It has now surprisingly been discovered that a particular series of novel aryloxy and arylthio propanolamine derivatives have good b3-adrenoreceptor agonist activity and in particular show good selectivity for b3-adrenoreceptors over the bl- or b2-adrenoreceptors, to the extent that these compounds are antagonists of the b1- and b2-adrenoreceptors. These compounds are indicated to have good anti-hyperglycaemic and/or anti-obesity activity coupled with especially good selectivity from cardiac and tremorigenic side effects.

These compounds are also indicated to have potential in the treatment of gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis and duodenitis, intestinal ulcerations, including inflammatory bowel disease, and irritable bowel syndrome and also for the treatment of gastrointestinal ulcerations, especially when induced by non-steroidal anti-inflammatory drugs or corticosteroids.

These compounds may also be of use in increasing the high-density- lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in human blood serum and are therefore of potential use in the treatment and/or prophylaxis of atherosclerosis. They are also indicated to be useful for the treatment of hyperinsulinaemia. They are also indicated to be useful for the treatment of depression.

These compounds also have potential as growth promoters for livestock and for decreasing birth mortality rate and increasing the post-natal survival rate in livestock.

Accordingly the present invention provides a compound of formula (I): or a salt thereof, or a solvate thereof, wherein, RO represents an aryl group optionally substituted with one, two or three substitutents selected from the list consisting of: hydroxy, hydroxymethyl, nitro, amino, alkylamino, dialkylamino, alkylsuiphonamido, arylsulphonamido, formamido, halogen, alkoxy and allyl; X represents 0 or S; R1 and R1a each independently represent hydrogen or an alkyl group or R1 together with Rla and the carbon atom to which they are attached represent a cycloalkyl group; R2 represents a moiety of formula (a): wherein R4 represent hydrogen, alkyl, hydroxyalkyl, arylalkyl, aryloxyalkyl, aralkyloxyalkyl or cycloalkyl and R5 represent hydroxy, alkoxy, arylalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, aryloxyalkyloxy, arylalkoxyalkyloxy or cycloalkyloxy or R5 represents hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl or R5 together with OR4 represents O(CH2)nO wherein n is 2, 3 or 4; and R3 and R3a each independently represent hydrogen, halogen, alkyl or alkoxy.

In one aspect, especially when R1 and R1 a each independently represent hydrogen or alkyl, the compounds of formula (I) comprise a moiety of formula (b) wherein R2 is as defined in relation to formula (I) and R3 and R3a independently represent halogen, alkyl or alkoxy.

Favourably, in moiety (b), R3 represents alkyl, for example methyl.

Favourably, in moiety (b), R3a represents alkyl, for example methyl.

In a further aspect, when R1 together with Rla and the carbon atom to which they are attached represent a cycloalkyl group, the compounds of formula (I) comprise a moiety of formula (c): wherein R2 is as defined in relation to formula (I) and R3a represents hydrogen halogen, alkyl or alkoxy.

Favourably, in moiety (c), R3a represents hydrogen or halogen.

Examples of R3 in moiety (c), include hydrogen and bromine.

Suitable aryl groups include phenyl or naphthyl groups, especially phenyl groups.

Suitable optional substitutents for RO include one, two or three substitutents selected from the list consisting of: hydroxy, hydroxymethyl, alkylsulphonamido and halogen.

Suitably, RO represents a phenyl group optionally substituted with hydroxy and/or hydroxymethyl and/or halogen, especially fluoro and/or alkylsulphonamido.

An example of RO is 4-hydroxyphenyl.

Suitably, R1 represents C16 alkyl, especially when the compounds of formula (I) represent a moety of formula (b).

Suitably, Kia represents C16 alkyl, especially when the compounds of formula (I) represent a moety of formula (b).

When R1 together with R1a and the carbon atom to which they are attached, represent a cycloalkyl group, a suitable cycloalkyl group is a C5 or C6 cycloalkyl group.

An example of a cycloakyl group represented by CR1Rla is a cyclopentyl group.

Preferably, R2 is a moiety of formula (a).

When R4 represents alkyl, it is suitably C1 -6 alkyl.

Favourably, R4 represent hydrogen or alkyl, especially hydrogen.

When R5 represents cycloalkyl an example is cyclohexyl.

Favourably, R5 represents cycloalkyl or aryl.

Preferably, X represents 0.

The compounds of formula (I) have one or two asymmetric carbon atoms, marked with an asterisk (*) or a double asterisk (**) in the formula. These compounds may therefore exist in up to four stereoisomeric forms. The present invention encompasses all stereo isomers of the compounds of the general formula (I) whether free from other isomers, or admixed with other isomers in any proportion, such as mixtures of diastereoisomers and racemic mixtures of enantiomers.

In addition when the substituents on the phosphorous atom of moiety (a) are different and other than OH the phosphorous atom is chiral: The invention extends to mixed and separated isomers of such compounds in an analogous fashion to that discussed for chiral carbon atoms.

Preferably, the asymmetric carbon atom indicated by a single asterisk (*) is in the S-configuration.

The term 'alkyl' when used alone or when forming part of other groups (such as the 'alkoxy' group) includes straight- or branched-chain alkyl groups containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group.

The term 'cycloalkyl' includes C38 cycloalkyl groups, especially C5 or C6 cycloalkyl groups.

When used herein the term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine.

When used herein the term "sulphonamido" refers to the moiety '-SO2NH-', for example methylsulphonamido refers to the moiety 'CH3-SO2-NH-'.

Suitable salts are pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts include acid addition salts and salts of phosphonic acid groups. Salts of phosphinic acids are also suitable pharmaceutically acceptable salts of the invention.

Suitable pharmaceutically acceptable acid addition salts include salts with inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid, or with organic acids such, for example as methanesulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid or acetylsalicylic acid.

Suitable pharmaceutically acceptable salts of phosphonic acid or phosphinic acid groups include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium and lithium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with C1 -6 alkylamines such as triethylamine, hydroxy-C 1-6 alkylamines such as 2-hydroxyethylamine, bis-(2- hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, 1 ,4-dibeiizylpiperidine, N-benzyl-b-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline.

Suitable solvates are pharmaceutically acceptable solvates.

Suitable pharmaceutically acceptable solvates are conventional solvates, preferably hydrates.

In a further aspect the invention also provides a process for the preparation of a compound of formula (I) or a salt thereof, or a solvate thereof, which process comprises reacting a compound of formula (II): wherein X is as defined in relation to formula (I) and R01 represents RO as defined in relation to formula (I) or a protected form thereof, with a compound of formula (III): wherein R1, R1af R2, R3 and R3a are as defined in relation to formula (I) and To represents hydrogen or a protecting group; and thereafter, if required, carrying out one or more of the following optional steps: (i) converting a compound of formula (I) to a further compound of formula (I); (ii) removing any protecting group; (iii) preparing a salt of the compound of formula (I) and/or a solvate thereof.

The reaction between compounds of formulae (II) and (III) may be carried out in any suitable solvent, such as methanol, at any temperature providing a suitable rate of formation of the required product, generally at an elevated temperature such as the reflux temperature of the solvent; preferably under an inert atmosphere such as nitrogen or argon, alternatively the reaction between compounds of formulae (II) and (III) may be carried out in a chlorinated solvent such as dichloromethane or in an aprotic solvent such as acetonitrile; suitably the reaction is carried out in the presence of a catalyst such as ytterbium triflate as described in Tetrahedron Letters, 1994, 35(3), 433 or a perchlorate such as lithium perchlorate.

Suitably K0 represents a protected form of RO, suitable protected forms being defined herein.

Suitable protecting groups represented by TO are benzyl or p- methoxybenzyl and preferably, tert-butoxycarbonyl groups.

Suitably TO is hydrogen.

A compound of formula (II) may be prepared by reacting an activated form of a compound of formula (IV): RO)-XH (IV) wherein K0, and X are as defined in relation to formula (II), with a compound of formula (V): wherein LO represents hydroxy or a leaving group.

A suitable activated form of a compound of formula (IV) is an ionic form, such as an alkali metal salted form, for example an alkali metal salted form, such as a sodium salted form.

An activated form of a compound of formula (IV) may be prepared by use of the appropriate conventional procedure, for example a salted form may be prepared by treating the compound of formula (IV) with a base such as an alkali metal hydride or carbonate, for example sodium hydride.

Suitably, LO represents leaving group such as a tosylate or, preferably a 3- nitrobenzenesulphonyloxy group.

The reaction between the compounds of formulae (IV) and (V) may be carried out in an aprotic solvent such as acetone or dimethylformamide at any temperature providing a suitable rate of formation of the required product, generally at an ambient to elevated temperature, suitably an elevated temperature, such as the reflux temperature of the solvent.

LO may also represent OH.

When LO represents OH, the compound of formula (V) is oxiranyl- methanol and the reaction between it and the compound of formula (IV) is conveniently effected using a Mitsunobu reaction, according to methods disclosed in Tetrahedron Letters., 1994, 35, 5997-6000 and Organic Reactions 1992, 42, 335-656.

A compound of formula (III) is prepared from an activated form of a compound of formula (VI): wherein R1, K1 a, R3, R3a and TO are as defined in relation to formula (III) with a compound of formula (VII): wherein R4 and R5 are as defined in relation to formula (I) and L1 is a leaving group; and thereafter, as required, removing any protecting group.

A suitable activated form of a compound of formula (VI) is an ionic form, such as a salted form, for example an alkali metal salted form.

An activated form of a compound of formula (VI) may be prepared by use of the appropriate conventional procedure, for example a salted form may be prepared by treating the compound of formula (VI) with a base such as an alkali metal hydride, for example sodium hydride.

The reaction between the compounds of formulae (VI) and (VII) may be carried out in any suitable solvent, generally an aprotic solvent such as dimethylformamide, methylpyrrolidinone or tetahydrofuran or mixtures of such solvents, at any temperature which provides a suitable rate of formation of the required product, for example at ambient temperature.

A suitable leaving groups L1 is a chlorobenzenesulphonyl group.

Protecting groups may be removed using any conventional method, for example, when TO is a tert-butoxycarbonyl group, it is conveniently removed using trifluoroacetic acid, usually at room temperature.

The compounds of formula (VII) are known compounds or they are prepared according to methods disclosed for preparing known compounds, for example those disclosed in International Patent Application, publication number W096/04233.

A compound of formula (VI) is prepared by reducing a compound of formula (VIII): wherein R1, R1a R3 and R3a are as defined in relation to formula (I); and thereafter, as required, protecting the amino group so formed.

The reduction of the compound of formula (VIII) is carried out under any suitable reducing conditions, for example by using H2 /Raney nickel in methanol, conveniently at atmospheric pressure and at ambient temperature.

Suitable amino protecting groups are conventional groups such as the tert butoxycarbonyl groups, which is formed by reaction of the appropriate amino group with di-tertbutyl dicarbonate, usually in dimethylformamide in the presence of triethylamine.

A compound of formula (VIII) is prepared from a compound of formula (IX): wherein R1 and R1a are as defined in relation to formula (I), by reaction with a compound of formula (X): wherein R3 and R3a are as defined in relation to formula (I).

The reaction between the compounds of formulae (IX) and (X) is suitably carried out in tetrabutyl ammonium fluoride at an elevated temperature, for example 1300C and preferably in an inert atmosphere, such as argon.

The compounds of formula (IX) are known, commercially available compounds.

The compounds of formula (X) are known compounds or they are prepared by use of analogous processes to those used to prepare known compounds, for example those methods disclosed by P. Claus et al, Monatsh.

Chem., 1972, 103 (4), 1178-93.

Suitable conversions of one compound of formula (I) into another compound of formula (I) include converting one group OR4 into another group OR4 and/or converting one group R5 into another group R5.

Suitable conversions of one group OR4 into another group OR4 include: (i) converting OR4 as hydroxy into OR4 as alkoxy; (ii) converting OR as alkoxy into OR4 as hydroxy; (iii) converting OR4 as alkoxy into OR4 as another alkoxy group.

The abovementioned conversion (i) may be carried out under conventional phosphonate alkylation methods, using for example the appropriate alcohol (R40H) in the presence of hydrogen chloride, alternatively, the appropriate alcohol may be used with benzotriazole-l -yloxy-tris- (dimethylamino)phosphonium hexafluorophosphate in dimethylformamide in the presence of diisopropylethylamine.

The abovementioned conversion (ii) may be carried out using conventional phosphonate hydrolysis methods, for example by treating the appropriate compound of formula (I) with an alkaline metal hydroxide, such as sodium hydroxide.

The abovementioned conversion (iii) may be carried out by first converting OR4 as alkoxy into OR4 as hydroxy using the conditions set out in respect of the abovementioned conversion (ii), followed by converting the hydroxy group so formed into another alkoxy group, using the conditions set out in respect of the abovementioned conversion (i).

The abovementioned conversion (iii) is of particular use for preparing compounds of formula (I) wherein OR4 represents methoxy: such compounds are generally prepared from compounds of formula (I) wherein OR4 represents an alkyloxy group other than methoxy (suitably ethoxy) by first hydrolysing the relevant OR4 group (via conversion (ii)) to prepare a compound of formula (I) wherein OR4 represents hydroxy and thereafter methylating (via conversion (i)) to provide the required compound wherein OR4 represents methoxy.

Suitable conversions of one group R5 into another group R5, when R5 represents hydroxy, alkoxy, arylalkyloxy, hydroxyalkyloxy, alkoxyalkyloxy, arylalkoxyalkyloxy or cycloalkyloxy, include analogous conversions to those mentioned above in regard to converting one group OR4 into another group OR4.

The protection of any reactive group or atom, may be carried out at any appropriate stage in the aforementioned processes. Suitable protecting groups include those used conventionally in the art for the particular group or atom being protected. Protecting groups may be prepared and removed using the appropriate conventional procedure, for example OH groups, including diols, may be protected as the silylated derivatives by treatment with an appropriate silylating agent such as di-tert-butylsilylbis(trifluoromethanesulfonate): The silyl group may then be removed using conventional procedures such as treatment with hydrogen fluoride, preferably in the form of a pyridine complex. Alternatively benzyloxy groups may be used to protect phenoxy groups, the benzyloxy group may be removed using catalytic hydrogenolysis using such catalysts as palladium (II) chloride or 10% palladium on carbon.

Amino groups may be protected using any conventional protecting group, for example tert-butyl esters of carbamic acid may be formed by treating the amino group with di-tert-butyl-dicarbonate, the amino group being regenerated by hydrolysing the ester under acidic conditions, using for example hydrogen chloride in ethyl acetate or trifluoroacetic acid in methylene dichloride. The amino group also may be protected as an aminoboronic acid, prepared from the appropriate amine and boron tribromide followed by work up with iced water.

The aminoboronic acid may be removed using catalytic hydrogenolysis, using for example a palladium on carbon catalyst. In addition, an amino group may be protected as a benzyl derivative, prepared from the appropriate amine and a benzyl halide under basic conditions, the benzyl group being removed by catalytic hydrogenolysis, using for example a palladium on carbon catalyst.

A leaving group or atom is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitabl examples of suchgroups unless otherwise specified are halogen atoms, mesyloxy groups and tosyloxy groups.

The salts and solvates of the compounds mentioned herein may be produced by methods conventional in the art: For example, acid addition salts may be prepared by treating a compound of formula (I) with the appropriate acid.

Compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof; or a pharmaceutically acceptable solvate thereof, produced by the above processes, may be recovered by conventional methods.

If required mixtures of isomers of the compounds of the invention may be separated into individual stereoisomers and diastereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.

Suitable optically active acids which maybe used as resolving agents are described in 'Topics in Stereochemistry', Vol. 6, Wiley Interscience, 1971, Allinger, N.L. and Eliel, W.L. Eds.

Alternatively, any enantiomer of a compound of the invention may be obtained by stereo specific synthesis using optically pure starting materials of known configuration.

The absolute configuration of compounds may be determined by conventional X-ray crystallographic techniques.

As previously indicated, the compounds of formula (I) have been discovered to possess valuable pharmacological properties.

The present invention accordingly provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.

In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of hyperglycaemia in human or non-human animals.

The present invention further provides a compound of formula (I), or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of obesity in human or non-human animals.

In addition the present invention provides a compound of formula (I), or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis and duodenitis, intestinal ulcerations, including inflammatory bowel disease, and irritable bowel syndrome and also for the treatment of gastrointestinal ulcerations, especially when induced by non-steroidal anti-inflammatory drugs or corticosteroids.

Finally, the present invention provides a compound of formula (I), or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in increasing the high-density-lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in human blood serum, in particular in the treatment and/or prophylaxis of atherosclerosis, and in the treatment of hyperinsulinaemia or depression.

A compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.

Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.

As used herein the term "pharmaceutically acceptable" embraces compounds, compositions and ingredients for both human and veterinary use: for example the term "pharmaceutically acceptable salt" embraces a veterinarily acceptable salt.

The composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.

Usually the pharmaceutical compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection, are also envisaged.

Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as powders presented in sachets, may also be used.

In accordance with conventional pharmaceutical practice the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.

Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate.

Most suitably the composition will be formulated in unit dose form. Such unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 2-100 mg or 0.1 to 500 mg, and more especially 0.1 to 250 mg.

The present invention further provides a method for treating hyperglycaemia in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, to a hyperglycaemic human or non-human mammal in need thereof.

The present invention further provides a method for treating obesity or for the treatment and/or prophylaxis of atherosclerosis in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.

The present invention further provides a method for treating gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis and duodenitis, intestinal ulcerations, including inflammatory bowel disease, and irritable bowel syndrome and also for the treatment of gastrointestinal ulcerations, especially when induced by non-steroidal anti-inflammatory drugs or corticosteroids, in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.

In addition the present invention provides a method for treating for increasing the high-density-lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in human blood serum, in particular in the treatment and/or prophylaxis of atherosclerosis, and in the treatment of hyperinsulinaemia or depression, in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharrnaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.

The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of: hyperglycaemia, obesity, gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis and duodenitis, intestinal ulcerations, including inflammatory bowel disease, and irritable bowel syndrome and also for the treatment of gastrointestinal ulcerations, especially when induced by non-steroidal anti-inflammatory drugs or corticosteroids, for increasing the high-density- lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in human blood serum, in particular in the treatment and/or prophylaxis of atherosclerosis, and in the treatment of hyperinsulinaemia or depression.

Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.

In treating hyperglycaemic or obese humans the compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg.

The treatment regimens for treating the abovementioned gastrointestinal disorders atherosclerosis, hyperinsulinaemia and depression are generally as described for hyperglycaemia.

In treating non-human mammals, especially dogs, the active ingredient may be adminstered by mouth, usually once or twice a day and in an amount in the range of from about 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg.

In a further aspect the present invention also provides a method for increasing weight gain and/or improving the feed utilisation efficiency and/or increasing lean body mass and/or decreasing birth mortality rate and increasing post/natal survival rate; of livestock, which method comprises the administration to livestock of an effective non-toxic amount of a compound of formula (I) or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate thereof.

Whilst the compounds of formula (I) and the veterinarily acceptable salts thereof or a veterinarily acceptable solvate thereof, may be administered to any livestock in the abovementioned method, they are particularly suitable for increasing weight gain and/or feed utilisation efficiency and/or lean body mass and/or decreasing birth mortality rate and increasing post-natal survival rate; in poultry, especially turkeys and chickens, cattle, pigs and sheep.

In the preceding method the compounds of formula (I) or veterinarily acceptable salts thereof will normally be administered orally although non-oral modes of administration, for example injection or implantation, are also envisaged. Suitably the compounds are administered in the feed-stuff or drinking water provided for the livestock. Conveniently these are administered in the feed-stuff at from 10-3 ppm - 500ppm of total daily fed intake, more usually 0.01ppm to 250ppm, suitably less than 100ppm.

The particular formulations used will of course depend upon the mode of administration but will be those used conventionally in the mode of administration chosen. For administration in feed-stuff the drugs are conveniently formulated as a premix in association with a suitable carrier.

Accordingly, the present invention also provides a veterinarily acceptable premix formulation comprising a compound of formula (I), or a veterinarily acceptable salt thereof; or a veterinarily acceptable solvate thereof, in association with a veterinarily acceptable carrier therefore.

Suitable carriers are inert conventional agents such as powdered starch.

Other conventional feed-stuff premix carriers may also be employed.

No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.

The following Examples and Procedures illustrate the invention but do not limit it in any way.

Procedure 1: (S)-2-(4-Benzoyloxyphenoxymethyl)oxirane A solution of 4-hydroxyphenyl benzoate (4.28g, 20mmol) in dimethylformamide (30ml) and sodium hydride (60% dispersion in oil, 800mg, 20mmol) was stirred at room temperature for 10 minutes. (2S)-Glycidyl-3-nitrobenzenesulfonate (5.18g, 20mmol) .was added and the mixture was stirred at room temperature for 3 hours. Ethyl acetate and water were added, the organic layer was separated, washed with water and brine and dried over magnesium sulfate. Filtration followed by removal of solvent gave the crude product. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexanes gave the title compound as a colourless solid.

b(CDC13): 8.19 (2H, dd, J = 8.4, 1.3Hz), 7.47-7.67 (3H, m), 7.13 (2H, d, J = 9.1Hz), 6.97 (2H, d, J = 9.1Hz), 4.24 (1H, dd, J = 11.0, 3.0Hz), 3.97 (1H, dd, J = <BR> <BR> 11.0, 5.5Hz), 3.30-3.4;3 (1H, m), 2.92 (1H, t, J = 5.0, 4.4Hz), 2.77 (1H, dd, J = 5.0, 2.8Hz).

Procedure 2: 2,6-Dimethyl-4-(2-nitro-2,2-dimethylethyl)phenol A mixture of 2,6-dimethyl-4-(hydroxymethyl)phenol (15.2g, O.lmol), tetra-n- butyl ammonium fluoride (5.0g) in 2-nitropropane (l00ml) was heated at 1300C under argon. After 24h the reaction was cooled and diluted with dichloromethane (200ml), the resultant solution washed with water (1 00ml), dried and evaporated to yield a dark brown oil. Chromatography over silica eluting with hexane containing 25% ethyl acetate gave the title compound.

6(CDC13): 6.70 (2H, s), 4.60 (1H, br), 3.05 (2H, s), 2.20 (6H, s), 1.55 (6H, s). Procedure 3: 2,6-Dimethyl-4-(2.amino-2,2-dimethylethyl)phenol Raney nickel was carefully added to a solution 2,6-dimethyl-4-(2-nitro-2,2- dimethylethyl)phenol (15.0g, 67mmol) in methanol (150ml). The resultant mixture was hydrogenated at atmospheric pressure until the required amount of hydrogen was adsorbed. The mixture was filtered and the solid residue washed with methanol (l00ml), finally the filtrate was evaporated and triturated with ethyl acetate to yield the title compound as a white solid.

6(CDCl3 + D20): 6.78 (2H, s), 2.52 (2H, s), 2.23 (3H, s), 2.22 (3H, s), 1.11 (6H, s).

Procedure 4: 2.(4-Hydroxy-3,5-dimethylphenyl)-1,1-dimethylethylcarbamic acid, t-butyl ester A solution of 2,6-dimethyl-4-(2-amino-2,2-dimethylethyl)phenol (12.0g, 62mmol) in dry dimethylformamide (250ml) was treated with triethylamine (10.3ml, 74mmol) and di-t-butyldicarbonate (13.0g, 60mmol) and the mixture stirred at room temperature. After 24h the mixture was evaporated and the residue partitioned between diethyl ether (1 00ml) and water (1 00ml), the organic layer was removed and the aqueous layer was extracted with diethyl ether (100ml). The combined organic phases were washed with water (3 x 100my), dried and evaporated to yield the title compound.

6(CDC13): 6.76 (2H, s), 4.51 (lH, br), 4.27 (1H, br), 2.83 (2H, s), 2.21 (6H, s), 1.47 (9H, s), 1.25 (6H, s).

Procedure 5: 2,6-Dimethyl-4-(2-t-butoxycarbonylamino-2,2- dimethylethyl)phenoxymethylcyclohexylphosphinic acid, n-butyl ester A solution of 2-(4-hydroxy-3 ,5-dimethylphenyl)- 1,1 -dimethylethylcarbamic acid, t-butyl ester (2.96g, 8mmol) in dry DMF (100 ml) was cooled in an ice-bath and treated with sodium hydride (60% in mineral oil 0.40g, 10mmol) with stirring under argon. When effervescence ceased a solution of 4- chlorobenzenesulfonyloxymethylcyclohexylphosphinic acid, n-butyl ester (3.5g, 8.5mmol) in dry DMF (25ml) was added and the resulting pale yellow solution stirred at room temperature. After 1 6h the solvent was evaporated and the residue partitioned between diethyl ether (1 00ml) and water (1 00m1) and the organic phase was separated. The aqueous phase was extracted with diethyl ether (2x 100ml). The combined organic phases were washed with water (3x 100ml) dried and evaporated to give the crude product. Chromatography over silica, eluting with hexane containing 60% ethyl acetate yielded the title compound as colourless oil.

6(CDC13): 6.79 (2H, s), 4.26-4.00 (5H, m), 2.85 (2H, s), 2.27 (6H, s), 2.20-1.25 (30H, m), 0.95 (3H, t, J = 7.2Hz).

Procedure 6: 2,6-Dimethyl-4-(2-amino-2,2 dimethylethyl)phenoxymethyleyclohexylphosphinic acid, n-butyl ester A solution of 2,6-dimethyl-4-(2-t-butoxycarbonylamino-2,2- dimethylethyl)phenoxymethylcyclohexylphosphinic acid, n-butyl ester (2.8g, 5.5mmol) and trifluoroacetic acid (loll) was stirred at room temperature. After 1 8h the solution was concentrated under reduced pressure and product dried in vacuo. The trifluoroacetic acid salt was neutralized with aqueous sodium bicarbonate and extracted with dichloromethane (1 00ml). The organic layer was dried and evaporated to give the title compound as a pale yellow gum.

Procedure 7: (S)-2,6-D imethyl4- (2- E3-(4-hyd roxyph enoxy)-2- hydroxypropylamiuoj-2,2-dimethylethyl)phenoxymethyl cyclohexylphosphinic acid, n-butyl ester A solution of 2,6-dimezithyl-4-(2-amino-2,2- dimethylethyl)phenoxymethylcyclohexylphosphinic acid, n-butyl ester (2.18g, 5.3mmol) and (S)-2-(4-benzoyloxyphenoxymethyl)oxirane (1.08g, 4.0mmol) in methanol (40ml) was heated under reflux for 48 hours. After cooling the solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with 15% methanol in ethyl acetate giving the title compound as a gum. 6(CDC13 + D20): 6.79 (2H, s), 6.75 (2H, d, J = 9.0Hz), 6.66 (2H, d, J = 9.0Hz), 4.25-3.85 (7H, m), 2.95-2.75 (2H, m), 2.59 (2H, s), 2.20 (6H, s), 2.15-1.25 (15H, m), 1.09 (6H, s), 0.95 (3H, t, J = 7.2Hz).

Procedure 8: 4-(2-Nitro-2,2-spirocyclopentylethyl)phenol A mixture of nitrocyclopentane (lOg, 87mmol), 4-hydroxybenzyl alcohol (5.39g, 43.5mmol) and tetra-n-butylammonium fluoride (5.69g, 21.8mmol) was heated at 13 00C under argon. After 24h the reaction was cooled and diluted with dichloromethane (200ml), the resultant solution washed with water (1 00ml), dried and evaporated to yield a dark brown oil. Chromatography over silica eluting with hexane containing 25% ethyl acetate gave the title compound as a white crystalline solid.

6(CDC13): 6.96 (2H, d, J = 8.53Hz), 6.73 (2H, d, J = 8.53Hz), 4.84 (1H, s, exchanges with D20), 3.21 (2H, s), 2.54-2.45 (2H, m), 1.94-1.82 (2H, m), 1.74- 1.69 (4H, m).

Procedure 9: 4-(2-Amino-2,2-spirocyclopentylethyl)phenol Raney nickel was carefully added to a solution of 4-(2-nitro-2,2- spirocyclopentylethyl)phenol (6.40g, 29mmol) in methanol (60ml). The resultant mixture was hydrogenated at atmospheric pressure until the required amount of hydrogen was adsorbed. The mixture was filtered and the solid residue washed with methanol (100ml), finally the filtrate was evaporated and triturated with ethyl acetate to yield the title compound as a white solid.

b(CDC13+D20): 6.99 (2H, d, J = 8.25Hz), 6.66 (2H, d, J = 8.25Hz), 2.55 (2H, s), 1.81-1.07 (8H, m).

Procedure 10: 2-(4-Hydroxyphenyl)-1,1-spirocyclopentylethylcarbamic acid, t-butyl ester 4-(2-Amino-2,2-spirocyclopentylethyl)phenol (3.90, 20mmol) in dry dimethylformamide (50ml) was treated with triethylamine (2.7ml, 20mmol) and di-t-butyldicarbonate (4.36g, 20mmol) and the mixture stirred at room temperature. After 24h the mixture was evaporated and the residue partitioned between diethyl ether (1 00ml) and water(100ml), the organic layer was removed and the aqueous layer was extracted with diethyl ether (100my). The combined organic phases were washed with water (3 x 100my), dried and evaporated to yield the title compound.

6(CDC13): 7.00 (2H, d, J = 8.52Hz), 6.74 (2H, d, J = 8.45Hz), 5.02 (lH, brd s, exchanges with D20), 4.23 (1H, s, exchanges with D20), 3.01-2.90 (2H, m), 1.79-1.52 (8H, m), 1.47 (9H, s).

Procedure 11: 4-(2-t-Butoxycarbonylamino-2,2- spirocyclopentylethyl)phenoxymethylphenylphosphinic acid, ethyl ester A solution of 2-(4-hydroxyphenyl)- 1,1 -spirocyclopentylethylcarbamic acid, t- butyl ester (2.91g, 10mmol) in dry DMF (10 ml) was cooled in an ice-bath and treated with sodium hydride (60% in mineral oil 0.80g, 20mmol) with stirring under argon. When effervescence ceased a solution of 4- chlorobenzenesulfonyloxymethylphenylphosphinic acid, ethyl ester (3.34g, lOmmol) in dry DMF (lOml) was added and the resulting pale yellow solution stirred at room temperature. After 1 6h the solvent was evaporated and the residue partitioned between diethyl ether (l00ml) and water (100ml) and the organic phase was separated. The aqueous phase was extracted with diethyl ether (2x 100ml). The combined organic phases were washed with water (3x 100ml) dried and evaporated to give the crude product. Chromatography over silica, eluting with hexane containing 60% ethyl acetate yielded the title compound as colourless oil.

8(CDCl3): 8.00-7.85 (2H, m), 7.65-7.44 (3H, m), 7.02 (2H, d, J = 8.52Hz), 6.78 (2H, d, J = 8.80 Hz), 4.50-4.14 (4H, m), 2.97 (2H, s), 1.87-1.66 (8H, m), 1.51 (9H, s), 1.40 (1.5H, t, J = 7.51Hz), 1.26 (1.5H, t, J 7.51Hz).

Procedure 12: 4-(2-Amino-2,2-spirocyclopentylethyl) phenoxymethylphenylphosphinic acid, ethyl ester 4-(2-t-Butoxycarbonylamino-2,2-spirocyclopentylethyl)phenoxy methyl phosphinic acid, ethyl ester (800mg, 1.66mmol) in dichloromethane (20ml) and trifluoroacetic acid (2.5ml) was stirred at room temperature. After 1 8h the solution was concentrated under reduced pressure and product dried in vacuo.

The trifluoroacetic acid salt was neutralized with aqueous sodium bicarbonate and extracted with dichloromethane (1 00ml). The organic layer was dried and evaporated to give the title compound as a pale yellow gum.

6(CDCl3): 8.00-7.76 (2H, m), 7.73-7.31 (3H, m), 7.17-6.90 (2H, m), 6.87-6.63 (2H, m), 4.79 (2H, brd s, exchanges with D20), 4.46-4.01 (4H, m), 2.80-2.63 (2H, m), 2.05-1.40 (4H, m), 1.40-1.33 (4H, m), 1.23 (3H, t, J = 7.51Hz).

Procedure 13: (S)-4-(2- [3-(4-Benzyloxyphenoxy)-2-hydroxypropylaminol-2,2- spirocyclopentylethyl}phenoxyrnethylphenylphosphinic acid, ethyl ester A mixture of 4-(2-amino-2,2-spirocyclopentylethyl)phenoxymethylphenyl phosphinic acid, ethyl ester (400mg, 1 .0mmol), and (S)-2-(4- benzyloxyphenoxymethyl)oxirane (240mg, 1 .Ommol) in methanol (30ml) was heated at reflux under argon. After 48h the reaction was cooled and the solvent evaporated. The residue was chromatographed over silica, eluting with dichloromethane containing 5% methanol, to yield the title compound as a gum.

b(CDC13+D20): 8.05-7.80 (2H, m), 7.61-7.33 (10H, m), 7.06 (2H, d, J = 8.53Hz), 6.84 (4H, m), 5.02 (2H, s), 4.47-4.04 (5H, m), 3.98-3.82 (2H, m), 3.00- 2.81 (2H, m), 2.74-2.65 (2H, m), 1.95-1.46 (4H, m), 1.40-1.21 (4H, m), 1.32 (3H, t, J = 7.52Hz).

Procedure 14: (S)-4-{2-[3-(4-Hydroxyphenoxy)-2-hydroxypropylamino]-2,2- spirocyclopentylethyl}phenoxymethylphenylphosphinic acid, ethyl ester A mixture of (S)-4-{2-[3-(4-benzyloxyphenoxy)-2-hydroxypropylamino]-2,2- spirocyclopentylethyl } phenoxymethylphenylphosphinic acid, acid, ethyl ester (70mg, O.lmmol) and 10% palladium on charcoal in methanol (20ml) was hydrogenated at atmospheric pressure. After 2.5h the catalyst was removed by filtration and the methanol evaporated to yield the title compound as gum, single peak by hplc.

Procedure 15: (S)-2-(4-Benzoyloxyphenoxymethyl)oxirane A solution of 4-hydroxyphenyl benzoate (4.28g, 20mmol) in dimethylformamide (30ml) and sodium hydride (60% dispersion in oil, 800mg, 20mmol) was stirred at room temperature for 10 minutes. (2S)-Glycidyl-3-nitrobenzenesulfonate (5.18g, 20mmol) was added and the mixture was stirred at room temperature for 3 hours. Ethyl acetate and water were added, the organic layer was separated, washed with water and brine and dried over magnesium sulfate. Filtration followed by removal of solvent gave the crude product. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexanes gave the title compound as a colourless solid.

6(CDCl3): 8.19 (2H, dd, J = 8.4, 1.3Hz), 7.47-7.67 (3H, m), 7.13 (2H, d, J = 9.1Hz), 6.97 (2H, d, J = 9.1Hz), 4.24 (lH, dd, J = 11.0,3.0Hz), 3.97 (lH, dd, J = <BR> <BR> 11.0, 5.5Hz), 3.30-3.40 (1H, m), 2.92 (1H, t, J = 5.0, 4.4Hz), 2.77 (1H, dd, J = 5.0, 2.8Hz).

Procedure 16: 4-(2-Amino-2,2-spirocyclopentylethyl)-2-bromophenol hydrobromide A solution of 4-(2-amino-2,2-spirocyclopentylethyl)phenol (10.6g, 55mmol) in glacial acetic acid (200ml) was treated with a solution of bromine (3.5ml, 66mmol) in glacial acetic acid (10ml). After stirring at room temperature for 30 minutes the solid was collected, washed with diethyl ether and dried giving the title compound as a colourless solid.

6(d6-DMSO): 10.2 (1H, br), 7.75 (3H, br), 7.39 (1H, d, J = 1.9Hz), 7.08 (1H, dd, J = 8.2, 1.9Hz), 6.93 (1H, d, J = 8.2Hz), 2.81 (2H, s), 1.9-1.5 (8H, m).

Procedure 17: 2-(3-Bromo-4-hydroxyphenyl)-1,1- spirocyclopentylethylcarbarnic acid, t-butyl ester The title compound was prepared from 4-(2-amino-2,2-spirocyclopentylethyl)-2- bromophenol hydrobromide (12.0g, 34mmol), triethylamine (10.5ml, 75mmol) and di-t-butyldicarbonate (7.4g, 34mmol) in dry DMF (250ml) according to the method described in Procedure 10.

6(CDCl3): 7.24 (1H, d, J = 1.9Hz), 6.99 (1H, dd, J = 8.2, 1.9Hz), 6.92 (1H, d, J = 8.2Hz), 5.45 (1H, br), 4.20 (1H, br), 2.97 (2H, s), 1.80-1.58 (8H, m), 1.48 (9H, s).

Procedure 18: 2-Brorno-4-(2-t-butoxycarbonylarnino-2,2- spirocyclopentylethyl)phenoxymethylcyclohexylphosphinic acid, n-butyl ester The title compound was prepared from 2-(3-bromo-4-hydroxyphenyl)-1,1- spirocyclopentylethylcarbamic acid, t-butyl ester (2.96g, 8mmol), 60% dispersion of sodium hydride (0.40g, 1 0mmol) and 4-chlorobenzenesulfonyloxymethylcy- clohexylphosphinic acid, n-butyl ester (3.5g, 8.5mmol) in dry DMF (125ml) according to the method described in Procedure 11.

6(CDCl3): 7.34 (1H, d, J= 2.0Hz), 7.05 (1H, dd, J = 8.2, 2.0Hz), 6.84 (1H, d, J = 8.2Hz), 4.27-4.00 (5H, m), 2.99 (2H, s), 2.10-1.25 (32H, m), 0.92 (3H, t, J= 7.4Hz).

Procedure 19: 2-Bromo-4-(2-amino-2,2-spirocyclopentylethyl) phenoxymethylcyclohexylphosphinic acid, n-butyl ester The title compound was prepared from 2-bromo-4-(2-t-butoxycarbonylamino-2,2- spirocyclopentylethylmphenoxymethylcyclohexylphosphinic acid, n-butyl ester (2.17g, 3.7mmol) and trifluoroacetic acid (lOml) in dichloromethane (10ml) according to the method described in Procedure 12.

Procedure 20: (S)-2-Bromo-4-{2-[3-(4-hydroxyphenoxy)-2- hydroxypropylamino] -2,2-spirocyclopentylethyl)phenoxyrnethyl cyclohexylphosphinic acid, n-butyl ester A solution of 2-bromo-4-(2-amino-2,2-spirocyclopentylethyl) phenoxymethylcyclohexylphosphinic acid, n-butyl ester (1.79g, 3.7mmol) and (S)-2-(4-benzoyloxyphenoxymethyl)oxirane (810mg, 3. 0mmol) in methanol (30ml) was heated under reflux for 48 hours. After cooling the solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with 15% methanol in ethyl acetate giving the title compound as a gum.

m/z = 652, 654 (MH+).

Procedure 21: 2-Bromo-4-(2-t-butoxyearbonylamino-2,2-spirocyclopentyl- ethyl)phenoxymethylphosphinic acid, dicyclohexyl ester The title compound was prepared from 2-(3 -bromo-4-hydroxyphenyl)- 1,1- spirocyclopentylethylcarbamic acid, t-butyl ester (2.00g, 5.4mmol), 60% dispersion of sodium hydride (0.25g, 6.25mmol) and 4-chlorobenzenesulfonyl- oxymethylphoshonic acid, dicyclohexyl ester (2.70g; 6.00mmol) in dry DMF (50ml) according to the method described in Procedure 11.

6(CDCl3 + D20): 7.34 (1H, d, J=2.0Hz), 7.05 (1H, dd, J=2.0Hz), 6.84 (1H, dd, J=2.0Hz), 4.60 (2H,m), 4.27 (2H, d ), 2.97 (2H,s), 2.05-1.23 (38H, m) Procedure 22: 2-Brorno-4-(2-arnino-2,2-spirocyclopentylethyl)phenoxy- methylphosphonic acid, dicyclohexyl ester The title compound was prepared from 2-bromo-4-(2-t-butoxycarbonylamino- 2 ,2-spirocyclopentylethyl)phenoxymethylphosphonic acid, dicyclohexyl ester (2.22g, 3.53mmol) and trifluoroacetic acid (5ml) in dichloromethane (25ml) according to the method described in Procedure 12.

6(CDCl3): 7.41 (1H, s), 7.15 (1H, d, J = 2.0Hz), 6.92 (1H, d,J = 2.0Hz), 4.62 (2H,m), 4.26 (2H,d), 2.69 (2H, s), 1.37-2.02 (30H, m) Procedure 23: (S)-2-Bromo-4-(2-[3-(4-hydroxyphenoxy)-2-hydroxypropyl- amino] -2,2-spirocyclopentylethyl)phenoxymethylphosphinic acid, dicyclohexyl ester The title compound was prepared from 2-bromo-4-(2-amino-2,2- spirocyclopentylethyl)phenoxymethylphosphonic acid, dicyclohexyl ester (1. 00g 1 .9mmol) and (S)-2-(4-benzoyloxyphenoxymethyl)oxirane (0.51g, 1 .9mmol) using the method described in Procedure 20.

m/z = 694, 718 (MNa+) Procedure 24: 4-(2-t-Butoxycarbonylamino-2,2- spirocyclopentylethyl)phenoxymethylcyclohexylphosphinic acid, n-butyl ester The title compound was prepared from 2-(4-hydroxyphenyl)-1 ,1 - spirocyclopentylethylcarbamic acid, t-butyl ester (2.5g), 60% dispersion of sodium hydride (0.4g) and 4-chlorobenzenesulfonyloxymethylcy- clohexylphosphinic acid, n-butyl ester (3.5g) in dry DMF according to the method described in Procedure 11.

6(CDCl3) 7.08 (2H, d, J = 8.8Hz), 6.85 (2H, d, J= 8.8Hz), 4.30-3.95 (5H, m), 3.00 (2H, s), 2.10-1.25 (32H, m), 0.92 (3H, t, J = 7.4Hz).

Procedure 25: 4-(2-Amino-2,2-spirocyclopentylethyl) phenoxymethylcyclohexylphosphinic acid, n-butyl ester The title compound was prepared from 4-(2-t-butoxycarbonylamino-2,2- spirocyclopentylethyl)phenoxymethylcyclohexylphosphinic acid, n-butyl ester (3.28g) and trifluoroacetic acid (5ml) in dichloromethane (50ml) according to the method described in Procedure 12.

6(CDCl3) 7.16 (2H, d, J = 8.5Hz), 6.88 (2H, d, J= 8.5Hz), 4.30-3.95 (4H, m), 2.72 (2H, s), 2.10-1.20 (25H, m), 0.92 (3H, t, J = 7.4Hz).

Procedure 26: (S)- (2- [3-(4-Hydroxyphenoxy)-2-hydroxypropylamino]-2,2- spirocyclopentylethyl)phenoxymethyl cyclohexylphosphinic acid, n-butyl ester The title compound was prepared from 4-(2-amino-2,2-spirocyclopentylethyl) phenoxymethylcyclohexylphosphinic acid, n-butyl ester (2.10g) and (S)-2-(4- benzoyloxyphenoxymethyl)oxirane (1.25g) in methanol (50ml) using the method described in Procedure 20.

Example 1: (S)-2,6-Dimethyl-4-(2-[3-(4-hydroxyphenoxy)-2- hydroxypropylamino]-2,2-dimethylethyl)phenoxymethyl cyclohexylphosphinic acid, lithium salt A mixture of (S)-2,6-dimethyl-4- { 2- [3 -(4-hydroxyphenoxy)-2- hydroxypropylamino] -2,2 -dimethylethyl } phenoxymethylcyclohexylphosphinic acid, n-butyl ester (1.1 5g, 2.0mmol) and 1.OM lithium hydroxide (20ml) in methanol (50ml) was stirred at room temperature. After 24h, dilute hydrochloric acid (2M) was added until pH9 was reached. The methanol was then evaporated and the aqueous solution chromatographed over Cl 8 reverse phase silica eluting firstly with water and then water/methanol mixtures. After evaporation of the appropriate fractions the resultant product was freeze-dried to yield the title compound as a white solid.

6(CD30D): 6.87 (2H s), 6.75 (2H, d, J = 9.2Hz), 6.70 (2H, d, J = 9.2Hz), 4.15- 3.90 (3H, m), 3.81 (2H, d, J = 7.7Hz), 3.15-2.92 (2H, m), 2.76 (2H, s), 2.29 (6H, s), 2.15-2.05 (2H, m), 1.90-1.25 (9H, m), 1.20 (6H, s).

Example 2: (S)-4-(2-[3-(4-Hydroxyphenoxy)-2-hydroxypropylamino] -2,2- spirocyclopentylethyl}phenoxymethylphenylphosphinic acid, lithium salt A mixture of (S)-4- { 2- [3 -(4-hydroxyphenoxy)-2-hydroxypropylamino] -2,2- spirocyclopentylethyl } phenoxymethylphenylphosphinic acid, ethyl ester (25mg, 46mol) and 1.OM lithium hydroxide (1 ml) in methanol (lOml)was stirred at room temperature. After 24h solid carbon dioxide was added until pH9 was reached. The methanol was then evaporated and the aqueous solution chromatographed over C18 reverse phase silica eluting firstly with water, then with 1:1 aqueous methanol. After evaporation of the appropriate fractions the resultant product was freeze-dried to yield the title compound as a white solid.

6(CD30D): 7.95-7.85 (2H, m), 7.40-7.38 (3H, m), 7.06 (2H, d, J = 8.61Hz), 6.76- 6.73 (4H, m), 6.69 (2H, d, J = 8.91Hz), 4.05 (2H, d, J = 8.44Hz), 3.91-3.89 (1H, m), 3.87-3.85 (2H, m), 2.85-2.63 (4H, m), 1.69-1.29 (8H, m).

Example 3: (S)-2-Bromo-4-(2-[3-(4-hydroxyphenoxy)-2 hydroxypropylaminoj-2,2-spirocyclopentylethyl) phenoxymethyl cyclohexylphosphinic acid, lithium salt The title compound was prepared from (S)-2-bromo-4-{2-[3-(4- hydroxyphenoxy)-2-hydroxypropylamino]-2,2- spirocyclopentylethyl } phenoxymethylcyclohexylphosphinic acid, n-butyl ester and l.OM lithium hydroxide in methanol according to the method described in Example 1.

b(CD30D): 7.44 (1H, d, J = 2.0Hz), 7.17 (1H, dd, J = 8.4, 2.0Hz), 6.94 (1H, d, J = 8.4Hz), 6.77 (2H, d, J= 9.0Hz), 6.71 (2H, d, J= 9.0Hz), 4.06-4.01 (1H, m), 3.99 (2H, d, J= 8.2Hz), 3.95-3.90 (2H, m) 3.05-2.95 (2H, m), 2.76 (2H, s), 2.05- 1.25 (19H, m).

Example 4: (S)-2-Bromo-4-(2-[3-(4-hydroxyphenoxy)-2- <BR> <BR> hydroxypropylamino]-2,2-spirocyclopentylethyl}phenoxymethylp hosphonic acid, cyclohexyl ester hydrochloride The title compound was prepared from (S)-2-bromo-4-(2-[3-(4-hydroxy- phenoxy)-2 -hydroxypropylamino] -2,2 -spirocyclopentylethyl } phenoxymethyl- phosphonic acid, dicyclohexyl ester and aqueous 1.OM lithium hydroxide solution in methanol according to the method described in Example 1, followed by neutralisation with dilute HCl.

m/z 614 (MH+).

Example 5: (S)-4-(2- [3-(4-Hydroxyphenoxy)-2-hydroxypropylami -2,2- spirocyclopentylethyl}phenoxymethyl cyclohexylphosphinic acid, lithium salt The title compound was prepared from (S)-4-(2-[3-(4-hydroxyphenoxy)-2- hydroxypropylamino] -2,2-spirocyclopentylethyl ) phenoxymethylcyclohexyl phosphinic acid, n-butyl ester and 1.OM lithium hydroxide solution in methanol according to the method described in Example 1.

m/z (NOBA/Na) 524 (MLi+).