WO1993010074A1

WO1993010074A1 - Arylethanolamine derivatives and their use as beta-3-adrenoceptor agonists

Info

Publication number: WO1993010074A1
Application number: PCT/GB1992/002135
Authority: WO
Inventors: Barrie Christian Charles Cantello; Lee James Beeley
Original assignee: Smithkline Beecham Plc
Priority date: 1991-11-19
Filing date: 1992-11-19
Publication date: 1993-05-27
Also published as: MX9206614A; NZ245157A; PT101066A; ZA928859B; TW222619B; AU2949192A; GB9124512D0

Abstract

A compound of formula (I), or a pharmaceutically acceptable acid salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof, wherein R represents hydrogen, halogen or CF3; a process for the preparation of such a compound, a pharmaceutical composition containing such a compound and the use of such a compound or composition in medicine and agriculture.

Description

ARYLETHANOLAMINE DERIVATIVES AND THEIR USE AS BETA-3-ADRENOCEPTOR 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.

European Patent Number 0023385 discloses certain compounds which are described as having activity as an anti-obesity and/or anti-hyperglycaemic agents.

It has now been discovered that a series of arylethanolamine derivatives falling within the general scope of the compounds disclosed in EP 0023385 have good β-adrenoreceptor agonist activity and in particular show good selectivity for β₃-adrenoreceptors rather than β₁- or β₂-adrenoreceptors. These compounds are therefore indicated to have good anti- hyperglycaemic and/or anti-obesity activity coupled with especially good selectivity from cardiac and tremorigenic side effects. 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. These compounds may also be of use in

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

Accordingly the present invention provides a compound of formula (I):

or a pharmaceutically acceptable acid salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof,

wherein R represents hydrogen, halogen or CF₃.

In particular, R is substituted in the 3-position on the phenyl ring. Suitably, R represents halogen, especially chlorine or bromine, or CF₃. Preferably, R represents chlorine, especially 3-chloro. The compounds of formula (I) have an asymmetric carbon atom, marked with an asterisk in the formula. These compounds may, therefore, exist in one of two stereoisomeric forms. The present invention encompasses all stereoisomers of the compounds of the general formula (I), whether free from other isomers or admixed with other isomers in any proportion, and thus includes for instance, racemic mixtures of enantiomers.

Preferably, the assymmetric carbon is in the R-configuration.

When used herein the term 'alkyl' when used alone or when forming part of other groups (such as the 'alkoxy' group) includes straight- or

branched-cham alkyl groups containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert. -butyl group. When used herein the term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably chlorine.

Suitable esters are in-vivo hydrolysable esters. When used herein the term "in-vivo hydrolysable ester" relates to a pharmaceutically acceptable ester which readily breaks down in the human or non-human animal body to leave the free hydroxy group.

Suitable in-vivo hydrolysable ester groups are those used conventionally in the art, for example those provided by C_1-6 alkyl carboxylic acids.

Generally, esters of compounds of formula (I) are esters of the carboxyl group of formula (I). In addition the hydroxy group present in the moiety -CH(OH)CH₂NH ('the ethanolamine hydroxyl group') or any hydroxyl group present in the compound of formula (I) may be derivatised as an ester.

Suitable esters of the carboxyl group of formula (I) include alkyl esters, especially C_1-6 alkyl esters such as methyl. Suitable esters of hydroxyl groups are those provided by an aryl carboxylic acid, an arylalkyl carboxylic acid or a C_1-6 alkyl carboxylic acid.

Preferably the ethanolamine hydroxyl group is present as a free hydroxyl group.

Suitable pharmaceutically acceptable amides are those of formula NR^sR^t wherein R^s and R^t each independently represent hydrogen, alkyl or alkoxy alkyl.

Suitable pharmaceutically acceptable salts of the compounds of formula (I) include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium, alkahne earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with C_1-6 alkylamines such as triethylamine, hydroxy- C_1-6 alkylamines such as 2-hydroxyethylamine, bis-(2- hydroxyethyl)- amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as

bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-b-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline. Compounds of formula (I) also form acid addition salts.

Pharmaceutically acceptable acid addition salts may be, for example, 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, toluenesulophonic 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.

The invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, which process comprises reacting an activated form of a compound of formula (II):

wherein R is as defined in relation to formula (I), R^x represents hydrogen or a hydroxy protecting group and R^y represents hydrogen or a nitrogen protecting group; with a compound of formula (III): L-CH₂COOR^z (III) wherein R^z is hydrogen or a protecting group and L represents a leaving group; and thereafter if necessary carrying out one or more of the

following optional steps:

(i) removing any protecting group; and

(ii) preparing a pharmaceutically acceptable salt, ester or amide of a compound of formula (I) or a pharmaceutically acceptable solvate thereof.

A suitable leaving group L is a halogen atom, preferably a bromine atom. A suitable activated form of a compound of formula (II) is an anionic form.

The reaction between an activated form of a compound of formula (II) and a compound of formula (III) may be carried out in any suitable solvent, generally an aprotic solvent such as acetone, tetrahydrofuran or

dimethylformamdde, at any temperature providing a suitable rate of formation of the required product at an ambient temperature or at an elevated temperature, such as in the range of from 20°C to 150°C, for example 60°C; conveniently when acetone is the solvent a suitable temperature is the reflux temperature.

An activated form of a compound of formula (II) may be prepared by the appropriate conventional procedure. Thus an anionic form may be prepared by treating a compound of formula (II) with a base such as sodium carbonate.

Generally, the activated form of compound (II) is prepared in situ.

The deprotection of a compound of formula (I) forms a separate aspect of the present invention: accordingly there is provided a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable acid salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof, which process comprises the deprotection

of a compound of formula (IA):

wherein R is as defined in relation to formula (I), R^x and R^y are as defined in relation to formula (II) and R^z is as defined in relation to formula (II), providing that at least one of R^x, R^y or R^z represents a protecting group; and thereafter if necessary carrying out one or more of the following optional steps:

(i) removing any protecting group; and

Suitable protecting groups R^x include trialkyl silyl groups. Preferably, R^x is hydrogen.

Preferably, R^y is a nitrogen protecting group, for example a tert-butyloxy carbonyl group

Suitable protecting groups R^z include conventional carboxyl protecting groups, such as C_1-6 alkyl groups.

Preferably, R^z is hydrogen.

The deprotection of the compound of formula (IA) may be carried out using any suitable, conventional procedure appropriate to the particular protecting group chosen. Thus for example when R^y is a tert-butyloxycarbonyl group the compound of formula (IA) is deprotected using mild acidic hydrolysis, using for example trifluoroacetic acid in an inert, solvent such as dichloromethane, preferably under an inert atmosphere such as nitrogen and preferably under anhydrous conditions.

When R^x represents a trialkyl silyl group it may be removed by mild acid hydrolysis.

When R^z represents a C_1-6 alkyl group then it may be removed by mild basic hydrolysis.

The compounds of formula (IA) may be prepared as described above by reaction between the compounds of formulae (II) and (III). The compounds of formula (II) may be prepared by reacting a compound of formula (IV):

wherein R and R^x are as defined in relation to formula (II) with tyramine, and subsequently reducing the resulting amide; and thereafter, if

necessary, removing any protecting group.

The reaction between a compound of formula (IV) and tyramine may be carried out under conventional amidation conditions, for example in an inert solvent, such as dry dichloromethane, in the presence of a coupling agent, at any temperature which provides a suitable rate of formation of the required product, conveniently at low to ambient temperature, for example 0°C or ambient temperature; and preferably in an inert

atmosphere such as nitrogen.

Suitable coupling agents are conventional coupling agents such as N,N'- dicylohexylcarbodiimide, benzotriazol-1-yloxy tris(dimethylamino)- phosphoniumhexafluorophosphate and benzotriazol-1-yloxy tripyrrolidinophosphoniumhexafluorophosphate.

The reduction of the resulting amide may be effected by use of any appropriate, conventional reducing method, for example by using a borane such as boranedimethylsulphide in refluxing tetrahydrofuran, preferably under nitrogen.

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, for example those mentioned hereinbefore.

Protecting groups may be prepared and removed using the appropriate conventional procedure: For example, tert-butyloxycarbonyl protecting groups may be prepared by treating the appropriate compound of formula (II) with di-tert-butyl dicarbonate in the presence of a base such as triethylamine. The

tert-butyloxycarbonyl protecting groups may be removed by mild acidic hydrolysis, such as by treatment with trifluoroacetic acid.

Also, when R^z is a C_1-6 alkyl group, it may be removed using mild, basic hydrolysis.

A leaving group is any group that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups are halogen atoms, mesyloxy groups and tosyloxy groups. Compounds of formula (IA) and (II) are considered to be novel and thus form a further aspect of the invention.

Compounds of formulae (III) and (IV) are either known compounds or can be prepared from known compounds by known processes or processes analogous to known processes for example those disclosed in Organic Synthesis, Collective Vol. 3 p. 381 (for compounds of formula (III) and p. 538 (for compounds of formula (IV)). Tyramine is a known compound. A compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof may also be prepared according to methods disclosed in EP 0023385, such methods are incorporated herein by reference. The salts, esters, amides and solvates of compounds of formula (I) 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.

Esters of compounds of formula (I) maybe prepared by conventional esterification procedures, for example alkyl esters may be prepared by treating the required compound of formula (I) with the appropriate alkanol under acidic conditions.

One convenient process for preparing C_1-6 alkyl esters of compounds of formula (I), and especially a methyl ester is provided by treating a compound of formula (II) with a compound of formula (III) wherein R^z represents C_1-6 alkyl, especially methyl.

Amides of compounds of formula (I) may be prepared using conventional amidation procedures, for example amides of formula CONR^sR^t of a compound of formula (I) may be prepared by treating a compound of formula (I) with an amine of formula HNR^sR^t wherein R^s and R^t are as defined above. Alternatively, a C_1-6 alkyl ester such as a methyl ester, of a compound of formula (I) may be treated with an amine of the

above defined formula HNR^sR^t to provide the required amide. Such reactions are most conveniently effected in the presence of the abovementioned coupling agents.

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

If required compounds of the invention may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent. Suitable optically active acids which maybe used as resolving agents are described in 'Topics in

Stereochemistry', Vol. 6, Wiley Interscience, 1971, Allinger, N.L. and Eliel, W.L. Eds.

Alternatively, any enantiomer of a compound of the invention may be obtained by stereospecific synthesis using optically pure starting

materials of known configuration: for example an enantiomer of the compound of formula (I) may be prepared by reaction of an enantiomer of the compound of formula (II) with a compound of formula (III), for example the R-enantiomer of compound (I) would be prepared from the R- enantiomer of compound (II). The relevant enantiomeric substrates are conveniently prepared using methods discussed above, for example the R- enantiomer of compound of formula (II) may be prepared from the R- enantiomer of the compound of formula (IV). The absolute configuration of any compound of the general formula (I) may be determined by conventional X-ray crystallographic techniques.

As previously indicated, the compounds of the present invention have valuable pharmacological properties:

The present invention accordingly provides a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide 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, ester or amide thereof; or a

pharmaceutically acceptable solvate thereof, for use in the treatment of hyperglycaemia in human or non-human animals.

Suitable non-human animals include non-human mammals especially pets such as dogs and cats.

The present invention further provides a compound of formula (I), or pharmaceutically acceptable salt, ester or amide thereof; or a

pharmaceutically acceptable solvate thereof, for use in the treatment of obesity and/or for the treatment and/or prophylaxis of atherosclerosis and/or for the treatment of hyperinsulinaemia in human or non-human animals.

In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, for tile manufacture of a medicament for the treatment of hyperglycaemia in human or non-human animals.

The present invention also provides the use a compound of formula (I), or pharmaceutically acceptable salt, ester or amide thereof; or a

pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of obesity and/or for the treatment and/or prophylaxis of atherosclerosis and/or for the treatment of

hyperinsulinaemia in human or non-human animals.

A compound of formula (I), or a pharmaceutically acceptable salt, ester or amide 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, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.

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

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

Usually the pharmaceutical compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection, are also envisaged. Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as powders presented in sachets, may also be used.

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

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

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

The present invention further provides a method for treating

hyperglycaemia in a human or non-human animal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, to a hyperglycaemic human or non-human animal 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 animal, which comprises administering an effective,

non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, to a human or non-human animal in need thereof.

Conveniently, the active ingredient may be administered as a

pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.

In treating hyperglycaemic or obese humans the compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg that is a total daily dosage in the range of from 1.4. 10^-3 mg/kg to 86 mg/kg , more usually in the range of from 0.014 mg/kg to 21.4 mg/kg.

The treatment regimens for atherosclerosis are generally as described for hyperglycaemia.

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

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

Whilst the compounds of formula (I) and the veterinarily acceptable salts, ester or amide 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, ester or amide thereof will normally be administered orally although non-oral modes of administration, for example injection or implantation, are also envisaged. Suitably the compounds are

administered in the feed-stuff or drinking water provided for the livestock.

Conveniently these are administered in the feed-stuff at from 10^-3 ppm -

500ppm of total daily fed intake, more usually 0.01ppm to 250ppm, suitably less than 100ppm. The particular formulations used will of course depend upon the mode of administration but will be those used conventionally in the mode of administration chosen. For administration in feed-stuff the drugs are conveniently formulated as a premix in association with a suitable carrier. Accordingly, the present invention also provides a veterinarily acceptable premix formulation comprising a compound of formula (I), or a

veterinarily acceptable salt, ester or amide thereof; or a veterinarily acceptable solvate thereof, in association with a veterinarily acceptable carrier therefore.

Suitable carriers are inert conventional agents such as powdered starch. Other conventional feed-stuff premix carriers may also be employed.

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

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

Procedure 1

(R)-3-Chloro-α-hydroxy-N-[2-(4-hydroxyphenyl)ethyl]benzeneacetamide

A mixture of 4.23g (30.8mM) of tyramine, 5.01g(26.9mM) of (R)-3- chloromandelic acid, 10.80g (24.5mM) of benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate and 2.72g (26.9mM) of triethylamine in 100ml of dry dichloromethane, under nitrogen, was stirred at ambient temperature for 48 hours. The solution was diluted with 500ml of ethyl acetate and washed with 50ml of saturated sodium hydrogen carbonate solution, 50ml of water, 50ml of 2M aqueous hydrochloric acid and 50ml of water. After drying (MgSO₄) and evaporation in vacuo the yellow residue was dissolved in 200ml of 1M sodium hydroxide, washed with 50ml of diethyl ether and acidified with 15ml of concentrated hydrochloric add. The aqueous phase was extracted with 2×100ml of ethyl acetate and the combined organic washings dried (MgSO₄). Evaporation in vacuo yielded the crude product as a pale yellow oil. Purification by chromatography on silica gel eluting with 50-90% ethyl acetate in n-hexane gave the title compound as a colourless foam.

¹H nmr δ (DMSO-d₆)

9.14 (1H, s, exchanged with D₂O), 7.99 (1H, t, exchanged with D₂O), 7.43 (1H, s), 7.33 (3H, m), 6.93 (2H, m), 6.65 (2H, m), 6.30 (1H, d, exchanged with D₂O), 4.92 (1H, d), 3.24 (2H, m), 2.59 (2H, t). [α]²⁵ _D

-41.3° (c = 1.25, methanol) Procedure 2

(R)-4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenol, hydrochloride salt

To a stirred solution of 6.10g (19.9mM) of (R)-3-chloro-α-hydroxy-N-[2-(4- hydroxyphenyl)ethyl]benzenacetamide in 130ml of dry tetrahydrofuran under nitrogen at reflux temperature was added 5.90ml (59.0mM) of 10M borane-dimethylsulphide, dropwise. The solution was refluxed for four hours, cooled to room temperature and treated with 75ml of methanol dropwise. After stirring a further 0.5 hours, the solution was refluxed 0.5 hours, then cooled and evaporated in vacuo. The crude product was dissolved in 70ml of isopropanol and treated with gaseous hydrogen chloride. Evaporation in vacuo and trituration with 100ml of diethyl ether gave the title compound as a white solid which recrystallised from acetone to yield white crystals, m.p. 162-30°C. ¹Η. nmr δ (DMSO-d₆)

9.39 (2H, s, exchanged with D₂O), 8.98 (1H, s, exchanged with D₂O), 7.47 (1H, s), 7.41 (3H, m), 7.03 (2H, d), 6.73 (2H, d), 6.36 (1H, d, exchanged with D₂O), 5.05 (1H, m), 3.11 (6H, br. m).

[α]²⁵ _D

-31.8° (c = 1.40, methanol) Procedure 3

(R)-1,1-Dimethylethyl-N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N-[2- (4-hydroxyphenyl)ethyl]carbamate

To a stirred solution of 3.30g (10.mM) of (R)-4-[2-[[2-(3-chlorophenyl)-2- hydroxyethyl]amino]ethyl]phenol hydrochloride salt in 20ml of dry dimethylformamide under nitrogen at room temperature was added 6.07g (60.mM) of triethylamine followed by 2.40g (11.0mM) of di-tert-butyl dicarbonate. The reaction was stirred for 18 hours, then diluted with 80ml of water and extracted with 2×30ml of diethyl ether. The combined organic phases were washed with 2×10ml of water, dried (MgSO₄) and evaporated in vacuo to yield the crude product as a white foam.

¹H nmr δ (CDCl₃)

7.34 (1H, s), 7.21 (3H, m), 6.96 (2H, d), 6.73 (2H, d), 4.83 (1H, m), 4.54 (2H, br. s, exchanged with D₂O), 3.34 (4H, br. m), 2.61 (2H, m), 1.45 (9H, s).

[α]²⁵ _D + 8.9 (c = 1.5, methanol) Procedure 4

(R)-Methyl 4-[2-[N-[2-(3-chlorophenyl)-2-hydroxyetlιyl]-N-[1,1- dimethyl-ethoxy)carbonyl]amino]ethyl]phenyloxyacetate

A mixture of 3.90g (9.95mM) of (R)-1,1-dimethylethyl-N-[2-(3- chlorophenyl)-2-hydroxyethyl]-N-[2-(4-hydroxyphenyl)ethyl]carbamate, 5.33g (3.48mM) of methyl bromoacetate and 4.13g (2.99mM) of potassium carbonate in 150ml of acetone was stirred at reflux temperature under nitrogen for 6 hours. The reaction was cooled, filtered and evaporated in vacuo to yield the crude product as an oil. Purification by

chromatography on silica gel, eluting with 25-50% ethyl acetate in n-hexane gave the title compound as a colourless oil.

¹H nmr δ (CDCL₃)

7.35 (1H, s), 7.27 (3H, m), 7.06 (2H, m), 6.83 (2H, m), 4.84 (1H, m), 4.61 (2H, s), 4.61 (1H, s, exchanged with D₂O), 3.79 (3H, s), 3.35 (4H, br. m), 2.67 (2H, m), 1.45 (9H, s).

[α]²⁵ _D + 0.8° (c = 1.3, methanol) Procedure 5

(R)-α-Hydroxy-N-[2-(4-hydroxyphenyl)ethyl]benzeneacetamide

Using an analogous method to that described in Procedure 1, reaction of tyramine (1.64 g, 11.9 mMol), with (R)-mandelic acid (1.79 g, 11.9 mMol) and benzotriazol-1-yl-oxytripyrrolidino phosphonium hexafluorophosphate (6.2 g, 11.9 mMol) gave the title compound as a white foam.

¹H nmr δ (DMSO-d₆)

8.0-7.9 (1H, br.s,exchanged with D₂O slowly); 7.5-7.2 (5H,m); 7.00 (2H,d); 6.70 (2H,d); 6.4-6.3 (1H,br.s,exchanged with D₂O); 4.9-4.8

(1H,br.s,exchanged withD₂O); 4.41 (1H,s); 3.5-3.3 (2H,m); 2.9-2.5 (2H,m).

Procedure 6 (R)-4-[2-[[2-hydroxy-2-phenylethyl]amino]ethyl]phenol

Using an analogous method to that described in Procedure 2 reaction of (R)-α-hydroxy-N-[2-(4-hydroxyphenyl)ethyl]benzeneacetamide (3.1 g, 11.4 mMol) withborane-dimethyl sulphide (12 ml of 10 M solution) gave, after chromatography over silica gel eluting with ethyl acetate containing 5% methanol and 5% triethylamine, the title compound as a colourless oil. ¹H nmr δ (DMSO-d₆)

7.3-7.2 (5H,m); 6.94 (2H,d); 6.70 (2H,d); 4.70 (1H,m); 4.6-4.5

(3H,br.s,exchanged with D₂O); 3.0-2.5 (6H,m).

Procedure 7

(R)-1,1-Dimethylethyl-N-[2-hydroxy-2-phenylethyl]-N-[2-(4- hydroxyphenyl)ethyl]carbonate

Using an analogous method to that described in Procedure 3 reaction of (R)-4-[2-[[2-hydroxy-2-phenylethyl]amino]ethylphenol (1.5 g, 5.84 mMol) with di-tert-butyl dicarbonate (1.9 g, 8.76 mMol) gave the title compound as a colourless, viscous oil.

¹H nmr δ (DMSO-d₆)

7.5-7.2 (5H,m); 6.96 (2H,d); 6.73 (2H,d); 5.9-5.8 (1H,m); 5.9-5.8

(1H,br.m,exchanged with D₂O); 4.6-4.3 (1H,br.m, exchanged with D₂O); 3.5-3.1 (4H,m); 2.8-2.6 (2H,m); 1.54 (3H,s), 1.45 (6H,s).

Procedure 8

(R)-Methyl 4-[2-[N-[2-hydroxy-2-phenylethyl]-N-[1,1- dimethylethozy)carbonyl]amino]ethyl]phenyloxyacetate

Using an analogous method to that described in Procedure 4. (R)-1,1- dimethylethyl-N-[2-hydroxy-2-phenylethyl]-N-[2-(4-hydroxyphenyl)- ethyl]carbonate (1.36 g, 3.8 mMole) and methyl bromoacetate (1.74 g, 11.4 mMol) gave, after chromatography over silica gel eluting with ethyl acetate containing 2% triethylamine, the title compound as a colourless gum. 1H nmr δ (CDCl₃)

7.3-7.2 (5H,m); 7.06 (2H,d,J=8.0 Hz), 6.83 (2H,d,J=8.0 Hz); 4.9-4.8, 1H,br.m,exchanged with D₂O); 4.60 (2H,s); 4.3-4.2 (1H,m); 3.78 (3H,s); 3.5-3.2 (4H,br.m); 2.9-2.7 (2H,br.m); 1.45 (9H,s).

Procedure 9

(R)-3-Bromo-α-hydroxy-N-[2-(4-hydroxyphenyl)ethyl-benzeneacetamide

Using a analogous method to that described in Procedure 1, reaction of tyramine (1.78 g, 13 mMol), with (R)-3-bromomandelic acid (3.0 g, 13 mMol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium

hexafluorophosphate (7.43 g, 14.2 mMol) gave the title compound as a yellow oil.

¹H nmr δ (CDCl₃)

7.7-7.5 (1H,br.m,exchanged slowly with D₂O); 7.55 (1H,s); 7.43 (1H,d); 7.3-7.1 (2H,m); 6.88 (2H,d); 6.76 (2H,d); 6.4-6.3 (1H,br.s,exchanged with D₂O); 5.30 (1H,s,exchanged with D₂O); 4.95 (1H,s); 3.5-3.3 (2H,m); 2.7-2.6 (2H,m).

Procedure 10 (R)-4-[2-[[2-(3-Bromophenyl)-2-hydroxyethyl]amino]ethyl]phenol

Using an analogous method to that described in Procedure 2 reaction of (R)-3-bromo-α-hydroxy-N-[2-(4-hydroxyphenyl)ethyl]benzene acetamide (6.28 g, 17.9 mMol) with borane-dimethylsulphide (20 ml of 10M solution) gave, after chromatography over silica gel eluting with dichloromethane containing 4% methanol , the title compound as a white foam.

¹H nmr δ (DMSO-d₆)

9.3-9.1 (1H,br.s,exchanged with D₂O); 7.64 (1H,s); 7.52 (1H,d); 7.4-7.3 (2H,m); 7.10 (2H,d); 6.71 (2H,d); 5.7-5.5 (1H,br.m,exchanged with D₂O); 4.64 (1H,m); 4.2-4.1 (1H,br.m,exchanged with D₂O); 3.0-2.6 (6H,m). Procedure 11

(R)-1,1-Dimethylethyl-N-[2-(3-bromophenyl)-2-hydroxyethyl]-N-[2- (4-hydroxyphenyl)ethyl]carbonate

Using an analogous method to that described in Procedure 3 reaction of (R)-4-[2-[[2-(3-bromophenyl)-2-hydroxyethyl]amino]ethylphenol (1.69 g, 5.5 mMol) with di-tert-butyldicarbonate (1.31 g, 6.0 mMol) gave the title compound as a yellow oil.

¹H nmr δ (CDCl₃) 7.52 (1H,s); 7.39 (1H,d); 7.25-7.20 (2H,m); 7.1-7.0 (1H,br.m, exchanged withD₂O); 7.05-6.9 (2H,m); 6.77 (2H,d); 4.9-4.7 (1H,m); 3.5-3.1

(5H,m,1H,exchanged withD₂O); 2.7-2.5 (2H,m); 1.55 (3H,s); 1.45 (6H,s).

Procedure 12

(R)-Methyl 4-[2-[N-[2-(3-bromophenyl)-2-hydoxyethyl]-N-[1,1- dimethylethoxycarbonyl]aminolethoxy]phenyloxyacetate

Using an analogous method to that described in Procedure 4. reaction of (R)-1,1-dimethylethyl-N-[2-(3-bromophenyl)-2-hydroxyethyl]carbonate (2.74 g, 6.3 mMol) with methyl bromoacetate (3.36 g, 22 mMol) gave the title compound as a yellow oil. 1H nmr δ (CDCl₃)

7.50 (1H,s); 7.41 (1H,d); 7.3-7.2 (2H,m); 7.0-7.1 (2H,m); 6.83 (2H,d); 4.84 (1H,m); 4.4-4.6 (1H,m,exchanged with D₂O); 4.61 (2H,s); 3.80 (3H,s); 3.7- 3.6 (1H,m); 3.5-3.1 (3H,m); 2.8-2.3 (2H,m); 1.45 (9H,s). Procedure 13

(R)-α-Hydroxy-3-trifluoromethyl-N-[2-(4-hydroxyphenyl)ethyl]- benzeneacetamide

Using an analogous method to that described in Procedure 1 reaction of tyramine (5.16 g, 37.6 mMol) with (R)-3-trifluoromethylmandelic acid (7.2 g, 32.7 mMol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (15.3 g, 29.4 mMol) gave, after chromatography over silica gel eluting with 35% hexane in ethyl acetate, the title compound as a pale yellow oil. ¹H nmr δ (CDCl₃)

8.40 (1H,s,exchanged with D₂O); 7.71 (1H,s); 7.58-7.39 (3H,br.m); 7.13 (1H,t); 6.92 (2H,d); 6.71 (2H,d); 5.71 (1H,d,exchanged with D₂O); 5.04 (1H,d); 3.43 (2H,m); 2.67 (2H,br.t). Procedure 14

(R)-4-[2-[[2-Hydroxy-2-(3-trifluonmethylphenyl)ethyl]amino]- ethyl]phenol

Using an analogous method to that described in Procedure 2 raection of (R)-α-hydroxy-3-trifluoromethyI-N-[2-(4-hydroxyphenyl)ethyl]

benzeneacetamide (10.0 g, 29.5 mMol) with borane dimethylsulphide (8.8 ml, 88.4 mMol) gave the titie compound a white foam.

¹H nmr δ (DMSO-d₆) 9.41 (1H,s,exchanged with D₂O); 9.25 (1H,br.s,exchanged with D₂O); 7.77 (1H,s); 7.69 (3H,m); 7.04 (2H,d); 6.74 (2H,s); 6.45 (1H,d,exchanged with D₂O); 5.16 (1H,m); 3.38-2.89 (6H,br.m).

[α]²⁵ _D

-30.8° (c=2.28 methanol)

Procedure 15

(R)-14-Dimethyl-N-[2-hydroxy-2-(3-trifluoromethylphenyl)ethyl]- N-[2-(4-hydroxyphenyl)ethyl]carbamate

Using an analogous method to that described in Procedure 3 reaction of (R)-4-[2-[[2-hydroxy-2-(3-trifluoromethylphenyl)ethyl]amino]ethylphenol (6.20 g, 17.1 mMol) with di-tert-butyldicarbonate (4.11 g, 18.9 mMol) gave a white foam.

¹H nmr δ (CDCl₃) 7.60 (1H,s); 7.46 (3H,br.m); 6.94 (2H,d); 6.73 (2H,d); 6.48

(1H,br.m,exchanged with D₂O); 4.90 (2H,m); 3.50-3.05 (4H,br.m); 2.63 (2H,m); 1.44 (9H,s).

Procedure 16

(R)-Methyl 4-[2-[N-[2-hydroxy-2-(3-trifluoromethylphenyl)ethyl]-N-[1,1-dimethylethoxycarbonyl]amino]ethyl]phenyloxyacetate

Using an analogous method to that described in Procedure 4 reaction of (R)-1,1-dimethylethyl-N-[2-(4-hydroxyphenyl)ethyl]carbamate (7.2 g, 16.9 mMol) with methyl bromoacetate (5.6 ml, 59.2 mMol) gave, after chromatography over silica eluting with 50% ethyl acetate in hexane, a colourless oil. 1H nmr δ (CDCl₃)

7.7 (1H,s); 7.49 (3H,m); 7.03 (2H,br.d); 6.83 (2H,d); 4.91 (1H,m); 4.73 (1H,br.s,exchanged with D₂O); 4.60 (2H,s); 3.79 (3H,s); 3.60-3.50 (4H,br.m); 2.80-2.52 (2H,br.m); 1.45 (9H,s).

[α]²⁵D

-3.5° (c=2.19, methanol)

Example 1

(R)-Methyl 4-[2-[N-[2-(3-chlorophenyl)-2- hydroxyethyl]amino]ethyl]-phenyloxyacetate hydrochloride salt

To a stirred solution of 1.97g (4.25mM) of (R)-methyl 4-[2-[N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N-[1,1-dimethylethoxy)carbonyl]amino]ethyl]- phenyloxyacetate in 25ml of dry dichloromethane under nitrogen at 0°C was added 3.63g (31.8mM) of trifluoroacetic acid dropwise. The reaction was stirred at room temperature for 6 hours then neutralized with aqueous sodium hydrogen carbonate. The organic phase was separated, washed with 5ml of water and dried (MgSO₄). Evaporation in vacuo gave the crude product as a yellow oil which was purified by chromatography on silica gel, eluting with ethyl acetate. The resultant colourless oil was dissolved in 20ml of methanol and treated with dry, gaseous hydrogen chloride. Evaporation in vacuo gave the title compound as a white solid which was recrystallized from isopropanol, m.p. = 130-1°C.

¹H nmr δ (DMSO-d₆)

9.28 (2H, br. s, exchanged with D₂O), 7.47 (1H, s), 7.41 (3H, m), 7.17 (2H, m), 6.89 (2H, m), 6.37 (1H, d, exchanged with D₂O), 5.07 (1H, m), 4.77 (2H, s), 3.69 (3H, s), 3.08 (6H, br. m).

[α]²⁵ _D

-24.5° (c = 1.3, methanol). Example 2

(R)-4-[2-N-[2-(3-chlorophenyl)-2- hydroxyethyl]amino]ethyl]phenoxyloxy acetic acid, sodium salt

To a stirred solution of (R)-methyl 4-[2-[N-[2-(3-chlorophenyl)-2- hydroxyethyl]amino]ethyl]phenyloxyacetate, hydrochloride salt

(600 mg, 1.5 mM) in water (60 ml) was added 2.0 M sodium hydroxide solution (3 ml, 6.0 mM). After 1 hour the reaction mixture was

neutralised with 2.0 M hydrochloric acid and then evaporated in vacuo. The residue was dissolved in a small volume of water and the solution was basified with sodium carbonate. This solution was then chromatographed on reverse phase silica with 0-30% methanol/water as eluent to give the required acid as its monohydrate,(white solid, m.pt.=179°C decomp.) 1H nmr δ (DMSO-d₆/D₂O) 7.4-7.26 (4H,complex m), 7.01 (2H,m), 6.71 (2H,m), 4.65 (1H,m), 4.9 (2H,s), 2.76-2.59 (6H,complex m).

[α]²⁵ _D -15.8° [C=0.5, Methanol/H₂O]

Example 3

(R)-Methyl 4-[2-[N-[2-hydroxy-2-phenylethyl]amino]ethyl]- phenyloxyacetate hydrochloride

Using an analogous procedure to that described in Example 1 reaction of (R)-methyl 4-[2-[N-[2-hydroxy-2-phenylethyl]-N-[1,1- dimethylethoxycarbonyl]-amino]ethyl]phenyloxyacetate (1.36 g, 3.2 mMol) with trifluoroacetic acid (3.6 g, 32 mMol) gave a yellow oil.

Chromatography over silica gel eluting with ethyl acetate containing 5% triethylamine furnished a colourless gum. This was dissolved in ethyl acetate and treated with dry hydrogen chloride. Cooling to -15°C yielded the title compound as a white solid, mp=161-2°C. ¹H nmr δ (DMSO-d₆)

9.1-8.3 (2H,br.m,exchanged with D₂O), 7.4-7.3 (4H,m); 7.33-7.31 (1H,m); 7.17 (2H,d); 6.89 (2H,d); 6.17 (1H,d exchanged with D₂O); 4.98-4.94 (1H,m); 4.77 (2H,s); 3.69 (3H,s); 3.18-3.11 (3H,m); 3.05-2.89 (3H,m).

[α]²⁰ _D -30.2° (c=1.3 ethanol) Example 4

(R)-Methyl4-[2-[N-[2-(3-bromophenyl-2-hydroxyethyl]- amino]ethyl]phenyloxyacetate hydrochloride

Using an analogous procedure to that described in Example 1 reaction of (R)-methyl 4-[2-[N-[2-(3-bromophenyl)-2-hydroxyethyl]-N-[1,1- dimethylethoxycarbonyl]amino]ethyl]phenyloxyacetate (2.78 g, 5.5 mMol) with trifluoroacetic acid (4.7 g, 41 mMol) gave, after chromatography over silica gel eluting with dichloromethane containing methanol (0 - 3%), a colourless oil. This was dissolved in ethyl acetate and treated with hydrogen chloride. The solvent was evaporated and the residual foam crystallised from ethyl acetate/methanol at -15°C to yield the title compound as a white solid, mp=146-7°C. 1H nmr δ (DMSO-d₆) 9.0-8.8 (2H,br.M,exchanged with D₂O); 7.60 (1H,s); 7.52 (1H,dxd); 7.51- 7.34 (2H,m); 7.17 (2H,d); 6.90 (2H,d); 6.30 (1H,d, exchanged with D₂O); 4.97 (1H,dxd); 4.77 (2H,s); 3.69 (3H,s); 3.25-3.10 (3H,m); 3.03 (1H,dxd); 2.94-2.89 (2H,m).

[α]²⁵ _D

-22.4° (c=2.12,methanol) Example 5

(R)-Methyl 4-[2-[N-[2-hydroxy-2-[3-trifluoromethyl

phenylethyl]amino]ethyl]phenyloxy acetate hydrochloride

Using an analogous procedure to that described in Example 1 reaction of (R)-methyl-4-[2-[N-[2-hydroxy-2-(3-trifluoromethylphenyl)ethyl]-N-[1,1- dimethylethoxycarbonyl]-amino]ethyl]phenyloxy acetate (6.65, 13.4 mMol) with trifluoroacetic acid (7.7 ml, 68 mMol) gave a colourless oil.

Chromatography over silica gel eluting with ethyl acetate containing 5% methanol followed by conversion to the hydrocholride salt with dry hydrogen chloride in methanol and crystallisation, gave the title

compound, mp=147-8°C. ¹H nmr δ (DMSO-d₆)

9.51 (1H,br.s,exchanged with D₂O); 9.09 (1H,br.s,exchanged with D₂O); 7.69 (4H,br.m); 7.18 (2H,d); 6.89 (2H,d); 6.46 (1H,br.s,exchanged with D₂O); 5.17 (1H,br.d); 4.77 (2H,s); 3.70 (3H,s); 3.43-2.95 (6H,m);

[α]²⁵ _D -25.3° (c=2.0 methanol) Pharmacological Data

Lipolysis Rat white adipocytes were prepared by collagenase digestion as described by Rodbell (1964) with the modification of Honnor et al. (1985), in that adenosine (200nM) was included in the preparation to inhibit basal lipolysis. lipolysis stimulated by β-agonists was measured over 30 minutes in medium where the adenosine concentration was controlled; the medium included (-)-N⁶-(2-phenylisopropyl)adenosine (100nM) + deaminase as decribed by Honnor et al. (1985). The incubation was stopped by addition of trichloracetic acid (0.2ml of 10% w/v) to 1ml of cells. Glycerol was measured by the fluorimetric method of Boobis and Maugham (1983).

References

1. Rodbell M. (1964) J. BioL Chem.239, 375-380

2. Honnor R.C., Dhellon G.S. and Londos C. (1985) J. Biol. Chem.

260, 15122-15129

3. Boobis L.H. and Maugham R.J. (1983) Clinica Chemica Acta 132, 173-179.

Example 2, EC₅₀ = 41.7nM (Intrinsic Activity = 1.0).

Agonist Activity at Rat β₁ and β₂ Adrenoceptors In Vitro β₁-Adrenoceptor Agonism

Female Sprague-Dawley rats (150-250g) were killed by a blow to the head and exsanguinated. Spontaneously beating right atria were removed by the method of Broadley and Lumley (1977) and mounted on a glass tissue holder. Each tissue was placed in 30 ml organ baths at 37°C containing Kreb's-Henseleit solution. Each atrium was attached to an isometric transducer by cotton and placed under an initial resting tension of lg. Rate recordings from the spontaneous beating atria were obtained from the tension signal using a Lectromed Type 4522 ratemeter. All traces were recorded on a Lectromed M4 chart recorder, β-adrenoceptor agonists were then added to the Krebs medium in a cumulative fashion and the results expressed as a percentage increase in atrial rate. β₂-Adrenoceptor Agonism

Rat uterine horns were removed and bisected longitudinally. Each tissue was tied to a glass tissue holder and placed in Krebs-Henseleit solution in a 30 ml organ bath as before. Tissues were placed under a resting tension of lg and allowed to equilibrate. Each uterine strip was pre-contracted by the addition of 40mM K⁺ to the bath to produced a steady tonic

contraction, β-agonists were then added to the bath in a cumulative manner and results were expressed as percentage inhibition of

contraction.

Agonist EC₅₀ (atria) and IC₅₀ (uteri) were calculated as the concentration of agonist producing 50% of their maximum increase in atrial rate or uterine relaxation. Relative intrinsic activity expressed as the maximal responses to test agonists relative to isoprenaline (=1.0) in both atria and uteri.

References

K.J. Broadley & P. Lumley (1977) Br. J. Pharmacol. 59. 51

Ki(nM) β₁ β₂

Example 2 7610 3656

Claims

1. A compound of formula (I):

or a pharmaceutically acceptable add salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof,

characterised in that R represents hydrogen, halogen or CF₃.

2. A compound according to claim 1, characterised in that R is substituted in the 3-position on the phenyl ring.

3. A compound according to claim 1 or claim 2, characterised in that R represents 3-chloro.

4. A compound according to any one of claims 1 to 3, characterised in that it is in the R-configuration.

5. A compound according to claim 1, being (R)-methyl 4-[2-[N-[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-phenyloxyacetate ; or

(R)-4-[2-N-[2-(3-cUorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxyloxy acetic add; or, as appropriate, a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof.

6. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a

pharmaceutically acceptable solvate thereof,

characterised in that the process comprises: a) deprotecting of a compound of formula (IA):

wherein R is as defined in relation to formula (I), R^x represents hydrogen or a hydroxy protecting group, R^y represents hydrogen or a nitrogen protecting group and R^z represents hydrogen or a protecting group , providing that at least one of R^x, R^y or R^z represents a protecting group; or b) reacting an activated form of a compound of formula (II):

wherein R is as defined in relation to formula (I), R^x represents hydrogen or a hydroxy protecting group and Ry represents hydrogen or a nitrogen protecting group; with a compound of formula (III):

L-CH₂COOR^z CΠD wherein R^z is hydrogen or a protecting group and L represents a leaving group; and thereafter if necessary carrying out one or more of the following optional steps: (i) removing any protecting group; and

7. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.

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

9. A compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, for use in the treatment of hyperglycaemia.

10. A compound of formula (I), or pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, for use in the treatment of obesity and/or for the treatment and/or prophylaxis of atherosclerosis and/or for the treatment of

hyperinsulinaemia.

11. The use of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of hyperglycaemia and/or for the treatment of obesity and/or for the treatment and/or prophylaxis of atherosclerosis and/or for the treatment of hyperinsulinaemia.

12. A veterinarily acceptable premix formulation comprising a

compound of formula (I), or a veterinarily acceptable salt, ester or amide thereof; or a veterinarily acceptable solvate thereof, in assodation with a veterinarily acceptable carrier therefore.

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