WO1997034905A1

WO1997034905A1 - Phosphorus containing aryloxy and arylthiopropanol amine derivatives useful as beta adrenoreceptor agonists

Info

Publication number: WO1997034905A1
Application number: PCT/EP1997/001286
Authority: WO
Inventors: Helen Kate Ann Morgan; Robert William Ward; Mervyn Thompson
Original assignee: Smithkline Beecham Plc
Priority date: 1996-03-15
Filing date: 1997-03-12
Publication date: 1997-09-25
Also published as: GB9605495D0

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein, Ro represents an aryl group optionally substituted with one, two or three substituents selected from the list consisting of: hydroxy, hydroxymethyl, nitro, amino, alkylamino, dialkylamino, alkylsulphonamido wherein the alkyl group is optionally substituted with one, two or three substituents selected from: halogen, haloalkyl, hydroxy, alkoxy, or arylsulphonamido wherein the aryl group is optionally substituted, providing that Ro is not 3-methylsulphonylaminophenyl when X represents O or S; R?1 and R1a¿ each independently represent hydrogen or an alkyl group; R2 represents a moiety of formula (a), wherein R?4 and R5¿ each independently represents hydrogen, alkyl, cycloalkyl, aryl or aralkyl or R5 together with R4 represent -(CH¿2?)n- wherein n is 3, 4 or 5; and R?3¿ represents hydrogen, halogen, alkyl or alkoxy; a pharmaceutical composition comprising such a compound, a process for preparing such a compound and the use of such a compound and composition in medicine.

Description

PHOSPHORUS CONTAINING ARYLOXY AND ARYLTHIOPROPANOL AMINE DERIVATIVES USEFUL AS BETA ADRENORECEPTOR AGONISTS

This invention relates to novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine and agriculture.

International Patent Application, Publication Number WO96/04233 discloses certain aryloxy and arylthio propanolamine compounds which are stated inter alia to have good anti-hyperglycaemic and/or anti-obesity activity coupled with especially good selectivity from cardiac and tremorigenic side effects. It has now been discovered that a novel series of phosphine oxide propanolamine derivatives are potent β-adrenoreceptor agonists showing good selectivity from cardiac and tremorigenic side effects and which show particularly good bioavailability. These compounds are therefore indicated to be particularly useful as anti-hyperglycaemic and/or anti-obesity compounds, especially in sufferers of Type II diabetes. 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 blood serum, especially 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):

(I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein,

R° represents an aryl group optionally substituted with one, two or three substitutents selected from the list consisting of: hydroxy, hydroxymethyl, nitro, amino, alkylamino, dialkylamino, alkylsulphonamido wherein the alkyl group is optionally substituted with one, two or three substituents selected from: halogen, haloalkyi, hydroxy, alkoxy, or arylsulphonamido wherein the aryl group is optionally substituted, providing that R° is not 3-methylsulphonylaminophenyl; X represents O or S;

Rl and R ^a each independently represents hydrogen or an alkyl group.; R2 represents a moiety of formula (a):

(a)

wherein ^ and R5 each independently represent hydrogen, alkyl, cycloalkyl, aryl or aralkyl or R^ together with R^ represents -(CH2)_n- wherein n is, 3,4 or 5; and R3 represents hydrogen, halogen, alkyl or alkoxy. Suitably, R° represents a moiety of formula (b):

wherein Y represents hydrogen, hydroxy, hydroxymethyl, alkylsulphonamido or phenylsulphonamido wherein the phenyl group is optionally substituted with one or two halogen atoms and γl represents hydrogen, hydroxy or hydroxymethyl.

Favoured aryl substituents for any arylsuphonamido group include one, two or three of halogen, alkyl, alkoxy and allyl.

Preferably R° is 4-hydroxyphenyl, 4-hydroxy-3-alkylsulphonmidophenyl, especially 4-hydroxy-3-methanesulphonamidophenyl. Suitably, R s an alkyl group and R^^a represents hydrogen.

Suitably, Rl and R^^a each represents hydrogen.

When Rl is alkyl, it is favourably a C\. alkyl group, especially a methyl group. Preferably, R-* is hydrogen. Suitably, R^ represent phenyl. Suitably, R^ represents phenyl.

Preferably, X represents O. A preferred compound of formula (I) is a compound wherein:R° is 4- hydroxyphenyl-3-methanesulphonamido; X is O;R is methyl; R^{l a} is hydrogen; R² is a moiety of formula (a) wherein R^ and R^ each represent phenyl; and R^ is hydrogen.

In particular, should be mentioned the compounds of example numbers 3, ό.and 8. The compounds of formula (I) have one or two asymmetric carbon atoms, marked with an asterisk (*) or two asterisks (**) in the formula. In addition when the substituents on the phosphorous atom of moiety (a) are different, then the phosphorous atom is chiral: These compounds may therefore exist in up to eight stereoisomeric forms. The present invention encompasses all stereoisomers ofthe compounds ofthe 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.

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

The term 'aryl' suitably includes phenyl or naphthyl groups, especially phenyl. Suitable substitutents for any aryl group one, two or three substitutents selected from the list consisting of: hydroxy, hydroxymethyl, nitro, amino, alkylamino, dialkylamino, alkylsulphonamido, arylsulphonamido, halogen, alkoxy, alkyl and allyl.

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, iso-propyl, n-butyl, wo-butyl or tert-butyl group.

The term 'cycloalkyl' includes Cβ.g cycloalkyl groups, especially C5 or Cg cycloalkyl groups.

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

Suitable pharmaceutically acceptable salts include acid addition salts.

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 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 pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, which process comprises reacting a compound of formula (II):

(II)

wherein X is as defined in relation to formula (I) and R⁰' represents R° as defined in relation to formula (I) or a protected form thereof, with a compound of formula (III):

(III)

wherein Rl and R^^a are as defined in relation to formula (I), R²' represents R² or a protected form thereof, R^' represents R^ or a protected form thereof and T° 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 pharmaceutically acceptable salt ofthe compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.

The reaction between compounds of formulae (II) and (III) is suitably carried out in an aprotic solvent such as acetonitrile or a chlorinated solvent such as dichloromethane, at any temperature providing a suitable rate of formation ofthe required product, suitably at ambient temperature and suitably in the presence of a perchlorate, such as lithium perchlorate; preferably the reaction is carried out under an inert atmosphere such as nitrogen or argon. Alternatively, the reaction can be carried out in an alkanolic solvent such as methanol at any temperature providing a suitable rate of formation ofthe final product, suitably at ambient temperature or at an elevated temperature, such as the reflux temperature ofthe solvent, preferably the reaction is carried out in an inert atmosphere such as nitrogen or argon.

Suitably, R⁰' represents a protected form of R°, protected in accordance with conventional chemical practice using such groups as defined herein, for example when R° comprises a hydroxy group it may be protected as a benzyloxy group.

Suitable protecting groups represented by T° are benzyl, p-methoxybenzyl and silyl groups.

Suitably, T° is hydrogen. Suitably, R²' is R².

A compound of formula (II) may be prepared by reacting an activated form of a compound of formula (IV):

R^O'-X-H (IV)

wherein R⁰' and X are as defined in relation to formula (II), with a compound of formula

(V):

_*

L°— CH₂— CH — CH₂ ^O (V)

wherein L° represents 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 a potassium 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 carbonate, for example potassium carbonate.

Suitably, L° represents 3-or 4-nitrobenzenesulphonyloxy group, preferably 3- nitrobenzenesulphonyloxy.

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 ofthe required product, generally at an ambient to elevated temperature, suitably an elevated temperature, for example the reflux temperature of acetone

L° also represents OH.

When L° 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), wherein Rl is alkyl, is suitably prepared by the hydrogenolysis of a

(VI) wherein R is as defined in relation to formula (I), R²' is a group convertible into a group R², Y² represents hydrogen or a moiety -B(OH)2 and the **CH carbon and ***CH carbon atoms are chiral carbon atoms; and thereafter converting the group R²' into a group R². Suitably, catalytic hydrogenolysis is used, using for example 10% palladium on charcoal, optionally in the presence of ammonium formate,_suitably in an alkanolic solvent such as methanol, at any temperature providing a convenient rate of formation of the required product, for example at ambient temperature or at an elevated (eg, 50°C)temperature A compound of formula (VI) wherein Y² is H and R* is alkyl may be prepared by stereoselective reduction of a compound of formula (VII):

(VII) wherein R^ is as defined in relation to formula (I), R6 is a moiety of formula

-OCH2R² , wherein R² is as defined in relation to formula (VI) and the***C carbon is a chiral carbon.

The reduction ofthe compound of formula (VII) may be carried out using catalytic reduction in the presence of hydrogen. A preferred catalyst is platinum oxide.

Suitable reduction conditions include using an alkanol solvent such as methanol or ethanol, at any temperature providing a convenient rate of formation ofthe required product, conveniently at ambient temperature using a pressure of 1-5 atmospheres of hydrogen. The compound of formula (VII) may be prepared by reacting a compound of formula (VIII):

(VIII) wherein R'and R^ are as defined in relation to formula (I) and R° is as defined in relation to formula (VII), with R-α-methylbenzylamine.

The reaction between compounds of formulae (VIII) and R-α-methylbenzylamine may be carried out under conventional reductive amination conditions, for example in a solvent such as methanol or toluene. Conveniently, the compound of formula (VII) is prepared in-situ by reacting a compound ofthe above defined formula (VIII) with R-or S-(as appropriate) α- methylbenzyl amine and thereafter reducing the compound of formula (VII) so formed using reaction conditions and catalysts as described above.

Compounds of formula (III) are conveniently prepared from compounds of formula (IX):

wherein R' , R^^a and R^ are as defined in relation to formula (I) and T^ is a protecting group, by reaction with a compound of formula (X):

wherein R^ and R^ are as defined in relation to formula (I) and L² is a leaving group or atom; and thereafter, as necessary removing any protecting group. Suitably, T^ is a t-butoxycarbonyl group.

Suitably, L² represents a 4-chlorobenzenesulphonyloxy group or a 3-or 4- nitrobenzenesulphonyloxy group. In the above mentioned reactions the compound of formula (IX) is usually in an activated form, such as an anionic form. The activated form is conveniently prepared im situ prior to addition ofthe compound of formula (X).

Preferably, the activated form ofthe compound of formula (IX) is prepared by reaction ofthe compound of formula (IX) with a base such as sodium hydride. The reaction between compounds of formulae (IX) and (X) is carried out in an aprotic solvent, such as dimethylformamide or dimethylsulphoxide at any temperature which provides a suitable rate of reaction, conveniently at ambient temperature. Suitably, R^ is a group convertible into a moiety of formula -OCH2R². One preferred value for R^ is a methoxy group, thus preferably R2' represents hydrogen.

R6 may be converted into a group of formula -OCH2R² by any conventional means, for example when R > is a methoxy group, by treatment with a Lewis acid, such as boron tribromide, followed by reaction ofthe phenol so formed with a compound ofthe above defined formula (X) under conditions analogous to those described above for the reaction between the compounds of formulae (IX) and (X).

The compounds of formula (IX) wherein R^ and R'^a each represent hydrogen are known compounds or they are prepared according to methods used to prepare known compounds, such as those disclosed for such compounds when T* is t-butoxycarbonyl in Can. J. Chem. 1985, 62, 153.

The compounds of formula (IX) wherein either R or R ^a is hydrogen are prepared according to known procedures, for example those disclosed in WO96/04233.

A compound of formula (X) may be prepared by hydroxymethylation of a compound of formula (XI):

wherein R^ and R^ are as defined in relation to formula (I),; and thereafter reacting the product so formed with a source of leaving group L².

The hydroxymethylation is carried out using formaldehyde, generally in the form of paraldehyde, using conventional procedures depending upon the exact nature ofthe substrate, such as those disclosed by Houben-Weyl in Phosphor Verbinungen p28, J. Amer. Chem.-Soc. 1955, 77, 3522, Phosphorus and Sulphur 1978, 5_, 455 or in Aust. J. Chem. 1979, 32, 463 or in Tet. Lett. 1986, 27, 1477.

The conditions of reaction ofthe hydroxymethylated compound with the source of the leaving group will depend upon the nature ofthe leaving group L² but the appropriate conventional conditions are employed. For example when L² represents a 4- chlorobenzenesulphonyloxy group the literature method of J. Cornforth et al (J.C.S. Perkin 1, 1994, 1897) may be employed.

In a further aspect ofthe present invention there is provided a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, which process comprises deprotecting a compound of formula (XII):

wherein R¹, R^{l a}, R², R^ and X are as defined in relation to formula (I), R° is as defined in relation to formula (II), and thereafter, if required, carrying out one or more ofthe following optional steps:

(i) converting a compound of formula (I) to a further compound of formula (I); (ii) removing any protecting group;

The deprotection ofthe compound of formula (XII) may be carried out using conventional deprotection procedures depending upon the nature ofthe protection in R⁰', for example when R° comprises a protected OH group such as a benzyloxy group, then the hydroxy group is reformed by using catalytic hydrogenolysis with hydrogen and a 5% or 10% Palladium-on-carbon catalyst.

The compounds of formula (IV) are either known commercially available compounds or they are prepared according to published methods or by use of analogous methods to the published methods, for example those disclosed in J.Chem. Soc. Perkin I;

1974, 1353.

The compounds of formula (V) are known commercially available compounds. The compounds of formula (XI) are known compounds or they may be prepared by processes analogous to those used to prepare known compounds, for example may be prepared according to methods disclosed in Phosphorus and Sulphur, 1978, 5_, 455, J.

Chem. Soc. 1959, 3950 or J. Amer. Chem. Soc.,1952, 74, 5418.

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 appropiate silylating agent, for example diols are protected by use of di-tert-butylsilylbis(trifluoromethanesulphonate): 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-lsU-butyldicarbonate, 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 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, or by treatment with a dilute mineral acid.

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. Suitable examples of such groups unless otherwise specified are halogen atoms, mesyloxy groups and tosyloxy groups, 3 -or 4-nitrobenzenesulphonyloxy and 4- chlorobenzenesulphony loxy .

The salts, esters, amides and solvates ofthe 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 salts thereof; or a pharmaceutically acceptable solvate thereof, produced by the above processes, may be recovered by conventional methods.

If required mixtures of isomers ofthe compounds ofthe invention may be separated into individual stereoisomers and diastereoisomers by conventional means, for example by the use ofan optically active acid as a resolving agent. Suitable optically active acids which may be 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 ofthe invention may be obtained by stereospecific 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 and Type II diabetes 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 blood serum, especially 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. 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 ofthe 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 ofthe 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 or Type II diabetes 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 blood serum, especially 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 pharmaceutically 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, Type II diabetes, 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 blood serum, especially 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 ofthe 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 ofan 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--> ppm - 500ppm of total daily fed intake, more usually O.Olppm to 250ppm, suitably less than lOOppm. 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 ofthe 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.

Procedures and Examples:

Procedure 1: Diphenylhydroxymethyl phosphine oxide.

A mixture of diphenylphosphine oxide (1.17g, 5.61mmol), paraformaldehyde (169mgs, 1 equivalent) and triethylamine (1ml) was heated under an atmosphere of argon in an oil bath at 80°C for 3 hours. The excess triethylamine was removed in vacuo and the residue purified by column chromatography on silica gel, to afford the title compound as a white solid (1.20g, 89%).

δ'H (250MHz, CDC1₃): 4.41 (2H, d); 5.09 (IH, m); 7.50 (6H, m) and 7.78 (4H, m). m/z: MH⁺ 233 (100%)

Procedure 2: 4-ChlorophenylsuIphonic acid, diphenyl phosphinylmethyl ester

°

A solution of 4-chlorobenzenesulphonyl chloride (1.20g, 5.51 mmol) in dichloromethane

(4ml) was added dropwise to a stirring solution of diphenylhydroxymethyl phosphine oxide (1.20g, 5.17mmol) and triethylamine (0.80ml, 5.75mmol) in dichloromethane

(20ml) which had been cooled to -10°C. The reaction mixture was stirred under argon atmosphere for 20hrs at room temperature and then poured onto brine. Extracted with dichloromethane (2x50ml). The extracts were washed (brine), dried over anhydrous magnesium sulphate and evaporated. Purification by column chromatography on silica gel afforded the title compound as a white solid (1.75g, 83%).

δ1H (250MHz, CDC1₃): 4.65 (2H, d); 7.41-7.54 (6H, m) and 7.56-7.78 (8H, m).

Procedure 3: (R)-3-[4-(Diphenylphosphinylmethy!)phenoxyJ-2-propylcarbamic acid, tert-butyl ester

Sodium hydride (80% dispersion in mineral oil, 74mgs, 2.47mmol) was added to a stirring solution of (R)-3-(4-hydroxyphenyl)-2-propyl carbamic acid, tert-butyl ester

(537mgs, 2.14mmol) in dry dimethylsulphoxide (12ml) with cooling in a cold water bath. Once the effervescence had ceased, a solution of 4-chlorophenylsulphonic acid, diphenylphosphinylmethyl ester (0.87g, 2.14mmol) in dry dimethylsulphoxide (12ml) was added slowly. The mixture was allowed to stir at room temperature for 72 hours. Partitioned between dilute brine and ethyl acetate. The organic phase was separated and the aqueous re-extracted with ethyl acetate. The combined organics were washed with water and dried over anhydrous sodium sulphate. Evaporation afforded the title compound as a white foam (1.0g, quant.).

δ'H (200MHz, CDC1₃): 1.05 (3H, d); 1.41 (9H, s); 2.57 (IH, dd); 2.76 (IH, dd); 3.82 (IH, m); 4.34 (IH, br s); 4.70 (2H, d); 6.84 (2H, d); 7.08 (2H, d); 7.45-7.63 (6H, m) and 7.88 (4H, m). m/z: 466(MH⁺, 30%), 410 (30%) and 366 (100%).

Procedure 4: tert-Buryl[2-(4-hydroxyphenyl)ethyl]carbamate

A solution of di-tert-butyl dicarbonate (27.50g, 0.126moles) in dichloromethane (120ml) was added dropwise over VA hours to a stirring suspension of tyramine (14.90g, 0.1086 moles) and 4-dimethylaminopyridine (0.13g, 1.06mmol) in tetrahydrofuran (1300 ml). The reaction mixture was stirred at room temperature for 20 hours to give a clear, peach- coloured solution which was evaporated to dryness. Purification by column chromatography on silica gel, elution with 0— >4% methanol in dichloromethane afforded the title compound as a pale solid (24.2g, 94%).

δ*H (250MHz, CDC1₃): 1.45 (9H, s); 2.70 (2H, t); 3.33 (2H, q); 4.60 (IH, broad s); 5.79 (IH, broad s); 6.78 (2H, d) and 7.03 (2H, d).

Procedure 5: (R,R)-2-(4-Hydroxyphenyι)-l-methylethy.-(l- phenylethyl)aminoboronic acid

(RR)-[2-(4-Methoxyphenyl)-l-methylethyl]-(l-phenylethyl)amine hydrochloride salt^ (lOg, 0.0327 Mol) in dichloromethane (50ml) was treated with boron tribromide (IN in CH2CI2, 72 ml) under argon and stirring continued ovemight at room temperature. The mixture was then evaporated to dryness and ice added to hydrolyse the complex. The resulting white solid was collected and dried to give the title compound.

δ*H (250MHz, CDCI3 + CD3OD): 7.50 (5H, m), 6.83 (2H, d), 6.72 (2H, d), 4.38 (IH, q), 3.23 (IH, dd), 3.00 (IH, m), 2.67 (IH, dd), 1.78 (3H, d), 1.24 (3H, d) m/z: FAB MH+: 300 (5%), 256 (100)

¹ D.E. Nichols, CF. Barfknecht and D.B. Rusterholz. J.Med.Chem., 1973, 16(5), 480.

Procedure 6: (R)-4-(2-Aminopropy.)phenol

Me

(RR)-2-(4-Hydroxyphenyl)-l -methylethyl-(l -phenylethyl)aminoboronic acid (9.73g, 0.0325 Mol) was dissolved in methanol (120ml) and hydrogenated at 50 psi and 50°C with 10% palladium on charcoal (lg) for 2 days. The mixture was allowed to cool, then filtered through Kieselguhr and evaporated to dryness to give the title compound as a pale yellow solid. δ!H (250MHz, CDCI3): 7.06 (2H, d), 6.80 (2H, d), 4.12 (3H, br s), 3.12 (IH, m), 2.96 (IH, dd), 2.73 (IH, dd), 1.30 (3H, d).

Procedure 7: (R)-2-(4-HydroxyphenyI)-l- ethylethylcarbamic acid, /-butyl ester

Me

(R)-4-(2-Aminopropyl)phenol (4.9 lg, 0.0325 mol) in dichloromethane (240 ml) and dry dimethylformamide (50ml) was treated with triethylamine (7.59 ml) and di-t- butyldicarbonate (11.77g, 1.2 equiv.) and the mixture stirred at room temperature for 1 day. After evaporation of volatile material in vacuo, the residue was washed with diethyl ether. The combined portions of diethyl ether (500ml) were washed with water (3 x 100ml) and dried over anhydrous sodium sulfate. After evaporation to dryness the residue was chromatographed on silica gel with 0-3% methanol in dichloromethane to give the title compound as a gum that slowly solidified.

δ*H (250MHz, CDCI3): 7.00 (2H, d), 6.76 (2H, d), 6.25 (IH, br s), 4.44 (IH, br s), 3.83 (IH, m), 2.73 (IH, m), 2.57 (IH, dd), 1.43 (9H, s), 1.07 (3H, d).

Procedure 8: (R)-2-[4-(Diphenylphosphinylmethyl)phenoxy]-ethylcarbamic acid, /er/-butyl ester

The title compound was prepared from tert-butyl [2-(4-hydroxyphenyl)ethyl]carbamate (503mg, 2.12mmol) and 4-chlorophenylsulphonic acid, diphenylphosphinylmethyl ester (0.86g, 2.11 mmol) using a method similar to that in procedure 3, the product being isolated as a white foam (0.87g, 91%) on evaporation. δ'H (250MHz, CDC1₃): 1.41 (9H, s); 2.73 (2H, t); 3.32 (2H, m); 4.51 (IH, br s);

4.71 (2H, d); 6.87 (2H, d); 7.10 (2H, d); 7.46-7.64 (6H, m) and 7.90 (4H, m). m z 452 (MH⁺, 25%), 396 (40%) and 352 (100%)

Procedure 9: (R)-4-(2-Aminopropyl)phenoxymethyl diphenyl phosphine oxide.

Trifluoracetic acid (5ml) was added to a stirring solution of (R)-3-[4- (diphenylphosphinylmethyl)phenoxy]-2-propylcarbamic acid, tert-butyl ester (l .Og, 2.15mmol) in dichloromethane (25ml). After stirring for 1 hour, the mixture was evaporated and the residue re-dissolved in dichloromethane. Washed with aqueous sodium bicarbonate solution (x3) and brine. After drying (Na₂SO ), the solution was evaporated to afford the title compound as a pale yellow oil (0.74g, 94%):

δ^!H (200MHz, CDClj): 1.10 (3H, d); 2.45 (IH, m); 2.65 (IH, m); 3.12 (IH, m); 4.71 (2H, d); 6.85 (2H, d); 7.09 (2H, d); 7.45-7.63 (6H, m) and 7.89 (4H, m). m/z 366 (MH\ 100%).

Procedure 10: [4-(2-Aminoethyl)phenoxymethyljdiphenyI phosphine oxide

The title compound was prepared from (R)-2-[4-(diphenylphosphinyl- methyl)phenoxy]ethylcarbamic acid, tert-butyl ester (0.86g, 1.91mmol) employing a method similar to that used in procedure 9, isolating the compound as a pale yellow oil (0.65g, 97%) after evaporation.

δ^JH (250MHz, CDC1₃): 2.60-3.20 (4H, m); 4.71 (2H, d); 6.86 (2H, d); 7.10 (2H, d);

7.43-7.62 (6H, m) and 7.88 (4H, m). m/z 352 (MH⁺, 100%).

Procedure 11: (S)-Glycidyl-4-benzyloxyphenol

A mixture of 4-benzyloxyphenol (2.0g, 10 mMol) and potassium carbonate (4.14g, 30 mMol) in acetone (50 ml) was heated under reflux for 15 mins. (S)-Glycidyl-3- nitrobenzenesulphonate (2.23 g, 10 mMol) was added and the reaction mixture was heated under reflux for 18 hours. After cooling, the reaction mixture was filtered and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic fractions were combined, washed with water and brine, dried and evaporated to give the title compound as an oil.

δ*H (270MHz , CDCI3): 7.35 (5H, m), 6.87 (4H, m), 5.01 (2H, s), 4.16 (IH, dd, J=11.0, 3.3Hz), 3.91 (IH, dd, J=11.0, 5.8Hz), 3.34 (IH, m), 2.89 (IH, dd, J=5.0, 4.1Hz) and 2.74 (IH, dd, J=5.0, 2.8Hz) ppm.

Procedure 12: (S,R) Diphenyl-4-{2-l2-hydroxy-3-(4-benzyI oxyphenoxy)propylamino] propyl} phenoxymethylphosphine oxide.

Me

Lithium perchlorate (213mg, 2.0mmol) was added to a stirring solution of 2-(4- benzyloxyphenoxyrnethyl)-oxirane (512mgs, 2.0mmol) in acetonitrile (8ml). After 10 minutes a solution of (R)-4-(2-aminopropyl)phenoxymethyldiphenyl phosphine oxide (0.73g, 2.0mmol) in acetonitrile (7ml) was added. The reaction mixture was allowed to stir under argon atmosphere at room temperature for 2 days. Diluted with ethyl acetate and washed (water, then brine), dried (anhydrous MgSO₄), filtered and evaporated. Purification by column chromatography on silica gel afforded the title compound as a colourless paste (0.57g, 46%). δ1H (250MHz, CDCI₃): 1.11 (3H, d); 2.55→3.03 (7H, m); 3.90 (2H, m); 4.12 (IH, m); 4.71 (2H, d); 5.00 (2H, s); 6.75-6.91 (6H, m); 7.17 (2H, d); 7.31→7.45 (5H, m); 7.46- 7.61 (6H, m) and 7.87 (4H, m).

m z 622 (MH⁺, 100%)

Procedure 13: (S)-Diphenyl-4-{2-[2-hydroxy-3-(4- benzyloxyphenoxy)propylamino]ethyl}phenoxymethyl phosphine oxide.

The title compound was prepared from [4-(2-aminoethyl)phenoxymethyl] diphenyl phosphine oxide (0.64g, 1.82mmol) and 2-(4-benzyloxy-phenoxymethyl)oxirane (0.47g, 1.83mmol) by stirring together in methanol solution (35ml) at room temperature and under argon atmosphere for 7 days. The mixture was evaporated and subjected to column chromatography to afford the product as a colourless oil (0.36g, 33%).

δ*H (250MHz, CDCI₃): 2.70-2.99 (8H, m); 3.91 (2H, d); 4.12 (IH, m); 4.71 (2H, d); 4.99 (2H, s); 6.83 (6H, m); 7.11 (2H, d); 7.30-7.44 (5H, m); 7.45-7.62 (6H, m) and 7.85 (4H, m). m/z (API⁺), 630 (MNa⁺, 40%), 608 (MH⁺, 100%) and 217 (40%).

Procedure 14: Di(3-phenylpropyl)phosphine oxide

A solution of l-bromo-3-phenylpropane (6.0g, 30.1 mmol) in diethyl ether was added to a stirring mixture of magnesium metal turnings (0.73g, 30.0mmol) in diethyl ether (40ml). cooling in a cold water bath at 10°C and under argon atmosphere. Stirring was continued at 10°C for 20 mins and then at room temperature for 2 hours. After re-cooling a solution of diethyl phosphite (1.73g, 12.5mmol) in ether (10ml) was added dropwise resulting in the formation of a thick, gelatinous precipitate which was left for 'Λhour. Dichloromethane (50ml) was added to dissolve up the precipitate, and, after 'Λhour, the mixture was poured onto aqueous ammonium chloride solution. The organic phase was separated, the aqueous being re-extracted with dichloromethane. The combined organics were washed (water then brine), dried and concentrated. Purification by column chromatography afforded the title compound as a colourless oil (0.93g, 26%).

δ'H (250MHz, CDC1₃): 1.61-2.06 (8H, m); 2.72 (4H, m); 6.84 (IH, d, J ~ 450Hz, PH) and 7.09-7.34 (1 OH, m).

Procedure 15: Hydroxymethyl, di(3-phenylpropyl)phosphine oxide.

A mixture of di(3-phenylpropyl)phosphine oxide (0.92g, 3.21 mmol), paraformaldehyde (98mgs, 1 equiv.) and triethylamine (2ml) was heated to 85°C under argon atmosphere for about an hour. Concentration, then column chromatography of the residue afforded the title compound as a colourless oil (0.90g, 89%).

δ'H (250MHz, CDCI₃): 1.60-1.95 (8H, m); 2.67 (4H, m); 3.82 (2H, d); 4.78 (IH, q) and 7.10-7.33 (10H, m).

Procedure 16: 4-Chlorophenylsulphonic acid, di(3-phenyIpropyl)-phosphinylmethyl ester.

A solution of 4-chlorobenzenesulphonyl chloride (0.6 lg, 2.80mmol) in dichloromethane (5ml) was added dropwise to a stirring solution of hydroxymethyl, di(3- phenylpropyl)phosphine oxide (0.84g, 2.66mmol) and triethylamine (0.41ml, 2.94mmol) in dichloromethane (15ml), under argon atmosphere and with ice cooling. Stirring was continued at 0°C for one hour and then at room temperature for 4 hours. Diluted with dichloromethane and washed with brine. Dried, concentrated and chromatographed on silica to afford the title compound as a white solid (1.1 Og, 84%).

δ1H (250MHz, CDCI₃): 1.67-2.00 (8H, m); 2.69 (4H, m); 4.17 (2H, d); 7.09-7.34

(10H, m); 7.53 (2H, d) and 7.79 (2H, d) Procedure 17: (R)-3-{4-[Di(3-phenylpropyι)phosphinylmethyl]-phenoxy}-2- propylcarbamic acid, tert-butyl ester.

<-

The title compound was prepared from 4-chlorophenylsulphonic acid, di(3- phenylpropyl)phosphinylmethyl ester (1.1 Og, 2.24mmol) and tert-butyl (R)-3-(4- hydroxyphenyl)-2-propyl carbamate (563mgs, 2.24mmol) using a method similar to that 0 in procedure 3. After chromatography a colourless gum was obtained (0.97g, 79%).

δ1H (250MHz, CDCI₃): 1.08 (3H, d); 1.42 (9H, s); 1.77-2.03 (8H, m); 2.54-2.80 (4H, m); 3.86 (IH, m); 4.36 (IH, br s); 6.78 (2H, d) and 7.07-7.31 (12H, m).

5 Procedure 18: (R)-4-(2-Aminopropyl)phenoxymethyldi(3-phenylpropyl)phosphine oxide.

The title compound was prepared from (R)-3-{4-[di(3- 0 phenylpropyl(phosphinylmethyl]phenoxy}-2-propylcarbamic acid, tert-butyl ester (0.96g, 1.75mmol) and trifluoroacetic acid (4ml) in a manner similar to that employed for procedure 9, the product being isolated as a pale yellow oil (0.76g, 97%).

δ^!H (250MHz, CDCI₃): 1.11 (3H, d); 1.77-2.10 (8H, m); 2.48 (IH, m); 2.70 (5H, 5 m); 3.13 (IH, m); 4.20 (2H, d); 6.80 (2H, d) and 7.07-7.30 (12H, m). m/z: 450 (MH⁺, 100%) and 433 (60%).

0

Procedure 19: 4-Benzy.oxy-3-nitroacetophenone

Potassium carbonate (41.2g, 0.298moles) was addded portionwise to a rapidly stirring mixture of 4-hydroxy-3-nitroacetophenone (27.0g, 0.149moles) and benzyl bromide (16.0ml, 0.134moles) in acetone (500ml). The reaction mixture was then refluxed, with efficient stirring, for two days. The mixture was concentrated somewhat and the residue partitioned between water and ethyl acetate. The organic layer was separated and the aqueous re-extracted with ethyl acetate (χ2). The combined organics were washed with water and then with brine. Dried, filtered and evaporated to leave a fawn-coloured solid which-was recrystallised from ethanol. This afforded the title compound as fawn crystals (19.23g, 48%).

δ *H (250MHz, CDCI3): 2.61 (3H, s); 5.33 (2H, s); 7.19 (IH, d); 7.42 (5H, m); 8.12 (lH, dd) and 8.46 (lH, d).

Procedure 20: Acetic acid, (4-benzyloxy-3-nitrophenyl)ester

3-Chloroperoxybenzoic acid (a total of 48.0g of approx 60% material) was added in four batches to a refluxing solution of 4-benzyloxy-3-nitroacetophenone (19.23g, 0.0709moles) and 4-toluenesulphonic acid monohydrate (l.Og, 5.3mmol) in dichloromethane (360ml) at approx. 24 hour intervals. After a final 24 hours of refluxing the reaction mixture was cooled slightly before pouring onto a stirring solution of aqueous sodium sulphite. After 20 minutes' stirring the organic phase was separated and washed with aqeous sodium hydrogen carbonate solution until the washes remained at pHlO. Washed with brine and then dried, filtered and concentrated to afford the title compound as a yellow solid (18.82g, 92%).

δ »H (250MHz, CDCI3): 2.31 (3H, s); 5.22 (2H, s); 7.11 (IH, d); 7.23 - 7.49 (6H, m) and 7.67 (lH, d).

Procedure 21: Acetic acid, (3-amino-4-benzyloxyphenyl) ester

A mixture of acetic acid, (4-benzyloxy-3-nitrophenyl) ester (4.50g) and platinum IV oxide (150mg) in dichloromethane (90ml) was hydrogenated at atmospheric pressure of H2 and at room temperature for 19 hours. The mixture was filtered through kieselguhr and the filtrate evaporated in vacuo to afford the title compound as a brown oil, 4.0g.

δ ^lU (250MHz, CDCI3): 2.26 (3H, s); 3.68 (2H, broad s); 5.06 (2H, s); 6.40 (IH, dd); 6.47 (IH, dd); 6.79 (IH, d) and 7.38 (5H, m). Procedure 22: Acetic acid, (4-benzyloxy-3-phenylsulphonylamino phenyl)ester

The title compound was prepared from acetic acid, (3-amino-4-benzyloxy phenyl)ester (3.67g, 14.28mmol) and benzenesulphonyl chloride using a method similar to that described in procedure 26. The compound was isolated as a white solid after chromatography (2.31 g, 41 %).

δ ^]H (250MHz, CDCΪ3): 2.29 (3H, s); 4.84 (2H, s); 6.73 (2H, s); 7.04 (IH, br s); 7.17 (2H, m); 7.38 (6H, m); 7.52 (IH, m) and 7.75 (2H, d).

Procedure 23: Acetic acid, 4-benzyloxy-3-(N- er/- butoxycarbonyι)pheny.sulphonylaminophenyl ester

The title compound was prepared from acetic acid (4-benzyloxy-3 -phenyl sulphonylaminophenyl)ester (2.20g,5.54mmol) and di-tert-butyldicarbonate employing a method similar to that of procedure 27, isolating the compound as a beige solid (2.69g, 98%). δ (250MHz, CDCI3): 1.28 (9H, s); 2.29 (3H, s); 5.02 (2H, s); 7.01 (IH, d); 7.14 - 7.33 (9H, m); 7.45 (IH, d) and 7.79 (2H, dd).

Procedure 24: 4-Benzyloxy-3-(N-tert-butoxycarbonyl)phenyl-sulphonylamino phenol

A solution of sodium hydroxide (0.249g, 6.22mmol) in water (5ml) was added to a stirring solution of acetic acid, 4-benzyloxy-3-(N-tert- butoxycarbonyl)phenylsulphonylaminophenyl ester (2.69g, 5.41mmol) in methanol

(10ml) and dichloromethane (10ml). After stirring for 20 minutes aqueous citric acid was added until neutralisation was achieved. The mixture was concentrated and the then re¬ dissolved in dichloromethane and washed with water. Dried and then evaporated to afford the title compound as a beige-coloured solid (2.39g, 97%).

δ »H (250MHz, CDCI3): 1.24 (9H, s); 4.82 (IH, s); 4.98 (2H, s); 6.91 (2H, m); 6.96 (IH, m); 7.18 - 7.30 (7H, m); 7.45 (IH, t) and 7.98 (2H, dd).

Procedure 25: (S)-2-[4-Benzyloxy-3-(N-/er/-butoxycarbonyl)phenyl- sulphonylamino]phenoxy methyl oxirane

The title compound was prepared from 4-benzyloxy-3-(N-tert-butoxy carbonyl)phenylsulphonylamino phenol (2.33g, 4.90mmol) and (2S)-(+)-glycidyl-3- nitrobenzenesulphonate (1.27g, 4.90mmol) using a method similar to that in procedure 29. The compound was isolated as a white solid (2.32g, 93%) after chromatography.

δ >H (250MHz, CDCI3): 1.23 (9H, s); 2.78 (IH, m); 2.92 (IH, t); 3.36 (IH, m); 3.95 (IH, m); 4.22 (IH, dd); 4.98 (2H, s); 6.96 (2H, br s); 7.15 (IH, m); 7.23 (7H, m); 7.45 (lH, m) and 7.98 (2H, dd).

Procedure 26: Acetic acid, [4-benzyloxy-3-(4-chIorophenyl)- sulphony laminopheny I] ester

A solution of 4-chlorobenzenesulphonyl chloride (0.776g, 3.67mmol) in dichloromethane (8ml) was added dropwise to a stirring solution of acetic acid, (3-amino-4- benzyloxyphenyl) ester (0.86g, 3.34mmol) and pyridine (0.33ml, 4.08mmol) in dichloromethane (22ml). After stirring at room temperature for 21 hours under an atmosphere of argon, the mixture was diluted with dichloromethane and washed successively with water, aqueous sodium bicarbonate solution and finally brine. Dried over anhydrous sodium sulphate, filtered and evaporated. Column chromatography on silica gel, elution with ethyl acetate-pentane gradient, afforded the title compound as an orange oil (1.06g, 73%).

δ »H (250MHz, CDCI3): 2.29 (3H, s); 4.87 (2H, s); 7.00 (IH, broad s, NH); 7.13 (3Η, m); 7.30 - 7.48 (7H, m) and 7.65 (2H, d).

Procedure 27: Acetic acid, 4-benzyIoxy-3-[N-/<?rt-butoxycarbonyl, (4- chlorophenyl)sulphonylamino]phenyl ester

4-Dimethylaminopyridine (60mg) was added in one portion to a stirring solution of acetic acid, [4-benzyloxy-3-(4-chlorophenyl)sulphonyl aminophenyl]ester (1.05g, 2.43mmol) and ti-tert-butyl dicarbonate (0.64g, 2.93mmol) in dichloromethane (25ml). The mixture was allowed to stir at room temperature for 5hrs and was then evaporated in vacuo. Column chromatography on silica gel, elution with dichloromethane, afforded the title compound as a white foam (0.9 lg, 70%).

δ »H (250MHz, CDCI3): 1.29 (9H, s); 2.31 (3H, s); 5.01 (2H, s); 7.02 (IH, d); 7.18 (6H, m); 7.31 (3H, ) and 7.89 (2H, d).

Procedure 28: 4-Benzyloxy-3-[N-ter/-butoxycarbonyl, (4- chlorophenyl)sulphonylamino]phenol

Aqueous sodium hydrogen carbonate (4ml of a saturated solution) was added to a stirring solution of acetic acid, 4-benzyloxy-3-[N-ter/-butoxycarbonyl, (4- chloropheny l)sulphony lamino]pheny 1 ester (0.91 g, 1.71 mmol) in methanol (6ml) and dichloromethane (10ml). After stirring at room temperature for 4 days, the mixture was diluted with dichloromethane and washed with dilute aqueous citric acid. The organic phase was separated and the aqueous re-extracted with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulphate, filtered and then evaporated in vacuo to afford the title compound as a white foam (0.76g, 91%)r

δ (250MHz, CDCI3): 1.30 (9H, s); 4.95 (2H, s); 5.09 (IH, s); 6.91 (3H, m); 7.18 (4H, m); 7.31 (3H, m) and 7.91 (2H, d).

Procedure 29: (S)-2-{4-Benzyloxy-3-[N-ter/-butoxycarbonyl, (4- chlorophenyl)sulphonylamino)phenoxymethyl}oxirane

Potassium carbonate (0.62g, 4.48mmol) was added to a stirring solution of 4-benzyloxy- 3-[N-tert-butoxycarbonyl, (4-chlorophenyl)sulphonylamino]phenol (0.73g, 1.49mmol) in dry acetone (50ml). The mixture was refluxed for 10 minutes under argon atmosphere and then re-cooled to room temperature. (2S)-(+)-Glycidyl-3-nitrobenzene sulphonate (0.50g, 1.93mmol) was added and the mixture was then refluxed for 19 hours under argon. Poured onto a half-saturated aqueous solution of ammonium chloride and extracted into ethyl acetate (χ2). The combined extracts were washed with brine, dried over anhydrous sodium sulphate and filtered. Evaporation followed by column chromatography on silica gel, elution with ethyl acetate-pentane gradient afforded the title compound as a white foam (0.77g, 95%).

δ ^JH (250MHz, CDCI3): 1.29 (9H, s); 2.78 (IH, m); 2.93 (IH, t); 3.38 (IH, m); 3.94 (IH, dd); 4.25 (IH, dd); 4.96 (2H, s); 7.01 (3H, m); 7.16 (4H, m); 7.30 (3H, m) and 7.90 (2H, d). Procedure 30: Acetic acid, (4-benzyloxy-3-methanesuIphonylaminophenyl)ester

Acetic acid, (3-amino-4-benzyloxyphenyl)ester (1.70g, 6.61 mMol) in dichloromethane (35ml) was treated with triethylamine (0.802g, 7.93mMol) and methanesulphonyl chloride (0.832g, 7.27mMol) and the mixture stirred at room temperature under argon for 20 minutes. The solution was washed with water (3x10ml), dried and the solvent evaporated in vacuo. Trituration with diethyl ether gave the title compound as an off- white solid.

δ1H (250MHz, CDC1₃): 7.40 (5H, m); 7.33 (IH, d, J=2.2Hz); 6.96 (IH, d, J=8.5Hz); 6.88 (IH, br s); 6.84 (IH, dd, J=8.2Hz and 2.1Hz); 5.08 (2H, s); 2.94 (3H, s); 2.31 (3H, s).

Procedure 31: Acetic acid, 4-benzyloxy-3-(N-/er/-butoxycarbonyl)methane- sulphonylaminophenyl ester

To a solution of acetic acid, (4-benzyloxy-3-methanesulphonylaminophenyl)ester (0.9g, 2.69mMol) in dichloromethane (10ml) was added di-tert-butyl dicarbonate (0.704g, 3.23mMol) and 4-dimethylaminopyridine (0.065g, 0.54mMol) at room temperature under argon. The mixture was stirred at room temperature for 1 hour after which the solvent was evaporated in vacuo. Purification by column chromatography on Kieselgel 60 eluting with diethyl ether gave the title compound as a white foam.

δ'H (250MHz, CDC1₃): 7.38 (5H, m); 7.15 (2H, m); 6.96 (IH, d, J=8.6Hz); 5.08 (2H, s); 3.24 (3H, s); 2.27 (3H, s); 1.40 (9H, s).

Procedure 32 : 4-Benzyloxy-3-(N-/er/-butoxycarbony l)methanesulphonyl- aminophenol

To a solution of acetic acid, 4-benzyloxy-3-(N-tert-butoxycarbonyl)- methanesulphonylaminophenyl ester (1.16g, 2.67mMol) in a mixture of methanol (10ml) and water (5ml) was added IM sodium hydroxide solution (3.20mMol) at room temperature. The mixture was stirred for 10 minutes and citric acid added to adjust to pH 6-7. The solvent was evaporated in vacuo and the residue taken up into dichloromethane (30ml), washed with water (3x15ml) and dried. Evaporation ofthe solvent gave the title compound as a white foam.

δ'H (250MHz, CDCI₃): 7.37 (5H, m); 6.82 (3H, m); 5.09 (2H, s); 4.95 (IH, br s); 3.24 (3H, s); 1.42 (9H, s).

Procedure 33: (5)-2-[4-Beiizyloxy-3-(N-tert^,-butoxycarbonyl)- methanesulphony lamino] phenoxy methy loxirane

To a solution of 4-benzyloxy-3-(N-tert-butoxycarbonyl)methanesulphonyl-aminophenol (3.90g, 9.92mMol) in acetone (75ml) at room temperature under argon was added potassium carbonate (2.74g, 19.85mMol). (2S)-(+)-Glycidyl-3-nitrobenzenesulphonate (2.57g, 9.92mMol) was added portionwise and the reaction mixture was heated at reflux for 40 hours. The solvent was removed under reduced pressure. The residue was taken into ethyl acetate and washed with water (2x25ml). The organic extracts were dried (Νa2Sθ4) and the solvent evaporated in vacuo. The crude product was purified by chromatography over normal phase silica eluting with 80% hexane in ether to give the title compound as a white foam.

δ1H (250MHz, CDCI₃): 7.35 (5H, m); 6.94 (3H, m); 5.05 (2H, s); 4.20 (IH, dd, J=l 1Hz and 2.7Hz); 3.90 (IH, m); 3.35 (IH, m); 3.25 (3H, s), 2.92 (IH, m); 2.77 (IH, m); 1.42 (9H, s). Procedure 34: (S,R)-Di(3-phenylpropyl)-4-{2-[3-(4-benzyloxy-3- methanesulphonylaminophenoxy)-2-hydroxypropylamino]propyl}-phenoxymethyl phosphine oxide.

Me

Lithium perchlorate (83mgs, 0.78mmol) was added to a stirring solution of (S)-(2- ben2yloxy-5-oxiranylmethoxyphenyl)-N(tert-butoxycarbonyl)-methanesulphonamide (350mgs, O δmmol) in dry acetonitrile (6ml). After 10 mins a solution of (R)-4-(2- aminopropyl)-phenoxymethyl di(3-phenylpropyl)phosphine oxide (350mgs, 0.78mmol) in dry acetonitrile (3ml) was added. The mixture was stirred under argon atmosphere at room temperature for 4 days. Diluted with ethyl acetate and washed with brine. Dried, filtered and evaporated to afford a pale foam (0.66g) which was re-dissolved in methanol (15ml). Dilute aqueous hydrochloric acid (2.5M, 5ml) was added and the mixture heated to 45°C for 7 hours and then at 40°C for 20 hours;neutralised with aqueous sodium hydrogen carbonate solution and extracted into ethyl acetate (x2). The extracts were washed (brine), dried and concentrated. Column chromatography on silica gel afforded the title compound as a colourless gum (0.29g, 47%).

δ*H (250MHz, CDC1₃): 1.11 (3H, d); 1.78-2.05 (8H, m); 2.57-3.01 (14H, m); 3.90 (2H, d); 4.00 (IH, m); 4.20 (2H, d); 5.04 (2H, s); 6.62 (IH, dd); 6.80 (2H, d); 6.89 (IH, d); 7.08-7.30 (13H, ) and 7.42 (5H, m). m/z (FAB) 799 (MH⁺, 35%).

Procedure 35: (S)-Diphenyl-4-{2-[2-hydroxy-3-(4-benzyloxy-3-(4- chlorophenylsulphonylamino)phenoxy)propylamino]ethyI}phenoxymethylphosphin e oxide

Lithium perchlorate (lOOmgs, 0.94mmol) was added to a stirring solution of (S)-2-{4- benzyloxy-3-[N-tert-butoxycarbonyl, (4-chlorophenyl)- sulphonylaminojphenoxymethyl} oxirane (0.48g, 0.88mmol) in dry acetonitrile (12ml). After 15 minutes a suspension of [4-(2-aminoethyl)phenoxymethyl]diphenyl phosphine oxide (0.33g, 0.94mmol) in dry acetonitrile (8ml) was added, and the mixture allowed to stir at room temperature for 4 days under an atmosphere of argon. Diluted with ethyl acetate and washed with water and then with brine. Dried, filtered and concentrated to afford an opaque, yellow oil which was subjected to column chromatography, eluting with methanol-ethyl acetate gradient. The resultant gum (120mgs) was re-dissolved in methanol (5ml) and dilute aqueous hydrochloric acid (2.5M, 2ml). After heating to 45°C for 4 days the mixture was diluted with ethyl acetate and neutralised on aqueous sodium hydrogen carbonate solution. The organic phase was brine-washed, dried and concentrated. Column chromatography on silica gel afforded the title compound as a fawn-coloured gum (90mgs, 13%).

δ (250MHz, CDCI3): 2.74 - 2.98 (6H, m); 3.10 - 3.50 (3H, broad s, exchangeables); 3.89 (2H, d); 4.08 (IH, m); 4.69 (2H, d); 4.78 (2H, s); 6.56 (IH, dd);

6.68 (IH, d); 6.84 (2H, d); 7.12 (5H, m); 7.28 (5H, m); 7.42 - 7.63 (8H, m) and 7.84 (4H, m).

Procedure 36: (S)-Diphenyl-4-{2-[2-hydroxy-3-(4-benzyloxy-3- phenylsulphonylaminophenoxy)propylamino] ethyl} phenoxy methyl phosphine oxide

The title compound was prepared from (S)-2-[4-benzyloxy-3-(N-tert- butoxycarbonyl)phenylsulphonylamino]phenoxymethyl oxirane (0.49g, 0.96mmol) and [4-(2-aminoethyl)phenoxymethyl]diphenyl phosphine oxide (0.40g, 1.14mmol) employing a method similar to that in procedure 35, isolating the compound as a dirty- white foam (0.25g, 34%).

δ »H (250MHz, CDCI3): 2.50 - 2.95 (9H, m, inc. exchangeables); 3.89 (2H, d); 4.07 (IH, m); 4.71 (2H, d); 4.77 (2H, s) 6.51 (IH, dd); 6.66 (IH, d); 6.85 (2H, d); 7.03 - 7.59 (17H, m); 7.71 (2H, d) and 7.85 (4H, m).

Procedure 37: (S,R)-Diphenyl-4-{2-[3-(4-benzyloxy-3-methane sulphonylaminophenoxy)-2-hydroxypropylamino)propyl}-phenoxymethyI phosphine oxide.

The title compound was prepared from (S)-(2-benzyloxy-5-oxiranylmethoxyphenyl)-N- (tert-butyoxycarbonyl)methansulphonamide and (R)-4-(2-aminopropyl)phenoxymethyl diphenyl phosphine oxide in a manner similar to that employed for Procedure 35, to give a beige foam.

δ*H (250MHz, CDCI₃): 7.81 (4H, m); 7.52 (6H, m); 7.36 (5H, m); 7.08 (3H, m); 6.83 (3H, m); 6.57 (IH, dd); 5.0 (2H, s); 4.73 (2H, d); 4.27 (IH, m); 3.89 (2H, m); 3.42 (IH, m); 3.23 (2H, d); 3.06 (IH, m); 2.97 (3H, s); 2.81 (IH, m); 1.26 (3H, d). m/z: MH⁺ 715

Procedure 38: (S)-Diphenyl-4-{2-[2-hydroxy-3-(4-benzyloxy-3- methanesulphonylaminophenoxy)propylamino]ethyl}phenoxymethyl phosphine oxide

The title compound was prepared from (S)-2-[4-benzyloxy-3-(N-tert-butoxy carbonyl)methanesulphonylamino]phenoxymethyl oxirane (0.45g, l.Ommol) and [4-(2- aminoethyl)phenoxymethyl]diphenyl phosphine oxide (0.39g, 1.1 lmmol) using a method similar to that in procedure 35. The compound was isolated as an off-white gum (0.2 lg, 30%).

δ'H (250MHz, CDCI3): 2.69 - 3.14 (9H, m); 3.89 (2H, m); 4.00 (IH, m); 4.70 (2H, d); 5.04 (2H, s); 6.62 (IH, dd); 6.87 (3H, m); 7.13 (3H, m); 7.38 (5H, m); 7.53 (6H, m) and 7.86 (4H, ). Procedure 39: Acetic acid, (4-benzyIoxy-3-ύø-propylsuIphonylaminophenyl)ester

4-Dimethylaminopyridine (0.70g) was added portionwise to a stirring solution of acetic acid, (3-amino-4-benzyloxyphenyl) ester (4.10 g, 15.9 mmol) and propane-2-sulphonyl chloride (2.50 ml) in toluene (60 ml). The mixture was stirred at room temperature under an atmosphere of argon for 6 days. Diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate solution and then with aqueous ammonium chloride solution. Dried over anhydrous sodium sulphate, filtered and concentrated. The title compound was isolated as a yellow solid after chromatography (2.30 g, 40%).

δ*H (250 MHz, CDCI3): 1.44 (6H, d); 2.28 (3H, s); 3.29 (IH, m); 5.10 (2H, s); 6.80 (2H, m); 6.94 (IH, d) and 7.40 (6H, m).

Procedure 40: Acetic acid, 4-benzyloxy-3-(N-/.?rf-butoxycarbonyl)-wø-propyl- sulphonylatninophenyl ester

The title compound was prepared from acetic acid, (4-benzyloxy-3-wø- propylsulphonylaminophenyl) ester (2.95 g, 8.13 mmol) and di-tert-butyldicarbonate employing a method similar to that used in procedure 27, isolating the compound as a lemon-yellow coloured foam (2.95g, 78%).

δ iH (250 MHz, CDCI3): 1.39 (15H, s); 2.28 (3H, s); 4.12 (IH, m); 5.11 (2H, br s); 6.95 (IH, d); 7.11 (2H, m) and 7.37 (5H, m). Procedure 41: 4-Benzyloxy-3-(N-/<?r/-butoxycarbonyl)-«o-propyI sulphonylamino phenol

The title compound was prepared from acetic acid, 4-benzyloxy-3-(N-/ert- butoxycarbonyl)-wo-propylsulphonylaminophenyl ester (2.92g, 6.31 mmol) using a method similar to that in procedure 24, isolating a brown foam (2.59g, 98%).

δ*H (250 MHz, CDCI3): 1.40 (15H, s); 4.12 (IH, m); 5.04 (3H, m); 6.78 (3H, m) and 7.38 (5H, m).

Procedure 42: (S)-2-[4-Benzyloxy-3-(N- ert-butoxycarbonyl) iso propyl- sulphonylamino] phenoxy methyl oxirane

The title compound was prepared from 4-benzyloxy-3-(N-tert-butoxycarbonyl) iso propylamino phenol (2.56 g, 6.08 mmol) and (2S)-(+) glycidyl-3-nitrobenzene sulphonate (2.05 g) employing a method similar to that used in procedure 29. After chromatography the compound was isolated as a yellow oil (2.62g, 90%).

δ iH (250 MHz, CDCI3): 1.40 (15H, s); 2.75 (IH, m); 2.91 (IH, t); 3.34 (IH, m); 3.90 (IH, dd); 4.15 (2H, m); 5.06 (2H, br s); 6.90 (3H, s) and 7.37 (5H, m).

Procedure 43: (S)-Diphenyl-4-{2-[2-hydroxy-3-(4-benzyloxy-3-wø-propylsulphonyl aminophenoxy)propylamino]ethyl}phenoxymethyl phosphine oxide

The title compound was prepared from (S)-2-[4-benzyloxy-3-(N-tert-butoxycarbonyl)- wø-propylsulphonylamino]phenoxymethyl oxirane (0.63 g, 1.32 mmol) and [4-(2- aminoethyl)phenoxymethyl]diphenyl phosphine oxide (0.50 g, 1.42 mmol) employing a method similar to that used in procedure 35. The compound was isolated as a white foam (0.40 g, 42%).

δ ^XH (250 MHz, CDC1₃): 1.33 (6H, d); 2.72 - 3.00 (6H, m); 3.24 (IH, m); 3.89 (2H, d); 4.09 (IH, m); 4.71 (2H, d); 5.03 (2H, s); 6.55 (IH, dd); 6.85 (3H, d); 7.1 1 (2H, d); 7.20 (IH, d); 7.31 - 7.64 (1 IH, m) and 7.87 (4H, m).

Procedure 44: Dimethyl phosphine oxide

A solution of diethyl phosphite (2.0 ml, 15.52 mmol) in tetrahydrofuran was added over 30 minutes to a stirring solution of methyl magnesium chloride (48.0 mmol) in tetrahydrofuran with cooling to 0°C and under an atmosphere of argon. After stirring at 0°C for ³λ hour and then at room temperature for 1 hour the mixture was poured carefully onto an ice-cooled solution containing potassium carbonate (6.63 g) in water (10 ml). After several minutes the resulting suspension was filtered under suction through kieselguhr, washing the precipitate several times with ethanol. The filtrate was then concentrated under reduced pressure (~10 mmHg), taken up in ethanol and dried over 4A molecular sieves. Filtration of the solution and re-evaporation under reduced pressure (-10 mmHg) left an opaque oil (0.95g, 78%).

δ ^lH (250 MHz, CDCI3): 1.62 (6H, dd) and 7.20 (IH, 2χm, J = 460 Hz)

Procedure 45: 4-Chlorophenylsulphonic acid, dimethyl phosphinylmethyl ester

A mixture of dimethyl phosphine oxide (0.94 g) and paraformaldehyde (362 mg) in triethylamine was heated to 80°C under an atmosphere of argon for one hour. The resulting mixture was then evaporated under reduced pressure (~10 mmHg) to give crude dimethyl, hydroxymethyl phosphine oxide which was taken up in dichloromethane and cooled in an ice/ethanol bath. Triethylamine (2.0 ml) was added followed by a solution of 4-chlorophenylsulphonyl chloride (3.0g) in dichloromethane, which was added dropwise under an atmosphere of argon. The reaction mixture was stirred at reduced temperature for ³A hour and then at room temperature for 20 hours. Diluted with dichloromethane and washed with aqueous sodium hydrogen carbonate solution, then with aqueous ammonium chloride solution and finally with saturated brine. Dried over anhydrous sodium sulphate, filtered and evaporated. Purification by column chromatography on silica gel afforded the title compound as a cream coloured solid (0.70 g, 21%). δ *H (250 MHz, CDC1₃): 1.60 (6H, d); 4.20 (2H, d); 7.59 (2H, d) and 7.86 (2H, d).

Procedure 46: 2-[4-(Dimethylphosphinylmethyl)phenoxy]ethylcarbamic acid, tert- butyl ester

The title compound was prepared from 4-chlorophenylsulphonic acid, dimethylsphosphinylmethyl ester (0.69 g, 2.44 mmol) and tert-butyl [2-(4- hydroxyphenyl)ethyl]carbamate (0.58 g, 2.45 mmol) using a method similar to that used in procedure 3, the product being isolated as a beige-coloured solid (0.68 g, 85%).

δ *H (250 MHz, CDCI3): 1.44 (9H, s); 1.66 (6H, d); 2.75 (2H, t); 3.33 (2H, m); 4.22 (2H, d); 4.54 (IH, broad s); 6.87 (2H, d) and 7.14 (2H, d).

Procedure 47: [4-(2-Aminoethyl)phenoxymethyl]dimethylphosphine oxide

The title compound was prepared from 2-[4-(dimethylphosphinylmethyl)phenoxy]ethyl- carbamic acid, tert-butyl ester (0.67 g, 2.05 mmol) employing a method similar to that of procedure 9, but using n-butanol to extract the product. This gave the product as a white semi-solid (0.50 g, still containing some n-butanol) after evaporation.

δ ^lH (250 MHz, CD3OD): 1.69 (6H, d); 2.83 (2H, t); 3.01 (2H, t); 4.37 (2H, d); 7.01 (2H, d) and 7.21 (2H, d).

Procedure 48: (S)-Dimethyl-4-{2-[2-hydroxy-3-(4-benzyloxyphenoxy)propylaminoJ- ethyl}phenoxymethyl phosphine oxide

The title compound was prepared from [4-(2-aminoethyl)phenoxymethyl]dimethyl phosphine oxide (0.37 g, 1.63 mmol) and 2-(4-benzyloxyphenoxymethyl)oxirane (0.41 g, 1.60 mmol) in a manner similar to that used in procedure 13. After chromatography, a white foam (0.23 g, 30%) was isolated.

δ *H (250 MHz, CD3OD): 1.67 (6H, d); 2.97 (2H, m); 3.06 - 3.44 (4H, m, overlapping methanol signal); 3.94 (2H, m); 4.20 (IH, m); 4.35 (2H, d); 5.01 (2H, s); 6.82 - 7.06 (6H, m) and 7.20 - 7.46 (7H, m).

Procedure 49: Acetic Acid, (4-benzyloxy-3-(l-naphthylsulphonylamino)phenyl) ester

The title compound was prepared from acetic acid, (3-amino-4-benzyloxyphenyl) ester (6.97 mmol) and 1-naphthylsulphonyl chloride using a method similar to that described in procedure 26. The compound was isolated as a pale pink solid (1.94g, 62%).

δ *H (250 MHz, CDCI3): 2.27 (3H, s); 4.65 (2H, s); 6.50 - 6.70 (2H, m); 6.98 (2H, m); 7.25 - 7.60 (8H, overlapping m); 7.90 (IH, d); 8.02 (IH, d); 8.22 (IH, d) and 8.59 (lH, d).

Procedure 50: Acetic acid, 4-benzyloxy-3-[(N-/er/-butoxycarbonyI)-l- naphthylsulphonylaminoj-phenyl ester

The title compound was prepared from acetic acid (4-benzyloxy-3-(l- naphthylsulphonylamino)phenyl ester (1.91g, 4.27 mmol) and di-tert-butyl dicarbonate employing a method similar to that of procedure 27, isolating the compound as a light brown foam (2.34g, 100%) that was used without further purification.

δ ΪH (250 MHz, CDC1₃): 1.20 (9H, s); 2.32 (3H, s); 4.51 (IH, br d); 4.80 (IH, br d); 6.75 (2H, d); 6.89 (IH, d); 7.05 - 7.25 (4H, m); 7.35 - 7.57; (4H, m); 7.80 (IH, m); 8.00 (IH, d); 8.28 (IH, m) and 8.57 (IH, d).

Procedure 51 : 4-Benzyloxy-3-[(N-/er/-butoxycarbonyI)-l-naphthylsulphonyl-amino]- phenol

The title compound was prepared from acetic acid 4-benzyloxy-3-[(N-tert- butoxycarbonyl)-l-naphthylsulphonylamino] phenyl ester (2.39g, 4.37 mmol) and sodium hydroxide by a method similar to that of procedure 24. After purification by column chromatography the title compound (2.09g, 95%) was obtained as a pale brown solid.

δ iH (250 MHz, CDCI3): 1.20 (9H, s); 4.36 (IH, br d); 4.70 (IH, br d); 5.00 (IH, br s); 6.63 (2H, d); 6.78 (IH, d); 6.92 (IH, dd); 7.00 - 7.20 (4H, m); 7.30 - 7.55 (3H, m); 7.76 (IH, d); 7.99 (IH, d); 8.26 (IH, d) and 8.56 (IH, d). Procedure 52: (S)-2-(4-Benzyloxy-3-([N-/er/-butoxycarbonyl]-l-naphthyl- sulphonylamino)phenoxymethyl)oxirane.

The title compound was prepared from 4-benzyloxy-3-[(N-tert-butoxycarbonyl)-l- naphthylsulphonylamino]phenol (2.03g, 4.02 mmol) and (S)-(+)-glycidyl-3- nitrobenzenesulphonate (1.35g, 5.21 mmol) by a method similar to that employed in procedure 29. The compound was isolated as a white solid (0.96g, 42%) after chromatography.

δ !H (250 MHz, CDC1₃): 1.20 (9H, s); 2.80 (IH, dd); 2.95 (IH, t); 3.41 (IH, m); 4.00 (IH, dd); 4.29 (IH, dd); 4.38 (IH, br d); 4.71 (IH, br d); 6.64 (2H, d); 6.82 (IH, d); 6.96 - 7.23 (5H, m); 7.39 - 7.55 (3H, m); 7.78 (IH, d); 7.99 (IH, d); 8.24 (IH, d) and 8.57 (IH, d).

Procedure 53: (S)-Diphenyl-4-{2-[2-hydroxy-3-(4-benzyloxy-3-(l-naphthyl- sulphonylamino)phenoxy)propylamino]ethyl}phenoxymethylphosphine oxide, trifluoroacetate salt.

[4-(2-Aminoethyl)phenoxymethyl]diphenylphosphine oxide (0.75g, 2.14 mmol) was added to a solution of (S)-2-{4-benzyloxy-3-([N-tert-butoxycarbonyl]-l- naphthylsulphonylamino)phenoxymethyl} oxirane (0.465g, 0.83 mmol) in dichloromethane (10ml) and stirred under argon at room temperature for 12 days. After evaporation to dryness the mixture was chromatographed on silica to give a clear gum. The gum was redissolved in dichloromethane (25 ml), trifluoroacetic acid (2.5 ml) added and the mixture stirred ovemight. After evaporation to dryness the title compound was obtained as a yellow gum (0.35g, 46%).

^m/z (API+): 813 (MH+, 7%). Procedure 54: Acetic acid, [4-benzyloxy-3-trifluoromethane-sulphonylaminophenyl] ester

Acetic acid, (3-amino-4-benzyloxyphenyl) ester (13.9 mmol) in dichloromethane (40ml) with 2,6-lutidine (1.79ml) was cooled to -60°C under argon and trifluoromethanesulphonic anhydride (2.22ml, 0.95 equiv.) in dichloromethane (20ml) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight and then washed with citric acid. The aqueous layer was extracted with dichloromethane ( 2) and the combined organics washed with brine and evaporated to dryness. The title compound was isolated as a yellow solid (2.83g, 52%) after purification by column chromatography.

δ*H (250MHz, CDCI3): 2.27 (3H, s); 5.10 (2H, s); 6.95 (2H, m); 7.22 (IH, br s) and 7.27 - 7.50 (6H, m).

Procedure 55: Acetic acid, [4-Benzyloxy-3-[N-(4-methoxybenzyl)- trifluoromethanesulphonylamino]phenyl] ester.

Acetic acid, [4-benzyloxy-3-trifluoromethanesulphonylaminophenyl]ester (lg, 2.57 mmol) was alkylated with 4-methoxybenzyl chloride under standard alkylating conditions (potassium carbonate in acetone at reflux ovemight). The title compound was obtained as a white solid (1.26g, 96%) after purification by column chromatography.

δ!H (250MHz, CDCI3): 2.22 (3H, s); 3.76 (3H, s); 4.55 - 5.15 (4H, br overlapping s with m); 6.72 (3H, m); 6.85 - 7.10 (4H, m) and 7.40 (5H, m). Procedure 56: 4-Benzyloxy-3-[N-(4-methoxybenzyl)-trifluoromethanesulphonyl- aminojphenol

The title compound was obtained as a colourless gum (0.9 lg, 100%) from acetic acid, [4- benzyloxy-3-[N-(4-methoxybenzyl)-trifluoromethanesulphonylamino]phenyl] ester

(0.99g, 1.94 mmol) employing a method similar to that of procedure 24.

δ*H (250MHz, CDC1₃): 3.75 (3H, s); 4.50 (IH, s); 4.53 - 5.1 (4H, overlapping br m with s at 5.04); 6.43 (IH, d); 6.75 (3H, m); 6.85 (IH, d); 7.02 (2H, d) and 7.41 (5H, m).

Procedure 57: (S)-2-[4-Benzyloxy-3-(N-4-methoxybenzyl)triiluoromethane- sulphony lamino] phenoxy meth l oxirane.

The title compound was obtained as a white solid (0.52g, 42%) from 4-benzyloxy-3-[N- (4-methoxybenzyl)-trifluoromethanesulphonylamino]phenol (1.12g, 2.4 mmol) and (2S)- (+)-glycidyl-3-nitrobenzenesulphonate (0.8 lg, 3.13mmol) using a method similar to that of procedure 29.

δtø (250MHz, CDCI3): 2.67 (IH, dd); 2.85 (IH, t); 3.22 (IH, m); 3.76 (4H, s and overlapping br m); 4.01 (IH, br m); 4.52 - 5.15 (4H, overlapping br m and s at 5.05); 6.50 (IH, d); 6.72 (2H, d); 6.87 (2H, m); 7.02 (2H, d) and 7.42 (5H, ). Procedure 58: (S)-Diphenyl-4-{2-[2-hydroxy-3-(4-benzyloxy-3-[(N-4- methoxybenzyl)-trifluoromethane- sulphonylamino] phenoxy)propylamino]ethyl} phenoxy methylphosphine oxide

The title compound (0.58g, 70%) was obtained was a white gum from [4-(2- aminoethyl)phenoxymethyl]diphenylphosphine oxide (2g, 5.7 mmol) and (S)-2-[4- benzyloxy-3-[(N-4-memoxybenzyl)-rrifluoromemanesulphonylamino]phenoxymethyl oxirane (0.49g, 0.936 mmol) by a method similar to that of procedure 53 using ethanol as a cosolvent.

δ!H (250MHz, CDC1₃): 2.58 - 2.94 (6H, overlapping m); 3.74 (5H, overlapping s and br m); 3.89 (IH, m); 4.53 - 5.10 (6H, overlapping br m with d (at 4.70) and s (at 5.04)); 6.49 (IH, d); 6.71 (2H, d); 6.85 (4H, m); 7.02 (2H, d); 7.10 (2H, d); 7.30 - 7.65 (HH, m) and 7.88 (4H, m).

Procedure 59: (S)-DiphenyI-4-{2-[3-(2,2-di-tert-butyl-4H-1 ,2-beιιzodioxasilinan-6- yl-oxy)-2-hydroxypropylamino]ethyl}phenoxymethyl phosphine oxide

The title compound was prepared from (S)-2,2-di-tert-butyl-6-(oxiran-2-ylmethoxy)-4H- 1,3,2-benzodioxasilinane [prepared by the method of Procedure 12, WO96/04233] (0.7g, 2.08mmol) and [4-(2-aminoethyl)phenoxymethyl] phosphine oxide (1.08g, 3.06mmol) using a method similar to that of Procedure 13. After chromatography the product was isolated as a white foam (0.49g, 34%).

δ1H (200MHz, CDCI₃): 1.03 (18H, s); 2.67 - 2.97 (6H, overlapping m); 3.89 (2H, d); 4.00 (IH, m); 4.70 (2H, d); 4.94 (2H, s); 6.49 (IH, d); 6.70 (IH, dd); 6.81 (IH, d); 6.85 (2H, d); 7.11 (2H, d); 7.42 - 7.64 (6H, m) and 7.87 (4H, m). Procedure 60: 4-Fluoro-3-nitroacetophenone.

To a 3 -neck R.B. flask fitted with a thermometer and an overhead mechanical stirrer, was placed sulfuric acid (S.G. 1.84) (15mL). The temperature ofthe acid was lowered to 3°C. 4-Fluoroacetophenone (4.9g) was added in small portions so that the reaction temperature ofthe mixture did not exceed 5°C. A mixture of nitric acid (S.G. 1.42) (4mL) and sulfuric acid (£G. 1.84) (6mL) at below 12°C was added dropwise to the stirred mixture at such a rate that the reaction temperature did not exceed 5°C. Stirring was continued for one hour at this temperature before the mixture was poured into icy water (200mL) and extracted with diethyl ether (2xl50mL). The combined ether extracts was washed with water, repeatedly until the washing was neutral, then brine and dried (sodium sulfate). The ether solution was filtered and evaporated to give a crude solid. Pure product as a colourless solid (4.32g, 53%) was obtained after purification by suction chromatography eluting with ethyl acetate (from 5% to 20%) in hexane.

δ^xH (250MHz, CDCI3): 2.69 (3H, s); 7.43 (IH, t); 8.27 (IH, m); 8.56 (IH, dd).

Procedure 61: Acetic acid, 4-fluoro-3-nitrophenyl ester.

The title compound was prepared from 4-fluoro-3-nitroacetophenone (1.07g) and 3- chloroperoxybenzoic acid (approximately 60% purity) (5mol. equivalents) employing a method similar to that of procedure 20. Pure product as an amber solid (0.6g, 52%) was obtained by suction chromatography eluting with ethyl acetate (from 5% to 10%) in hexane.

δ1H (250MHz, CDCI3): 2.35 (3H, s); 7.34 (IH, d); 7.40 (IH, m); 7.86 (IH, dd). Procedure 62: Acetic acid, 3-amino-4-fluorophenyl ester.

A solution of acetic acid, 4-fluoro-3-nitrophenyl ester (0.6g) in ethyl acetate (200mL) in the presence of 10% palladium on carbon (0.09g) was allowed to stir under one atmospheric pressure of hydrogen at room temperature for eighteen hours. The catalyst was removed by filtration through a pad of Kieselghur. The filtrate was evaporated to dryness under reduced pressure to afford product as a brown oil (0.6g).

δ'H (250MHz, CDCI3): 2.26 (3H, s); 3.50 (2H, br. s); 6.40 (IH, br. d); 6.51 (IH, br. d); 6.95 (lH, t).

Procedure 63: Acetic acid, 4-fluoro-3-phenylsulphonyIaminophenyl ester.

The title compound was prepared from acetic acid, 3-amino-4-fluorophenyl ester (0.59g), phenylsulphonyl chloride (0.53g) and pyridine (0.47g) employing a method similar to that of procedure 26. Pure product was obtained as a colourless solid (0.39g).

δ'H (250MHz, CDCI3): 2.30 (3H, s); 6.80 (2H, m); 6.95 (IH, t); 7.40-7.60 (4H, m); 7.81 (2H, d). Procedure 64: Acetic acid, 3-[(N-tert-butoxycarbonyl)-phenylsulphonylamino]-4- fluorophenyl ester.

The title compound was prepared from acetic acid, 4-fluoro-3- phenylsulphonylaminophenyl ester (0.69g), di-tert-butyl dicarbonate (0.54g) and 4- dimethylaminopyridine (5mg) employing a method similar to that of procedure 27. Pure product as a colourless solid (lg) was obtained by suction chromatograhpy eluting with ethyl acetate (from 10% to 30%) in hexane.

δ*H (250MHz, CDC1₃): 1.33 (9H, s); 2.30 (3H, s); 7.10-7.25 (3H, m); 7.50-7.71 (3H, m); 8.03 (2H, d).

Procedure 65: 3-[(N-tert-Butoxycarbonyl)-phenylsulphonylamino]-4-fluorophenol.

The title compound was prepared from acetic acid, 3-[(N-ter/-butoxycarbonyl)- phenylsulphonylamino]-4-fluorophenyl ester (1.75g) and potassium hydroxide (0.23 g) employing a method similar to that of procedure 24. Pure product was obtained as a colourless solid (1.54g).

δ1H (250MHz, CDCI3): 1.31 (9H, s); 5.10 (IH, s); 6.80-6.95 (2H, m); 7.05 (IH, t); 7.50- 7.75 (3H, m); 8.05 (2H, d). Precedure 66: (S)-2-{3-[(N-rert-Butoxycarbonyl)-phenylsulphonyIamino]-4-fluoro}- phenoxymethyl oxirane.

The title compound was prepared from 3-[(N-tert-butoxycarbonyl)- ρhenylsulphonylamino]-4-fluorophenol (1.54g), (2S)-(+)-glycidyl-3- nitrobenzenesulfonate (1.2g) and potassium carbonate (0.95g) employing a method similar to that of procedure 29. Pure product as a colourless solid (lg) was obtained by suction chromatography eluting with ethyl acetate (from 15% to 50%) in hexane.

δ*H (250MHz, CDC1₃): 1.31 (9H, s); 2.78 (IH, dd); 2.93 (IH, t); 3.37 (IH, m); 3.94 (IH, dd); 4.27 (IH, dd); 6.90-7.02 (2H, m); 7.09 (IH, t); 7.50-7.71 (3H, m); 8.04 (2H, d).

Procedure 67: (S)-Diphenyl-4-{2-[2-hydroxy-3-({3-[(N-tert-butoxycarbonyl)- phenylsulphonylamino]-4-fluoro}-phenoxy)-propylamino]-ethyl}-phenoxymethyl- phosphine oxide.

To a solution of (S)-2-{3-[(N-tert-butoxycarbonyl)-phenylsulphonylamino]-4-fluoro}- phenoxymethyl oxirane (0.43g) in methanol (30mL), was added 4-[(2-amino)-ethyl]- phenoxymethyl diphenyl phosphine oxide (1.08g). The mixture was allowed to stir at room temperature for two days. The methanol was removed in vacuo and the residue purified by suction chromatography eluting with methanol (0%-10%) in ethyl acetate to give pure product as a colourless solid (0.6 lg).

δ^!H (250MHz, CDCI3): 1.31 (9H, s); 2.70-3.00 (6H, m); 3.96 (2H, d); 4.09 (IH, m); 4.61 (2H, d); 6.80-7.20 (7H, m); 7.45-7.72 (8H, m); 7.80-7.95 (4H, m); 8.00-8.08 (2H, d). Procedure 68: 2-(4-Hydroxyphenyl)-l,l-dimethylethyIcarbamic acid, tert-butyl ester

The title compound was prepared from 4-(2-amino-2,2-dimethylethyl)phenol,(as described in. B. Renger., Arch Pharm. 1983, 316, 193.) triethylamine and di-tert- butylcarbonate using a method similar to that described in Procedure 7, as a colourless solid.

δ*H (270MHz, CDCI3 + D₂O): 1.24 (6H, s), 1.47 (9H, s), 2.88 (2H, s), 6.75 (2H, d, J = 8.4Hz), 7.00 (2H, d, J = 8.4Hz).

Procedure 69: 2-[4-(Diphenylphosphinylmethyl)phenoxy]-l,l- dimethylethylcarbamic acid, tert-butyl ester

The title compound was prepared from 2-(4-hydroxyphenyl)- 1,1 -dimethylethylcarbamic acid, tert-butyl ester and 4-chlorophenylsulphonic acid, diphenylphosphinylmethyl ester using a method similar to that described in Procedure 3, as a colourless solid.

δ1H (270MHz, CDCI₃): 1.22 (6H, s), 1.46 (9H, s), 2.91 (2H, s), 4.20 (IH, br), 4.71 (2H, d, J = 8Hz), 6.82 (2H, d, J = 8.6Hz), 7.05 (2H, d, J= 8.6Hz), 7.45-7.90 (10H, m). Procedure 70: [4-(2-Amino-2,2-dimethylethyl)phenoxymethyl)diphenyl phosphine oxide

The title compound was prepared from 2-[4-(diphenylphosphinylmethyl) phenoxy]- 1,1- dimethylethylcarbamic acid, tert-butyl ester and trifluoroacetic acid using a method similar to that described in Procedure 9 as a gum. This material was used directly in Example 14.

Procedure 71: (S)-2-(4-Benzoyloxyphenoxy)-methyloxirane

A solution of 4-hydroxyphenyl benzoate (4.28g, 20mmol) in NN-dimethylformamide (30ml) and sodium hydride (60% dispersion in oil, 400mg, 20mmol) was stirred at room temperature for 10 minutes. (2S)-glycidyl-3-nitrobenzenesulphonate (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 ofthe residue by flash chromatography on silica gel eluting with 20% ethyl acetate in hexanes gave the title compound as a colourless solid.

δ'H (270MHz, CDC1₃): 2.77 (IH, dd, J = 5.0, 2.8Hz), 2.92 (IH, t, J = 5.0, 4.4Hz), 3.30- 3.40 (IH, m), 3.97 (IH, dd, J = 11.0, 5.5Hz), 4.24 (IH, dd, J = 11.0, 3.0Hz), 6.97 (2H, d, J = 9.1Hz), 7.13 (2H, d, J = 9.1Hz), 7.47-7.67 (3H, m), 8.19 (2H, dd, J = 8.4, 1.3Hz). Example 1: (S,R) Diphenyl-4-{2-[2-hydroxy-3-(4-hydroxy phenoxy)propy.amino]propyl e oxide

A mixture of (S,R) diphenyl-4-{2-[2-hydroxy-3-(4-benzyloxyphenoxy) propylamino]propyl}phenoxymethylphosphine oxide (0.56g, 0.90mmol) and 5% Palladium on carbon (150mgs) was hydrogenated at atmospheric pressure of H₂ and at room temperature for 6 hours. The catalyst was removed by filtration through kieselguhr, and the filtrate was evaporated to afford the title compound as a beige-coloured foam (0.44g, 92%).

δ1H (250MHz, CD₃OD): 1.08 (3H, d); 2.57 (IH, m); 2.82 (3H, m); 3.01 (IH, m); 3.86 (2H, d); 4.01 (IH, m); 4.86 (2H, d, partially obscured by H₂O signal); 6.72 (4H, m); 6.90 (2H, d); 7.14 (2H, d); 7.53-7.70 (6H, m) and 7.88 (4H, m). m/z 532 (MH⁺, 100%).

Example 2:(S)-Diphenyl-4-{2-[2-hydroxy-3-(4-hydroxy phenoxy)propylamino]ethyl}phenoxy methyl phosphine oxide

The title compound was prepared from (S)-diphenyl-4-{2-[2-hydroxy-3-(4- benzyloxyphenoxy)propylamino] ethyl }phenoxymethyl phosphine oxide (0.35g,

0.58mmol) in a manner similar to that in example 1, isolating the compound as a beige- coloured foam (0.28g, 94%).

δ'H (250MHz, CD₃OD): 2.81 (3H, m); 2.97 (3H, m); 3.86 (2H, m); 4.06 (IH, m); 4.90 (2H, d, obscured by H₂O signal); 6.72 (4H, m); 6.93 (2H, d); 7.16 (2H, d); 7.52-7.71 (6H, m) and 7.87 (4H, m). m/z 518 (MH⁺, 100%) and 217 (30%). Example 3: (S,R)Di(3-phenyIpropyl)-4-{2-[2-hydroxy-3-(4-hydroxy-3- methanesulphonylaminophenoxy)propylamino]-propyl}phenoxymethyl phosphine oxide.

Me

A mixture of (S,R)-di(3-phenylpropyl)-4-{2-[3-(4-benzyloxy-3- memanesulphonylaminophenoxy)-2-hydroxypropylamino]propyl}phenoxy-methyl phosphine oxide (250mgs, 0.31mmol) and 10% Palladium on carbon (50mgs) in methanol (50ml) was hydrogenated under atmospheric pressure of H₂, and at room temperature for 6 hours. The mixture was filtered through kieselguhr and the filtrate was evaporated. Purification by column chromatography on silica gel afforded the title compound as a beige-coloured foam (146mgs, 66%).

δ'H (250MHz, CDC1₃): 1.18 (3H, d); 1.87 (8H, m); 2.63-3.21 (12H, m); 3.80 (2H, m); 4.02-4.80 (7H, m); 6.33 (IH, dd); 6.66 (2H, d); 6.80 (IH, d, J~8Hz); 6.89 (IH, d, J~2Hz) and 7.01-7.31 (12H, m).

m z (NH₃ CI) 709 (MH⁺, 100%), 631 (30%) and 303 (30%).

Example 4: (S)-Diphenyl-4-{2-(2-hydroxy-3-(3-(4-chlorophenyl-sulphonylamino)-4- hydroxy)phenoxy)propylamino]ethyl}phenoxy methyl phosphine oxide, hydrochloride salt

A mixture of (S)-diphenyl-4-{2-[2-hydroxy-3-(4-benzyloxy-3-(4- chloropheny lsulphonylamino)phenoxy)propy lamino] ethyl } phenoxymethyl phosphine oxide (70mgs, 0.09mmol), 10% Palladium on charcoal (20mgs), aqueous hydrochloric acid (2 drops of 5M) and methanol (15ml) was hydrogenated under atmospheric pressure and at room temperature for 23 hours. The mixture was filtered through kieselguhr and the filtrate evaporated. Purification by column chromatography on silica gel afforded the title compound as a pale gum (20mgs, 31%). δ (250MHz, CD3OD): 2.76 - 3.11 (6H, m); 3.85 (2H, m); 4.11 (IH, m); 4.88 (2H, d, partially obscured by H2θ-signal); 6.49 - 6.64 (2H, m); 6.96 (3H, ); 7.19 (2H, d); 7.42 (2H, d); 7.52 - 7.78 (8H, m) and 7.86 (4H, m).

Example 5: (S)-Diphenyl-4-{2-[2-hydroxy-3-(4-hydroxy-3- phenylsulphonylaminophenoxy)propylamino]ethyl}phenoxymethyl phosphine oxide

A mixture of (S)-diphenyl-4-{2-[2-hydroxy-3-(4-benzyloxy-3-phenyl sulphonylaminophenoxy)propylamino]ethyl}phenoxymethyl phosphine oxide (0.24g, 0.31 mmol) and 10% Palladium on charcoal (50mg) in methanol (50ml) was hydrogenated under atmospheric pressure of H2, and at room temperature for 30 hours. Filtered through kieselguhr and then evaporated. Purificaiton by column chromatography on silica gel afforded the title compound as a colourless gum (90mg, 41%).

δ ^!H (250MHz, CDCI3): 2.68 - 2.95 (6H, m); 3.03 - 3.51 (4H, broad s, exchangeables); 3.73 (2H, m); 4.00 (IH, m); 4.49 (2H, d); 6.13 (IH, dd); 6.54 - 6.70 (3H, m); 6.86 (IH, m); 7.00 (2H, d); 7.28 (2H, m, overlapping CHCI3 signal); 7.49 (IH, m); 7.58 (6H, m) and 7.80 (6H, m). m/z (API+): 673 (MH+, 60%)

Example 6: (S,R)-Diphenyl-4-{2-[2-hydroxy-3-(4-hydroxy-3- methanesulphonylaminophenoxy)propylamino]propyl phenoxymethyl phosphine oxide

The title compound was prepared from (S,R)-diphenyl-4-{2-[3-(4-benzyloxy-3- methanesulphonylaminophenoxy)-2- hydroxypropylamino)propyl}phenoxymethylphosphine oxide in a manner similar to that employed for example 5, to give a beige foam, m/z: MH⁺ 625

Example 7: (S)-Diphenyl-4-{2-[2-hydroxy-3-(4-hydroxy-3- methanesulphonylaminophenoxy)propylamino]ethyl}phenoxymethyl phosphine oxide

The title compound was prepared from (S)-diphenyl-4-{2-[2-hydroxy-3-(4-benzyloxy-3- methanesulphonylaminophenoxy)propylamino]ethyl } -phenoxymethyl phosphine oxide (180mg, 0.26mmol) by hydrogenolysis, employing a method similar to that used in example 5. The compound was isolated as a white foam (80mg, 51%) after silica-gel chromatography.

δ»H (250MHz, CD3OD): 2.80 - 3.09 (9H, m); 3.89 (2H, m); 4.10 (IH, m);

4.90 (2H, d, partially obscured by H₂O-signal); 6.65 (IH, dd); 6.80 (IH, d); 6.96 (3H, m); 7.19 (2H, d); 7.52 - 7.71 (6H, m) and 7.88 (4H, m).

m/z (API-): 609 (M-l, 20%)

Example 8: (S)-Diphenyl-4-{2-[2-hydroxy-3-(4-hydroxy-3-isø-propylsulphony.- aminophenoxy)propylamino]ethyl}phenoxymethyl phosphine oxide

The title compound was prepared from (S)-diphenyl-4-{2-[2-hydroxy-3-(4-benzyloxy-3- wo-propylsulphonylaminophenoxy)propylamino]ethyl}phenoxymethyl phosphine oxide (0.37 g, 0.51 mmol) using a method similar to that of Example 5. After chromatography the compound was isolated as a white foam (0.20 g, 62%).

δ iH (250 MHz, CDCI3 + CD3OD): 1.35 (6H, d); 2.76 - 3.01 (6H, m); 3.13 (4H, broad s, exchangeables, overlapping with H2O - signal); 3.21 (IH, m, partially obscured by H₂O - signal); 3.81 (2H, d); 4.07 (IH, m); 4.68 (2H, d); 6.35 (IH, dd); 6.78 (3H, m); 7.04 (IH, d); 7.11 (2H, d); 7.54 (6H, m) and 7.83 (4H. m). ^m/z (API+): 639 (MH+, 100%) and 352 (80%).

Example 9: (S)-Dimethyl-4-{2-[2-hydroxy-3-(4-hydroxyphenoxy)propylamino]- ethyljphenoxymethyl phosphine oxide

The title compound was prepared from (S)-dimethyl-4-{2-[2-hydroxy-3-(4- benzyloxyphenoxy)propylamino]ethyl}phenoxymethyl phosphine oxide (210 mgs, 0.43 mmol) in a manner similar to that used in example 5, isolating the compound as a white foam (170 mgs, quant).

δ ^!H (250 MHz, CD3OD): 1.67 (6H, d); 2.70 - 3.28 (6H, m); 3.90 (2H, m); 4.18 (IH, m); 4.36 (2H, t); 6.69 (2H, d); 6.78 (2H, d); 6.99 (2H, m) and 7.23 (2H, t).

Example 10: (S)-Diphenyl-4-{2-[2-hydroxy-3-(3-(l-naphthylsulphonylamino)-4- hydroxy)phenoxy)propylamino] ethyl} phenoxy methyl phosphine oxide, trifluoroacetate salt.

The title compound was prepared by hydrogenation of (S)-diphenyl-4-{2-[2-hydroxy-3- (4-benzyloxy-3-(l-naphthylsulphonylamino)phenoxy)propylamino]ethyl}phenoxy- methylphosphine oxide, trifluoroacetate salt (0.38g, 0.41 mmol) at atmospheric pressure by a method similar to that employed in Example 5. Purification by column chromatography on silica gel and freeze drying gave the title compound as an off-white foam (0.10g, 29%).

^m/z (FAB): 723 (MH⁺, 3%) Example 11 : (S)-Diphenyl-4-{2-hydroxy-3-(3-trifluoromethanesulphonamino)-4- hydroxy)phenoxy)propylamino]ethyI}phenoxymethyl phosphine oxide

The title compound was prepared by hydrogenation of (S)-diphenyl-4-{2-[2-hydroxy-3- (4-benzyloxy-3-[(N-4-methoxy benzyl)- trifluoromethanesulphonylamino]phenoxy )- propylaminojethyl} phenoxymethyl phosphine oxide (0.44g, 0.503mmol) at atmospheric pressure by a method similar to that employed in Example 5. After freeze drying the title compound was obtained as a very pale violet foam (0.127g, 38%).

m/z (FAB): 665 (MH+, 8%).

Example 12: (S)-Diphenyl-4-{2-[2-hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino] ethyljphenoxymethyl phosphine oxide

The title compound was prepared from (S)-diphenyl-4-{2-[3-(2,2-di-tert-butyl-4H- 1,3,2- benzodioxasilinan-6-yl-oxy)-2-hydroxypropylamino]ethyl } -phenoxymethyl phosphine oxide (0.48g, 0.7mmol) by treatment with hydrogen fluoride/pyridine using a method similar to example 4 of W96/04233.

^m/_z (FAB): 548 (MH⁺, 22%)

Example 13: (S)-Diphenyl-4-(2-{2-hydroxy-3-[(3-phenylsulfonylamino-4-fluoro)- phenoxy]-propylamino}-ethyl)-phenoxymethylphosphine oxide hydrochloride.

HCI

To a solution of (S)-diphenyl-4-{2-[2-hydroxy-3-({3-[(N-tert-butoxycarbonyl)- phenylsulfonylamino]-4-fluoro}-phenoxy)-propylamino]-ethyl}- phenoxymethylphosphine oxide (0.57g) in methanol (20mL), was added 5M hydrochloric acid (20mL). The mixture was allowed to stand at room temperature for five days. Volatiles were removed in vacuo. To the acidic residue, fresh methanol (30mL) was added and the solution was evaporated in vacuo again. This was repeated several times so that the product is free of hydrochloric acid. A light brown solid (0.42g) was obtained.

δ1H (250MHz, CD3OD): 3.00 (2H, m); 3.10-3.40 (4H, m); 3.96 (2H, t); 4.24 (IH, m); 4.91 (2H, d); 6.70 (IH, dt); 6.93 (IH, t); 7.00 (2H, d); 7.14 (IH, m); 7.24 (2H, d); 7.50- 7.95 (15H, m).

Example 14: (S)-Diphenyl-4-{2-[2-hydroxy-3-(4-hydroxyphenoxy) propy lamino] -2,2- dimethylethyl}phenoxymethyI phosphine oxide

A solution of [4-(2-amino-2,2-dimethylethyl)phenoxymethyl]diphenyl phosphine oxide (663mg, 1.75mmol) and (S)-2-(4-benzoyloxyρhenoxy)-methyloxirane (375mg, 1.75mmol) in methanol (30ml) was heated under reflux for 64 hours. After cooling, the solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with 25% methanol in ethyl acetate to give the title compound as a colourless solid.

δ*H (270MHz, d₆-DMSO + D₂O): 0.91 (3H, s), 0.93 (3H, s), 2.52-2.75 (2H, m), 3.75- 3.90 (3H, m), 4.91 (2H, d, J = 6.0Hz), 6.66 (2H, d, J = 9.0Hz), 6.74 (2H, d, J = 9.0Hz), 6.89 (2H, d, J = 8.5Hz), 7.08 (2H, d, J = 8.5Hz), 7.53-7.90 (10H, m).

Pharmacological Data: The activity ofthe present compounds is tested by use ofthe following procedures:

Antagonist and Agonist Activity at Human βj, β_2» and β3-Adrenoceptors. Subclones of CHO cells are stably transfected with each of the human β i , β2 and β3-adrenoceptorsl. c_eu_s ^g gn disrupted by immersion in ice-cold lysis buffer (10 mM TRIS, 2mM EDTA , pH 7.4) containing protease inhibitors leupeptin and benzamidine (5 mg / ml) and soyabean trypsin inhibitor (10 mg / ml). Membranes are prepared by the method of Bouvier et. al.2 and stored in 1 ml aliquots in liquid N2 for future use.

β3-Adrenoceptor- Mediated Adenylyl Cyclase Activity

Adenylyl cyclase activity is assayed by the method of Kirkham et. al.3 by the addition of 40 ml (70 -80 mg protein) to the incubation medium ofthe above CHO cell plasma membranes transfected with the human b3 -adrenoceptor . cAMP produced over 20 minutes is separated from ATP by the method of Salomon et alA Agonist EC50 values and intrinsic activities are expressed as the concentration of agonist producing 50 % activation of adenylyl cyclase and the maximum response produced by each agonist relative to that produced by (-) isoprenaline respectively.

Antagonist Binding at βj, and β2~Adrenoceptors

Displacement of [125i]_i₀docyanopindolol fro CHO cell plasma membranes transfected with either the human βi , or β2-adrenoceptors is carried out by the method of Blin et. alA Ki values (nM) are calculated from the binding IC50 values for each agonist, using the Cheng -Prusoff equation.

Results All compounds showed an EC5 <10μM in the β3 cyclase assay

Example Beta-3 Beta-1 Beta-2

EC₅₀ (IA) uM Ki uM Ki uM

2 0.60(0.38)

3 0.01(0.68)

6 0.01(1.47) 0.13 0.12

References

1. T. Frielle et. al., Proc. Natl. Acad. Sci., 1987, 84, 7920; B. Kobilka, Proc. Natl. Acad. Sci., 1987, 84, 46; S. Liggett and D. Schwinn, DNA Sequence, 1991, 2, 61.

2. M. Bouvier et. al., Mol. Pharmacol., 1987, 33, 133. 3. D. Kirkham et. al., Biochem. J., 1992, 284, 301.

4. Y. Salomon et al., Anal. Biochem., 1974, 58, 541.

5. N. Blin, et. al., Br. J. Pharmacol., 1994, 112, 911.

Claims

Claims:

1. A compound of formula (I):

R-X-CH₂- OCH₂R²

R° represents an aryl group optionally substituted with one, two or three substitutents selected from the list consisting of: hydroxy, hydroxymethyl, nitro, amino, alkylamino, dialkylamino, alkylsulphonamido wherein the alkyl group is optionally substituted with one, two or three substituents selected from: halogen, haloalkyi, hydroxy, alkoxy, or arylsulphonamido wherein the aryl group is optionally substituted, providing that R° is not 3-methylsulphonylaminophenyl when X represents O or S; Rl and R*^a each independently represents hydrogen or an alkyl group.; R2 represents a moiety of formula (a) :

O

II

— P— R⁴

(a)

wherein R^ and R5 each independently represent hydrogen, alkyl, cycloalkyl, aryl or aralkyl or R^ together with R^ represents -(CH2)_n- wherein n is, 3,4 or 5; and R3 represents hydrogen, halogen, alkyl or alkoxy.

2. A compound according to claim 1 , wherein R° represents a moiety of formula (b):

3. A compound according to claim 1 or claim 2, wherein R° is 4-hydroxyphenyl or 4-hydroxy-3-alkylsulphonamidophenyl.

4. A compound according to any one of claims 1 to 3, wherein R^ represent phenyl and R^ represents phenyl.

5. A compound according to any one of claims 1 to 4, wherein X represents O.

6. A compound according to claim 1, wherein R° is 4-hydroxyphenyl-3- methanesulphonamido; X is O; R is methyl; R^^a is hydrogen; R^ is a moiety of formula (a) wherein R^ and R^ each represent phenyl and R^ is hydrogen.

7 A compound according to claim 1 , selected from:

(S,R) diphenyl-4- {2-[2-hydroxy-3-(4-hydroxy phenoxy )propylamino]propyl } phenoxymethylphosphine oxide;

(S)-diphenyl-4- { 2- [2-hydroxy-3 -(4-hydroxy phenoxy )propylamino]ethyl } phenoxymethyl phosphine oxide

(S,R)Di(3-phenylproρyl)-4-{2-[2-hydroxy-3-(4-hydroxy-3- methanesulphonylaminophenoxy)propylamino]-propyl}phenoxymethyl phosphine oxide; (S)-diphenyl-4-{2-[2-hydroxy-3-(3-(4-chlorophenyl-sulphonylamino)-4- hydroxy)phenoxy)propylamino]ethyl} phenoxy methyl phosphine oxide;

(S)-diphenyl-4-{2-[2-hydroxy-3-(4-hydroxy-3- phenylsulphony laminophenoxy)propylamino]ethy 1 } phenoxymethyl phosphine oxide

(S,R)-diphenyl-4-{2-[2-hydroxy-3-(4-hydroxy-3- methanesulphonylaminophenoxy)propylamino]propyl phenoxymethyl phosphine oxide;

(S)-diphenyl-4-{2-[2-hydroxy-3-(4-hydroxy-3- methanesulphonylaminophenoxy)propylamino]ethyl} phenoxymethyl phosphine oxide;

(S)-diphenyl-4-{2-[2-hydroxy-3-(4-hydroxy-3-wo-propylsulphonyl- aminophenoxy)propylamino]ethyl} phenoxymethyl phosphine oxide; (S)-dimethyl-4-{2-[2-hydroxy-3-(4-hydroxyphenoxy)propylamino]-ethyl}phenoxymethyl phosphine oxide;

(S)-diphenyl-4-{2-[2-hydroxy-3-(3-(l-naphthylsulphonylamino)-4- hydroxy)phenoxy)propylamino]ethyl} phenoxymethyl phosphine oxide;

(S)-diphenyl-4-{2-hydroxy-3-(3-trifluoromethanesulphonamino)-4- hydroxy )phenoxy)propylamino]ethyl } phenoxymethyl phosphine oxide

(S)-diphenyl-4-{2-[2-hydroxy-3-(4-hydroxy-3- hydroxymethylphenoxy)propylamino] ethyl} phenoxymethyl phosphine oxide; (S)-diphenyl-4-(2-{2-hydroxy-3-[(3-phenylsulfonylamino-4-fluoro)-phenoxy]- propylamino}-ethyl)-phenoxymethylphosphine oxide hydrochloride; (S)-diphenyl-4-{2-[2-hydroxy-3-(4-hydroxyphenoxy) propylamino]-2,2- dimethylethyl} phenoxymethyl phosphine oxide;or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

8. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, which process comprises: (i) reacting a compound of formula (II) :

R°— X — CH,-CH — CH,

(II)

R¹" R^3'

T°NH — CR¹-CH // ' \\ OCH₂R'

(III)

wherein R and R*^a are as defined in relation to formula (I), R.2¹ represents R^ or a protected form thereof, R^' represents R^ or a protected form thereof and T° represents hydrogen or a protecting group; (ii) deprotecting a compound of formula (XII):

wherein Rl, Rl^a, R2, R3 and X are as defined in relation to formula (I), R⁰' is as defined in relation to formula (II); and thereafter, if required, carrying out one or more ofthe 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 pharmaceutically acceptable salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.

9. 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.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.

11. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of hyperglycaemia, Type II diabetes, obesity, gastrointestinal disorders, intestinal ulcerations, gastrointestinal ulcerations, hyperinsulinaemia and depression and for increasing the high-density- lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in blood serum.

12. 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, Type II diabetes, obesity, gastrointestinal disorders, intestinal ulcerations, gastrointestinal ulcerations, hyperinsulinaemia and depression and for increasing the high-density-lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in blood serum.

13. A method for treating hyperglycaemia, Type II diabetes, obesity, gastrointestinal disorders, intestinal ulcerations, gastrointestinal ulcerations, hyperinsulinaemia and depression and for increasing the high-density-lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in blood serum; 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.