WO1994024090A1

WO1994024090A1 - Arylethanolamine derivatives and their use in the treatment of obesity and hyperglycaemia

Info

Publication number: WO1994024090A1
Application number: PCT/GB1994/000829
Authority: WO
Inventors: Lee James Beeley; John Michael Berge; Richard Anthony Godwin Smith
Original assignee: Smithkline Beecham Plc
Priority date: 1993-04-21
Filing date: 1994-04-19
Publication date: 1994-10-27
Also published as: ZA942674B; TW282452B; AU6541894A; GB9308178D0

Abstract

A compound of formula (I) or a salt, ester or amide thereof, or a solvate thereof, wherein, R0 represents a substituted or unsubstituted aryl group; R1 represents hydrogen or an alkyl group; R2 represents a moiety of formula (a), wherein R4 represents a moiety (CH¿2?)nCO2H wherein n is zero or an integer in the range of from 1 to 3 and R?5¿ represents a moiety (CH¿2?)pCO2H, (CH2)pOH, (CH2)pCN, (CH2)pCOCH3 or (CH2)pNH2 wherein p is zero or an integer in the range of from 1 to 3; and R?3¿ represents hydrogen, halogen, alkyl or alkoxy; a process for the preparation of such a compound, a pharmaceutical composition comprising such a compound and the use of such a compound in medicine.

Description

ARYLETHANOLAMINE DERIVATIVES AND THEIR USE IN THE TREATMENT OF OBESITY AND HYPERGLYCAEMIA

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 application, publication number 0023385 discloses certain arylethanolamine derivatives which are stated to have anti-obesity and/or anti- hyperglycaemic activity.

It has been discovered that a novel series of arylethanolamine derivatives have good β3 agonist activity. They are therefore indicated to possess particularly good anti-hyperglycaemic and/or anti-obesity activity.

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 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. They are also indicated to be useful for the treatment of depression.

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

(I)

or a salt, ester or amide thereof, or a solvate thereof, wherein,

R° represents a substituted or unsubstituted aryl group; R.1 represents hydrogen or an alkyl group; R. represents a moiety of formula (a): *** _S

— CH

R⁵ (a) wherein R⁴ represents a moiety (CH2)_n CO2H wherein n is zero or an integer in the range of from 1 to 3 and R^ represents a moiety (CH.2)p CO2H, (CH2)pOH, (CH2)_pCN, (CH2)_pCOCH3 or (CH2>_pNH2 wherein p is zero or an integer in the range of from 1 to 3; and

R3 represents hydrogen, halogen, alkyl or alkoxy.

An example of R° is a 3-chlorophenyl group Suitably, R* is an alkyl group.

When R! is alkyl, it is favourably a C g alkyl group, especially a methyl group.

Suitably, R^ represents hydrogen.

An example of R^ is a CO2H group, or a pharmaceutically acceptable salt or ester thereof; an example of an ester is an ethyl ester, an example of a salt is a sodium salt. An example of R^ is a CO2H group, or a pharmaceutically acceptable salt or ester thereof; an example of an ester is an ethyl ester, an example of a salt is a sodium salt.

Suitably, n is zero. Suitably, p is zero.

The compounds of formula (I) have two or more asymmetric carbon atoms, for example those marked with asterisks in the formula. These compounds may therefore exist in different 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, such as mixtures of diastereoisomers and racemic mixtures of enantiomers. Of particular interest are those carbon atoms marked with one (*) or two (**) asterisks in the formula.

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

Preferably, the asymmetric carbon atom indicated by two asterisks (**) is in the R-configuration.

It should also be mentioned that the carbon atom in moiety (a) marked with three asterisks (***) may also be chiral when R^ and R^ are different.

When the (***) carbon is non-chiral, a suitable form of a compound of formula (I) is a mixture of the R(*)R(**) and S(*)S(**) enantiomers, such as a racemic mixture. When the (***) carbon is non-chiral, a preferred form of a compound of formula (I) is the R(*)R(**) enantiomer.

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

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

When used herein the term 'aryl' includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, amino, nitro, nitrile, carboxy and pharmaceutically acceptable salts, esters and amides thereof, sulphonamide, alkylsulphonamide, dialkylsulphonamide, alkoxycarbonylalkyl, alkylcarbonyloxy and alkylcarbonyl groups or two substituents on adjacent carbon atoms together with the carbon atoms to which they are attached may form a heterocyclic group.

A preferred aryl group is a substituted or unsubstituted phenyl group.

Preferred optional substituents for the aryl group include up to three substituents selected from halogen, hydroxy, alkoxy, hydroxyalkyl and amino.

Suitable heterocyclic groups are single ring heterocyclic groups having 4 to 7, generally 5 or 6, ring atoms including 1 or 2 hetero atoms selected from O or N. Examples of such heterocyclic groups include imidazoline and imidazolone, especially 2-imidazolone.

Suitable esters are pharmaceutically acceptable esters.

Esters of compounds of formula (I) include 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 also be derivatised as an ester.

Suitable pharmaceutically acceptable esters of the carboxyl group of formula (I) include alkyl esters, especially Cj.g alkyl esters such as methyl. Suitable pharmaceutically acceptable esters of hydroxyl groups are those provided by an aryl carboxy lie acid, an arylalkyl carboxylic acid or a C^-g alkyl carboxylic acid.

Suitable pharmaceutically acceptable esters also includes 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 and free carboxyl group. Suitable in-vivo hydrolysable ester groups are those used conventionally in the art, for example those provided by C\. alkyl carboxylic acids. Preferably the ethanolamine hydroxyl group is present as a free hydroxyl group.

Suitable amides are pharmaceutically acceptable amides. Suitable pharmaceutically acceptable amides include those of formula CO.NR^sR^l wherein R^s and R^l each independently represent hydrogen, alkyl or alkoxyalkyl.

Suitable salts are pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts include acid addition salts and salts of carboxy groups. 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 salts of carboxy groups include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with Cχ_6 alkylamines such as triethylamine, hydroxy-Ci.g 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.

Suitable solvates are pharmaceutically acceptable solvates. Suitable pharmaceutically acceptable solvates are conventional solvates, preferably hydrates.

The esters, amides, salts and solvates of the compounds of formula (I) which are not pharmaceutically acceptable may be used to prepare the corresponding pharmaceutically acceptable esters, amides, salts and solvates and hence they also form a useful part of the present invention.

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

(ID

wherein R°, R¹, R^ and R^ are as defined in relation to formula (I), and thereafter, if necessary, carrying out one or more of the following optional steps: (i) converting one compound of formula (I) to another compound of formula (I); and (ii) preparing a pharmaceutically acceptable salt, ester or amide of a compound of formula (I) or a pharmaceutically acceptable solvate thereof. The reduction of the compound of formula (II) may be carried out using any suitable reduction procedure, for example by using catalytic reduction in the presence of hydrogen.

Suitable catalysts include platinum oxide and palladium on charcoal.

Suitable reduction conditions include using an alkanol solvent such as methanol, at any temperature providing a convenient rate of formation of the required product, for example ambient temperature, under a pressure of 1-5 atmospheres of hydrogen.

The compound of formula (II) may be prepared by reacting a compound of formula (III):

OH

R -CH-CH₂-NH₂

(HI)

wherein R° is as defined in relation to formula (I) with a compound of formula (IN):

(IV)

wherein R , R^ and R^ are as defined in relation to formula (I). The reaction between compounds of formulae (III) and (IV) may be carried out under conventional amination conditions, for example in a solvent such as methanol or toluene. Conveniently, the compound of formula (II) is prepared in-situ by reacting a compound of the above defined formula (III) with a compound of the above defined formula (IV) under reductive amination conditions.

Suitable reductive amination conditions include reacting the compounds of formula (III) and (IV) in an alkanolic solvent, such as methanol, in the presence of a suitable reduction catalyst, such as platinum oxide or palladium on charcoal, at any temperature providing a convenient rate of formation of the required product, generally ambient temperature, under hydrogen at a pressure of 1-5 atmosphere.

A compound of formula (TV) may be prepared by reducing a compound of formula (V):

(V)

wherein R*, R^ and R^ are as defined in relation to formula (I).

The reduction of the compound of formula (V) may be carried out using any appropriate reduction procedure, for example by using iron powder in the presence of acetic acid in an aqueous solvent such as aqueous methanol, at any temperature providing a suitable rate of formation of the required product, generally at an elevated temperature and conveniently at the reflux temperature of the solvent.

A compound of formula (V) may be prepared by reacting a compound of formula (VI):

(VI)

wherein, R^ and R^ are as defined in relation to formula (I), with a nitroalkane, such as nitroethane; for compound (V) wherein R* is CH3. Generally, the carbon atom of the -CHO group of compound of formula (VI) is in an activated form, a suitable activated form being provided by forming an imine of the said carbonyl group: The i ine may be prepared by reacting the compound of formula (VI) with an amine, suitably a primary alkyl amine such as n-butylamine. The reaction of the compound of formula (VI) and the amine may be carried out in any suitable solvent, such as toluene, at any temperature providing a suitable rate of formation of the required product, generally at an elevated temperature such as the reflux temperature of the solvent; and preferably in the presence of a catalytic amount of toluenesulphonic acid.

The reaction between the compound of formula (VI) and nitroalkane may be carried out in glacial acetic acid, preferably in the presence of an ammonium acetate catalyst, generally at an elevated temperature such as in the range of from 60°C to 120°C, for example 100°C. When the compound of formula (VI) is in the form of an imine, the reaction with nitroalkane may be carried out in glacial acetic acid, generally at an elevated temperature such as in the range of from 60°C to 120°C, for example 100°C.

A compound of formula (VI) may be prepared from a compound of formula (Nil):

(Nil)

wherein R^ is as defined in relation to formula (I) with a compound of formula (NIII):

A

- /^R L -HC

(NIII)

wherein R^ and R^ are as defined in relation to formula (I) and 1?- is a leaving group or atom, such as a halogen atom, for example a chlorine atom.

Preferably, the compound of formula (VII) is in an activated form, such as a salted form.

An activated form of a compound of formula (VII) may be prepared by use of the appropriate conventional procedure, for example a salted form may be prepared by treating the compound of formula (VII) with a base such as an alkali metal hydride, for example sodium hydride, or an alkali metal hydroxide, for example potassium hydroxide. The reaction between the compounds of formulae (VII) and (VIII) may be carried out in any suitable solvent, for example ethanol at any suitable temperature which provides a convenient rate of formation of the required product, generally being an elevated temperature and conveniently the boiling point of the solvent; as stated preferably the reaction is carried out in the presence of a base, such as potassium hydroxide.

Suitable conversions of one compound of formula (I) into another compound of formula (I) include:

(1) conversion of one or both of R^ and R^, when each independendy represents a carboxylic ester, into a carboxylic acid or a salt thereof;

(2) conversion of one or both of R^ and R^, when each independendy represents a carboxylic ester, into a carboxylic amide.

Conversion (1) may be carried out using any conventional means for hydrolysing esters, such as alkali metal hydroxide hydrolysis in aqueous medium. Conversion (2) may be carried out using conventional amidation methods such as tiiose mentioned hereinafter.

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.

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.

The compounds of formulae (II), (IV), (V) and (VI) are considered to be novel compounds and as such form part of the present invention.

The compounds of formulae (III), (VII) and (VIII) are known compounds or they may be prepared by processes analogous to those used to prepare known compounds, for example the compounds of formula (III) may be prepared according to methods disclosed in J.Org.Chem., 1974, 39, 914; the compounds of formula (VII) may be prepared according to methods disclosed in Org. Synthesis 1967, 47,1 and the compounds of formula (VIII) may be prepared according to methods disclosed in Synthesis 1987, 188 or Org. Synthesis, Collective Vol. IV 1963, 590. The salts, esters, amides and solvates of the compounds mentioned herein may be produced by methods conventional in the art:

For example, acid addition salts may be prepared by treating a compound of formula (I) with the appropriate acid. Esters of carboxylic acids may be prepared by conventional esterification procedures, for example alkyl esters may be prepared by treating the required carboxylic acid widi the appropriate alkanol, generally under acidic conditions.

Amides may be prepared using conventional amidation procedures, for example amides of formula CONR^sR^l may be prepared by treating the relevant carboxylic acid with an amine of formula HNR^SR¹ wherein R^s and R^l are as defined above, in the presence of a suitable dehydrating agent, for example dicyclohexylcarbodiimide. Alternatively, a C\. alkyl ester such as a methyl ester of the acid may be treated with an amine of the above defined formula HNR^sR to provide the required amide.

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

If required mixtures of isomers of the compounds of the invention may be separated ΪRto 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.

The absolute configuration of compounds 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.

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 in human or non-huma 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 2-100 mg or 0.1 to 500 mg, and more especially 0.1 to 250 mg.

The present invention further provides a method for treating hyperglycaemia in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide 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, ester or amide 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 or for the treatment of gastrointestinal ulcerations in a human or non-hum mammal, 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 mammal in need thereof.

Conveniently, the active ingredient may be administered as a pharmaceutica composition herein before defined, and this forms a particular aspect of the present invention. In treating hyperglycaemic or obese humans the compound of formula (I), o pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, may be taken in doses, such as those described above, o 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 atherosclerosis, gastrointestinal disorders or gastrointestinal ulcerations are generally as described for hyperglycaemia.

In treating non-human mammals, especially dogs, the active ingredient may be administered by mouth, usually once or twice a day and in an amount in the ran 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 increasi 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 acceptab salt, ester or amide thereof, or a veterinarily acceptable solvate thereof.

Whilst the compounds of formula (I) and the veterinarily acceptable salt, es or amides thereof or a veterinarily acceptable solvate thereof, may be administered any livestock in the above mentioned method, ti ey are particularly suitable for increasing weight gain and/or feed utilisation efficiency and/or lean body mass and 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 salt, ester or amides thereof will normally be administered orally althou 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 0.01 ppm to 250ppm, suitably less than lOOpp .

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.

Example 1

(RR SS)-Disodium 4-[2-[N-[2-(3-chIorophenyl)-2-hydroxyethyl]- amino]propy]phenyloxymalonate

To a solution of (RR SS)-diethyl 4-[2-[N-(3-chlorophenyl)-2- hydroxyethyl]aminopropyl]phenyloxymalonate hydrobromide (100 mg, 0.18 mMol) in dioxane (2 ml) was added 2.5 M sodium hydroxide solution (2.0 ml). The resultant mixture was stirred at 30°C for 24 h. Solid carbon dioxide was added until the solution reached pH9. Chromatography of the mixture over Cjg reverse phase silica eluting with water then a water/isopropanol mixture (0→50% isopropanol) gave the title compound on a white powder, mp>250°C. *H NMR δ (D2O) + water suppression

7.4-7.3 (3H,m); 7.20 (lH.dxd); 7.07 (2H,d); 6.84 (2H,d); 4.89 (lH,s); 3.1-3.0 (2H,m); 2.83 (lH,dxd); 2.78 (lH,dxd); 2.58 (lH,dxd); 1.14 (3H,d).

Example 2

(RR SS)-Diethyl 4-[2-[N-[2-(3-chlorophenyI)-2-hydroxyethyI]- amino]propyl]phenyloxymalonate hydrobromide

CO₂Et A mixture of (RS)-l-(3-chlorop enyl)-2-aminoethanol (0.84 g, 4.9 mMol), diethyl 4-(2-oxopropyI)phenyloxymalonate (1.5 g, 4.9 mMol) and platinum (IV) oxide (25 mg) in methanol (50 ml) was hydrogenated at atmospheric pressure for 14 h. After hydrogen uptake had ceased the mixture was filtered and the solvent evaporated under reduced pressure. The crude compound was chromatographed over silica eluting with 3% methanol in dichloromethane to yield a pale yellow gum. This was dissolved in ethyl acetate (25 ml) and treated with anhydrous hydrogen bromide. The solvent was evaporated and the residue was dissolved in ethyl acetate/methanol and crystallised at -15°C. The resultant crystals were filtered and washed with diethyl ether, mp=160-3°C to yield a single diastereoisomer of RR,SS configuration.

9.0-8.7 (2H,br.m,exchanged with D₂O); 7.7-7.5 (4H,m); 7.28 (2H,d); 7.03 (2H,d); 6.5-6.3 (lH,br.m,exchanged with D2O); 5.76 (lH,s,exchanged with 2O); 5.2-5.1 (lH,m); 4.4-4.2 (4H,m); 3.6-3.5 (lH,m); 3.3-3.1 (3H,m); 2.70 (lH,t); 1.28 (6H,t); 1.17 (3H,d).

Preparation 1

Diethyl 4-(2-oxopropyl)phenyIoxymalonate

To a mixture of diethyl 4-(2-nitropropenyl)phenyloxymalonate (10.33 g, 30.6 mMol) and iron powder (17 g, 306 mMol) suspended in a mixture of methanol (75 ml) and water (25 ml) under reflux was added, with vigorous stirring, acetic acid (60 ml) dropwise.

After completion of addition the mixture was heated for 3 h then cooled and the methanol and acetic acid evaporated under reduced pressure. The residue was diluted with water (500 ml) and ethyl acetate (500 ml), the mixture filtered and the layers separated. The aqueous layer was extracted with ethyl acetate (200 ml) and the combined organic layers were washed with water (250 ml) and brine (200 ml). The yellow solution was dried and evaporated to yield the crude product as an oil. Chromatography over silica gel eluting with 20% ethyl acetate in hexane and gave the title compound as a pale yellow oil.

*H NMR (CDCI3)

7.12 (2H,d); 6.93 (2H,d); 5.18 (lH,s); 4.4-4.2 (4H,m); 3.64 (2H,s); 2.14 (3H,s); 1.30 (6H,t).

Preparation 2

Diethyl 4-(2-nitropropenyl)phenyloxymaIonate

•

A mixture of diethyl 4-formylphenyloxymalonate (10.2 g, 36.4 mMol) and n- butylamine (4 ml, 45 mMol) in benzene (40 ml) was heated under reflux with separation of the water formed. After 1.5 h the mixture was cooled and the benzene evaporated, the residue was dissolved in acetic acid (40 ml) and nitroethane (3 ml, 40 mMol). The mixture was heated on a steam bath for 1.5 h, cooled and poured into water. The organic material was extracted into ethyl acetate (2x150 ml) and the combined extracts washed with water (2 150 ml) dried and evaporated to yield a dark yellow oil. !H NMR δ (CDCI3)

8.02 (lH,s); 7.47 (2H,d); 7.05 (2H,d); 5.31 (lH,s); 4.33 (4H,q); 2.45 (3h,s); 1.27 (6H,t). Preparation 3

Diethyl 4-formyIphenyloxymalonate

To a solution of potassium hydroxide (2.8 g, 50 mMol) in ethanol (40 ml) was added 4-hydroxybenzaldehyde (6.1 g, 50 mMol). After stirring at room temperature for 0.25 h diethyl chloromalonate (9.7 g, 50 mMol) was added and the resultant mixture stirred at reflux for 2 h. The mixture was cooled and the solvent evaporated, the residue partitioned between water (200 ml) and diethyl ether (200 ml). The layers were separated the aqueous layer extracted with diethyl ether (1x100 ml) the combined etheral extracts were washed once with dilute sodium carbonate solution (100 ml) dried and evaporated to yield d e product as a light yellow oil. *H NMR δ (CDC1₃) 9.95 (lH,s); 7.87 (2H,d); 7.13 (2H,d); 5.35 (lH,s); 4.34 (4H,q); 1.34 (6H,t).

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 (-)-N^-(2- phenylisopropyl)adenosine (lOOnM) + deaminase as described 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). Example 1, EC50 = 26.3nM (Intrinsic Activity = 0.74).

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.

Claims

1. A compound of formula (I):

(I)

or a salt, ester or amide thereof, or a solvate thereof, wherein,

R° represents a substituted or unsubstituted aryl group; R represents hydrogen or an alkyl group; R represents a moiety of formula (a):

R⁴

*** y —

— CH

R⁵ (a)

wherein R^ represents a moiety (CH2)_n CO2H wherein n is zero or an integer in the range of from 1 to 3 and R^ represents a moiety (CH2)p CO2H, (CH2)pOH, (CH2)pCN, (CH2)pCOCH3 or (CH2)pNH2 wherein p is zero or an integer in the range of from 1 to 3; and R3 represents hydrogen, halogen, alkyl or alkoxy.

2. A compound according to claim 1, wherein R° represents a phenyl group optionally substituted with up to three substituents selected from halogen, hydroxy, alkoxy, hydroxyalkyl and amino.

3. A compound according to claim 1 or claim 2, wherein R is a methyl group.

4. A compound according to any one of claims 1 to 3, wherein R^ represents a CO2H group or a salt or ester thereof.

5. A compound according to any one of claims 1 to 4, wherein R^ represents a CO2H group or a salt or ester thereof.

6. A compound according to any one of claims 1 to 5, wherein R^ represents hydrogen.

7. A compound according to claim 1, being:

4-[2-[N-[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propy]phenyloxymalonate or a salt, ester or amide thereof, or a solvate thereof.

8. A compound according to any one of claims 1 to 7, wherein the asymmetric carbon atom corresponding to that indicated in formula (I) of claim 1 by a single asterisk (*) is in the R-configuration.

9. A compound according to any one of claims 1 to 8, wherein the asymmetric carbon atom corresponding to that indicated in formula (I) of claim 1 by two asterisks (**) is in the R-configuration.

10. A process for the preparation of a compound of formula (I), or a salt, ester or amide thereof or a solvate thereof, which process comprises reducing a compound of formula (II):

(II)

wherein R°, R , R^ and R^ are as defined in relation to formula (I), and thereafter, if necessary, carrying out one or more of the following optional steps:

(i) converting one compound of formula (I) to another compound of formula (I); and (ii) preparing a salt, ester or amide of a compound of formula (I) or a solvate thereof.

11. 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.

12. 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.

13. 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, obesity, atherosclerosis, hyperinsulinaemia, gastrointestinal disorders or the treatment of gastrointestinal ulcerations.

14. The use of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide diereof; or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of hyperglycaemia, obesity, atherosclerosis, hyperinsulinaemia, gastrointestinal disorders or the treatment of gastrointestinal ulcerations.

15. A method for treating hyperglycaemia, obesity, atherosclerosis, hyperinsulinaemia, gastrointestinal disorders or the treatment of gastrointestinal ulcerations 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, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, to the human or non-human mammal in need thereof.

16. 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.

17. A veterinarily acceptable premix formulation comprising a compound of formula (I), or a veterinarily acceptable salt, ester or amide diereof; or a veterinarily acceptable solvate thereof, in association with a veterinarily acceptable carrier therefore.

18. An intermediate

a) of formula (II):

(II) wherein R°, R¹, R² and R^ are as defined in relation to formula (I) in claim 1; b) of formula (IV):

(IV)

wherein R , R^ and R^ are as defined in relation to formula (I) in claim 1; c) of formula (V):

(V)

wherein R , R^ and R^ are as defined in relation to formula (I) in claim 1; or d) of formula (VI):

(VI) wherein R^ and R^ are as defined in relation to formula (I).