intermediate 4 (1.8g) in ME (40ml) was refluxed overnight. A further quantity of Intermediate 4 (0.49) was added and the solution refluxed for 24h. The solvent was removed and the residue triturated with a mixture of ER and EA to give a white solid (1.9g).

The filtrate was evaporated and the residue purified by FCC eluting with ER to give a colourless gum which was triturated with ER to give a white solid (1.0g). The above fractions were combined with 450mg of the white solid prepared in the same manner in a separate experiment and recrystallised from EA-ER to give colourless crystals (3.09) m.p. 94-95".

(iv) R(-)2-[2-ll2-63,5-DihydroxyphenylJ-2-hydroxyethyly amino]ethoxyjbenzeneacetamide hemifumarate A suspension of the product from stage (iii) (2.9g) in ET (70ml) was hydrogenated over 10% Pd-C (0.3g) for 16h. Catalyst and solvent were removed to give the free base of the title compound as a white solid (1.6g). The free base was dissolved in hot ET (20ml) and treated with a solution of fumaric acid (270mg) in hot ET (10ml). An oil separated out on cooling and the mixture was evaporated to dryness to leave a white glass. This was dissolved in ME (15ml) and the solution seeded to give the title compound as colourless microcrystals (1.3g) m.p. 199-200".

Analysis. Found C,59.3; H,6.0; N,6.8 [CiaHaaNaOaJaC4H4O4 requires C,59.4; H,6.0; N;6.9% Example 5 S(+)2-[2-[2-[[2-(3,5-Dihydroxyphenyl)-2-hydroxyethyl]amino]-ethoxy]benzeneacetamide (i) S(+)(Bromomethy/)-3,5-bislohenyImethoxy) benzenemethanol A solution of 1-[3,5-bis(phenylmethoxy)phenyl]-2-bromo-ethanone (209) in dry tetrahydrofuran (15ml) was added to freshly prepared alpine-borane [from 9-BBN (12.259) and (-)-a-pinene (17.5m1)J and heated at 65" for 5h under nitrogen. The mixture was stirred at 60" overnight under nitrogen and the solution was cooled in an ice-bath. Acetaldehyde (lOml) was added and the solution was stirred at 20" for 0.5h and evaporated in vacuo.The residue was dissolved in ER (125ml) and ethanolamine (6.5ml) added. The mixture was stirred at 0" for 0.25h and the resulting solid was removed by filtration. The filtrate was washed with brine (lOOml), dried and evaporated to leave a pale yellow semi-solid. Purification by FCC eluting with T and recrystallization twice from Es gave the title compound as white fluffy crystals (1.779) m.p. 78-80".

(ii) S(+)J3, 5-Bis(pheny/methoxy)phen y/Joxfrane A mixture of the product from stage (i) (1.77g), potassium carbonate (805mg) in ME (21ml) and water (16ml) was heated under reflux with stirring for 1h. The mixture was allowed to cool and the solvent evaporated. The residue was extracted with ER (3x25ml). The combined extracts were dried and evaporated to leave the title compound as a clear oil (1.39g).

Analysis Found: C,79.56; H,6.26 CaaHaaOa requires C,79.49; H,6.06% (iii) S(+)2-[2-[[2-[3,5-Bis(phenylmethoxy)phenyl]-2-hydroxy- ethyl7(phenylmethylVamino]ethoxylYbenzeneacetamide A mixture of the product from stage (ii) (1.32g) and Intermediate 4 (1.16g) in ME (30ml) was heated under reflux for 24h under nitrogen. The solution was concentrated in vacuo and the residue purified by FCC eluting with ER to give the title compound as a white crystalline solid (1.2g) m.p. 96-96.5".

(iv) S(+)2-[2-[[2-(3,5-Dihydroxyphenyl)-2-hydroxy-ethyl]amino]ethoxy]benzeneacetamide A solution of the product from stage (iii) (1.2g) in ethanol (50ml) was hydrogenated over 10% Pd-C catalyst (120mg) until hydrogen uptake ceased (139ml). The catalyst was removed by filtration through hyflo and the filtrate evaporated in vacuo to leave a pale yellow oil, which was triturated under ER (20ml) to give the title compound as a white crystalline solid (580mg) m.p. 154-5".

Analysis Found C,61.84; H,6.33; N,7.88 C,8H22N205.0.2EtOH requires C,62.16; H, 6.53; N,7.88% Example 6 2-[2-[[2-(3,5-Dihydroxyphenyl)-2-hydroxyethyl]amino]-ethoxy]benzeneacetamide A suspension of 2-[2-[[2-[3,5-bis(phenylmethoxy)phenylj-2-hydroxyethylj(phenylmethyl)aminojethoxy]- benzeneacetamide (18.29) in ET (150ml) was- hydrogenated over 10% Pd-C (1.8g). When hydrogen uptake had ceased the mixture was diluted with ME to redissolve the precipitated product and the resulting mixture was filtered. A colourless solid crystallised from the filtrate on standing.The solid was filtered off and dried to give the title compound as a crystalline solid (4.29) m.p. 106-7 , Analysis Found C,61.5; H,7.3; N,7.0 C,,H,,N,O,.C,,,OH requires C,61.2; H,7.2; N,7.1% Example 7 2-[2-[[2-[3, 5-Bis(phen ylmethoxy)ph en y11-2-h ydroxyethyl] amino' ethoxy]benzeneacetamide A solution of Intermediate 3 (2.58g) in dry DMF (10ml) was added during 10 min to a stirred solution of Intermediate 7 (5.249) and N,N-diisopropylethylamine (3.889) in dry DMF (40ml) at 90" under nitrogen.

Stirring was maintained for 1h, after which the solution was evaporated onto sand and purified by FCC eluting with MC-ET-A (150:8:1) to give the title compound as a white solid (3.37g) m.p. 105.5-107".

Analysis Found: C,71.7; H,6.3; N,5.1 Ca7Ha4NaOa.O.3HaO requires C.72.2; H,6.6; N,5.3% Example 8 2-[2-[[2-[3,5-Bis(phenylmethoxy)phenyl]-2-hydroxyethyl] aminojethoxyjhenzeneacetamide A solution of Intermediate 6 (0.95g) in ET (ism) was added slowly to a solution of 3,5 [bis(phenylmethoxy)J -a-oxo-benzeneacetaldehyde (1.7g) in ET (15ml) and the mixture heated at reflux for 2h. To the cooled solution sodium borohydride (0.37) was added and the mixture stirred for 18h. ME (25ml) was added and the solution warmed to 40"C for 10 min.The solvent was evaporated and the residue purified by short path chromatography on silica gel (Merck 7747) eluting with MC-ET-A (200:8:1) to give the title compound (10mg) which-was identical to the product of Example 7.

Example 9 (i) 2-[2-[[2-[3,5-Bis(phenylmethoxy)phenyl]-2-hydroxyethyl](phenylmethyl)amino]ethoxy]-N-ethyl-benze- neacetamide Pivaloyl chloride (0,579) was added to a solution of Intermediate 15 and triethylamine (4.269) in dry THF (50ml) and stirred under nitrogen at 0 . After 5 min, ethylamine hydrochloride (0.66g) was added, the reaction flask was sealed and the solution stirred at room temperature for 16h. The solution was evaporated and then partitioned between water (80ml) and EA (3x80ml). The organic portions were combined, dried and evaporated to give an orange oil.Purification by FCC eluting with ER gave the title compound as a colourless gum (0.589) T.l.c. (EA) Rf 0.53 (ii) 2-[2-[[2-(3,5-Dihydrnxypheny)-2-hydroxyeth 2-[2-[[2-(3,5-Dih ydroxyphen yu amino]ethoxy]-N-ethylbenzeneacetamide hemifumar- ate A solution of the product from stage (i) (0.56g) in ET (40ml) was hydrogenated over dry 10% Pd-C catalyst (0.10g) until hydrogen uptake had ceased (63.0ml). The catalyst was removed by filtration through hyflo (RTM) and was washed with warm ME (50ml). The filtrate was treated with a solution of fumaric acid (0.05g) in ME (5ml) and evaporated to give a colourless gum.This residue was triturated under ER (20ml) for 4h and filtered off to give the title compound as a cream solid (0.309). T.l.c. (MC-ET A 25:8:1) Rf= 0.31 Analysis Found C,59.4; H,6.9; N,5.5 (CaaHaaNaOa)aC4H4O4.0.8Ha O+1.8C2H5OH requires C,59.4; H,7.2; N,5.8% Example 10 2-[2-[[2-(3,5-Dihydroxyphenyl)-2-hydroxyethyl]amino]-ethoxy]benzeneacetamide, phosphate, hemihydrate 2-[2-[[2-(3,5-Dihydroxyphenyl)-2-hydroxyethyl]am ino]-ethoxy]benzeneacetam ide hemifa marate (16.19) was suspended in water (40ml), treated with 85% phosphoric acid (2.64ml) and warmed to 60" to give a solution.The solution was stirred and cooled to 0" for 1 h. Fumaric acid was filtered off and the filtrate was evaporated in vacuo to a total volume of 30ml. After warming to dissolve the solid, ET (80ml) was added and the solution was stirred and cooled to 0". The crystalline solid was filtered off, washed with ET (20ml) and dried at 50" in vacuo to give the title compound (16.8g) m.p. 138-40".

Analysis Found C,47.8; H,6.15; N,5.85; P,6.4 C18H22N2O5.H3PO4.0.5H2O+0.4C2H5OH requires C,48.1; H,6.1; N,5.9; P,6.5% Example ii (i) 2-[2-[5-[3,5-Bis(phenylmethoxy)phenyl]-2-oxo-3-oxazolidinyl]ethoxy]benzeneacetamide A solution of 1,1'-carbonyldiimidazole (0.68g) in dry THF (5ml) was added to a stirred solution of 2-[2 [[2-[3,5-bis(phenylmethoxy)phenyl]-2-hydrnxyethyl] amino]ethoxy]benzeneacetamide (1.0g) in dry THF (7ml) at 50 under nitrogen. Stirring was maintained for 18h, then the solution was evaporated. The resi due was dissolved in EA (50ml), washed with water (2x25ml), brine (25ml), dried and evaporated to give a white solid.Purification by FCC eluting with MC-ET-A initially (150:8:1) then (100:8:1) gave the title compound as a white solid (0.309) m.p. 145-146 .

(ii) 2-[2-[[2-[3,5-Bis(phenylmethoxy)phenyl]-2-hydroxyethyl]amino]ethoxyl]benzeneacetamide A suspension of the product of stage (i) (40mg) in 2N sodium hydroxide solution (0.8ml) and ET (1.6ml) was stirred at 60"C for 8h. The ET was evaporated off and the remaining solution extracted with EA (3x5ml). The organic portions were combined, dried and evaporated to give a white solid. Purification by FCC eluting with MC-ET-A (100:8:1) gave the title compound as a white solid (5mg) which was identical to the product of Example 7.

Example 12 2-[2-[[2-(3,5-Dihydroxyphenyl)-2-hydroxyethyl]amino]-ethoxy]-N-propylbenzeneacetamide (i) 2-[2-ff2-f3, 5-Bis(phen y/methoxy)phen ylJ-2-h ydroxy-eth ylllphenylmethyllamino]ethoxy]-N-prop y/ben- zene-acetamide A solution of Intermediate 15 (3.0g) in DMF (40ml) and 1,1-carbonyldiimidazole (0.87g) was stirred under nitrogen at room temperature for 2.5h. n-Propylamine (0.316g) was added and the reaction mixture was stirred at room temperature for 21h. The solution was evaporated and the residue dissolved in EA.

The solution was washed with 8% sodium bicarbonate, water and brine, dried and evaporated. The residue was purified by FCC eluting with EA-PE 1:1 to give the title compound as a colourless oil (1.3g). T.l.c.

(EA-PE) 1:1 Rf 0.25.

(i ) 2-f2-[[2-(3,5-Dih ydroxyphen yl)-2-hydroxyeth y/]-aminojethoxy]-N-prop ylbenzeneacetamide A solution of the product from stage (i) (1.24g) in absolute ET (50ml) was hydrogenated over 10% Pd-C (400mg). The catalyst was filtered off through hyflo and the ethanolic filtrates evaporated.The residue was purified by short path column chromatography on silica (Merck 7747) eluting with EA-isopropanol 7:3 to give the title compound as a white foam (187mg). T.l.c. (EA-isopropanol 7:3) Rf= 0.35. b(D4 Methanol) 0.88 (3H, t, CH2CH2CH3), 1.51 (2H, m, CH2CH2CH3), 2.75-2.90 (2H, AB part ABX, CH(OH)CH2N), 3.13 (2H, t, CH2CH2CH3), 3.22 (2H, m, NHCH2 CH7), 3.48 (2H, s, ArCH2CO), 4.11 (2H, t, NHCH7CH7O), 4.67 (2H, dd, NHCH2CHOH), 6.1-7.3 (7H, m, aromatics).

Example 13 2-[2-[[2-[3,5-(Dihydroxy)phenyl]-2-hydroxyethyl]amino]-ethoxy]benzenepropanamide (i) Methyl 2-hydroxybenzenepropenoate A solution of 2-hydroxybenzenepropenoic acid (16.429) and sulphuric acid (18M; 0.1 ml) in ME (100ml) was refluxed for 70h, cooled and filtered to give a pale brown solid (10.9g). The filtrate was evaporated, the residue partitioned between dichloromethane (2x50ml) and aqueous sodium bicarbonate (1M;50ml) and the insoluble material (4.7g) was collected. The organic phase was dried and evaporated to leave a light brown solid (2.909). The three batches of product were combined to give the title compound in a total yield of 18.59. m.p. 133-137".

(ii) Methyl 2-(2-bromoethoxy)benzenepropenoate A mixture of the product from stage (i) (10.69g), potassium carbonate (9.66g) and tris[2-(2-methoxyethoxy) ethyl]amine (1g) in dibromoethane (100ml) was refluxed for 72h, filtered, evaporated, dissolved in T, filtered through silica (Merck 9385) and evaporated to leave the title compound as a white solid (13.229) m.p. 57-59".

(iii) Methyl 2-[2-[[2-(3,5-dihydroxyphenyl)-2-hydroxy-ethyl]amino]ethoxy]benzenepropenoate A solution of &alpha;-(aminomethyl)-3,5-dihydroxybenzenemethano (3.5g), sodium iodide (3.0g) and diisopropylethylamine (3.5ml) in DMF (80ml) at 80 was treated with a solution of the product from stage (ii) (5.79) in DMF (20ml) for 1 h, and evaporated. The resulting gum was adsorbed on sand and purified twice by chromatography on silica (Merck 9385) to give the title compound as a friable off-white solid (1.459).

Tic. (T-ET-A 79:20:1) Rf 0.13.

(iv) Methyl-2[2-[[2[3,5-(dihydroxy)phenyl]-2-hydroxy-ethyl]amino]benzen epropan oa te A mixture of the product from stage (iii) (2.29) and 10% PdO-C (0.5g) in absolute ET (50ml) was hydrogenated until uptake had ceased. The catalyst was removed by filtration and the filtration evaporated under reduced pressure. The residue was purified by FCC eluting with dichloromethane- ET-A (100:8:1) to give the title compound as a pale brown oil (1.6g). T.l.c. Dichloromethane-ET-A (100:8:1) Rf 0.35.

(v) 2-f2-ff2-f3, 5-(dih ydroxy)phen ylj-2-hydroxyeth yq amino]ethoxyjbenzenepropanamide A mixture of the product from stage (iv) (1.5g), ME (30ml) and liquid ammonia (20ml) was heated at 80" in an autoclave (50ml) for 16h. The solution was evaporated under reduced pressure and the residue purified by FCC eluting with dichloromethane-ET-A (50:8:1) to give the title compound as a fawn foam (0.49). T.l.c. Dichloromethane-ET-A (50:8:1) Rf 0.15.

Assay Found: C,60.1; H,6.9; N,7.2.

C1gH24N205.0.75H20.0.5EtOH requires C,60.5; H,7.2; N,7.1% Example 14 2-[2-[[3,5-(Dihydroxyphenyl)-2-hydroxyethyl]amino]-ethoxy]-N-metbylbenzeneacetamide (i) 2-[2-[[2-[3,5-Bis(phenylmethoxy)phenyl]-2-hydroxy-ethyl](phenylmethyl)amino]ethoxy]-N-methylbenzene- acetamide A mixture of Intermediate 5 (1.5g), ET (20ml) and 33% ethanolic methylamine (20ml) was heated at 95" in an autoclave for 16h. Solvent was evaporated to leave a gum (1.5g) which was purified by FCC eluting with ER to give the title compound as a colourless gum (1.1g).

(ii) 2-[2-[[3,5-(Dihydroxyphenyl)-2-hydroxyethyl]amino]-ethoxy]-N-methylbenzeneacetamide A solution of the product from stage (i) (1.0g) in absolute ET (70ml) was hydrogenated over 10% Pd-C (300mg). The catalyst was filtered off and the filtrate evaporated. The residue was purified by FCC eluting with EA-ME (:2) to give the title compound as an off-white solid (387mg) m.p. 82-85".

Analysis Found: C,61.9; H,6.2; N,7.7 CiaHaaNaOa.O.5HaO requires C,61.8, H,6.8; N,7.6% The following are examples of suitable formulations of compounds of the invention. The term "active ingredient" is used herein to represent a compound of the invention and may be, for example, the compound 2-[2-[[2-(3,5-dihydroxyphenyl)-2-hydroxyethyl]amino]ethoxy] benzeneacetamide Example A - Tablets - Direct Compression mg/tablet Active ingredient 50.0 Microcrystalline Cellulose B.P.C. 149.0 Magnesium Stearate 1.0 200.0 The active ingredient is sieved through a 250pm sieve, blended with the excipients and compressed using 8.5mm punches. Tablets of other strengths may be prepared by altering the compression weight and using punches to suit.

Example B - Tablets - Wet Granulation mg/tablet Active Ingredient 50.0 Lactose B.P. 119.0 Starch B.P. 20.0 Pregelatinised Maize Starch B.P. 10.0 Magnesium Stearate B.P.

Compression weight 200.0 The active ingredient is sieved through a 250pm sieve and blended with the lactose, starch and pregelatinised starch. The mixed powders are moistened with purified water, granules are made, dried, screened and blended with the Magnesium Stearate. The lubricated granules are compressed into tablets as described in Example A.

The tablets m-ay be film coated with suitable film forming materials , e.g. methyl cellulose or hydroxypropylmethyl- cellulose using standard techniques. Alternatively the tablets may be sugar or enteric coated.

Example C- Capsules mg/capsule Active ingredient 50.0 *Starch 1500 149.0 Magnesium Stearate B.P. 1.0 Fill weight 200.0 *A form of directly compressible starch supplied by Colorcon Ltd. Orpington, Kent, UK.

The active ingredient is sieved through a 250m sieve and blended with the other materials. The mix is filled into No 1 hard gelatin capsules using a suitable filling machine. Other doses may be prepared by altering the fill weight and if necessary changing the capsule size to suit.

Example D - Sucrose Syrup mg/5ml dose Active ingredient 50.0 Sucrose B.P. 2750.0 Glycerine B.P. 500.0 Buffer) Flavour) as required Colour) Preservative) Purified water BP to 5.0ml The active ingredient, buffer, flavour, colour and preservative are dissolved in some of the water, and the glycerine is added. The remainder of the water is heated to dissolved the sucrose and is then cooled.

The two solutions are combined, adjusted to volume and mixed. The syrup produced is clarified by filtration.

Example E - Sucrose-Free Syrup mg/5ml dose Active ingredient 50.0 Hydroxypropyl methylcellulose USP (viscosity type 4000) 22.5mug 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 solution is adjusted to volume and mixed. The syrup produced is clarified by filtration.

Example F - Suppositories Active ingredient 50.0mg *Witepsol(RTM)H15 to 1.0g *A proprietary grade of Adeps Solidus Ph. Eur.

A suspension of the active ingredient in the matter Witepsol H15 is prepared and filled using a suitable machine into 1g size suppository moulds.

Example G - Injection for lntravenous Administration %w/v Active ingredient 1.00 Water for injections B.P. to 100.00 Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to that of maximum stability andlor to facilitate solution of the active ingredient using dilute acid or alkali or by the addition of suitable buffer salts. Antioxidants and metal chelating salting may also be included.

The solution is prepared, clarified and filled into appropriate sized ampoules sealed by fusion of the glass. The injection is sterilised by heating in an autoclave using one of the acceptable cycles. Alternatively the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions.

The solution may be packed under an inert atmosphere of nitrogen.

Example 15 2-f2-ff2-(3, 5-Dihydroxyphenyl)-2-hydroxyethyljamino]-ethoxy]benzeneacetamide A solution of 2-[2-[[2-[3,5-bis(phenyl methoxy)-phenyl]-2-hydroxyethyl]amino]ethoxy]benzeneacetamide (0.6g) in ET (20ml) was hydrogenated over 10% Pd-C (0.06g) until hydrogen uptake had ceased (58ml).

The catalyst was filtered off through hyflo and washed with ET (20my). The volume of ET was reduced to 10ml under reduced pressure and the title compound crystallised as a white solid (0.239). m.p. 105-1079.

The product was identical to the sample prepared in Example 6.

Claims (10)

1. Compounds of the general formula (I)

wherein R represents a hydrogen atom or a straight chain Cia alkyl group and n is lor 2, and physiologically acceptable acid addition salts, solvates and metabolically labile esters thereof.

2. Compounds as claimed in claim 1 in which n is 1.

3. Compounds as claimed in claim 1 or 2 in which R represents a hydrogen atom.

4. 2-[2-[[2-3,5-Dihydroxyphenyl )-2-hydroxyethyllamino]- ethoxy]benzene-acetamide and physiologically acceptable acid addition salts thereof.

5. Compounds as claimed in claim in which R represents a hydrogen atom, a methyl group or an ethyl group and n is 1 or 2.

6. A process for the preparation of compounds as claimed in any of claims 1 to 5 which comprises: (1) an alkylation reaction between a component of formula II

wherein -NA represents a group

R2, Ra, R4 and R5 each represent a hydrogen atom or a protecting group and X is a readily displaceable atom or group, and a compound of formula (III)

wherein R and n are as defined in formula (I), Ra is a hydrogen atom or a protecting group, and Y represents hydrogen when -NA represents -NRSCH,CH,X,

or Y represents the group CH2CH2X where X is a readily displaceable atom or group when -NA represents -NHRS, followed, if necessary, by removal of any protecting groups which are present: or (2) reacting a compound of formula (VIII)

wherein R2 and R3 are as defined above in process (1) and R6 represents a group

where R4 and X are as defined in process (1) with an amine of formula (IX)

where R and n are as defined in formula (I) and Ri and R5 are as defined above in process (1), followed, if necessary, by removal of any protecting groups which are present; or (3) reacting a compound of formula (X)

wherein R7 represents the group -COCHO or

-and R2, R3, R4 and Ra are as defined above in process (1) with a compound of formula (XI)

wherein Z represents the group CHO when R7 is -CHCH2NHR 5 or Z represents the group CH2NHR6 when R7 is -COCHO, R and n are as defined in formula (I) and R1 and R5 are as defined above in process (1), in the presence of a reducing agent, followed, if necessary, by removal of any protecting groups which are present; or (4) reduction of a compound of formula (XIV)

where R and n are as defined in formula (I) and Rr, R2, R3 and RS are as defined above in process (1), followed, if necessary, by removal of any protecting groups which are present; or (5) amination of a compound of formula (XV)

where n is as defined in formula (I), Ra, R3, R4 and R5 are as defined above in process (1) and Rs represents a carboxylic acid group or a salt or a reactive derivative thereof, with an amine RNH2 where R is as defined in formula (I), followed, if necessary, by removal of any protecting groups which are present; or (6) for the production of compounds for formula (I) in which R is hydrogen, hydrolysis of a compound of formula (XVI)

where n is as defined in formula (I) and Rt, R3, R4 and Rs are as defined above in process (1), followed, if necessary, by removal of any protecting groups which are present; or (7) deprotection of a compound of formula (XVII)

where R and n are as defined in formula (I) and R', R2, R3, R4 and R5 are as defined above in process (1), provided that at least one of Ri, R2, R3, R4 and R5 represents a protecting group; and optionally converting the compound of formula (I) or a salt thereof into a physiologically acceptable acid addition salt, solvate or metabolically labile ester.

7. A pharmaceutical composition comprising a compound of formula (I) or a physiologically acceptable acid addition salt, solvate or metabolically labile ester thereof, together with at least one physiologically acceptable carrier or excipient.

8. Compounds of the general formula (XV)

where n is 1 or 2, R2, R3, R4 and R5 each represent a hydrogen atom or a protecting group and Ra represents a carboxyl group, or a salt or C,5 alkyl ester thereof.

9. Compounds as claimed in claim 8 in which n is 1 or 2, R2, R3, R4 and R5 each represent a hydrogen atom and Ra represents a carboxyl group or a C1-3 alkyl ester thereof.

10. 2-[2-[[2-(3,5-Dihydroxyphenyl)-2-hydroxyethyl]amino]-ethox]benzeneacetic acid.