This invention relates to certain 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.

International Patent Application, Publication Number WO91/19702 discloses certain 3-aryl-2-hydroxypropionic acid derivatives which are stated to have useful hypoglycaemic and hypocholesterolaemic activity. WO92/03425 disclose certain hydroxyurea derivatives which are also stated to be useful as hypoglycaemic and hypocholesterolaemic agents.

It has now surprisingly been discovered that certain novel compounds, show particularly good blood-glucose lowering activity and are therefore of potential use in the treatm -t and/or prophylaxis of hyperglycaemia and are of particular use in the treatment of Type II diabetes. These compounds are also indicated to be of potential use for the treatment and/or prophylaxis of other diseases including hyperlipidaemia and hypertension. They are also indicated to be of use in the treatment and/or prophylaxis of cardiovascular disease, especially atherosclerosis. In addition these compounds are considered to be useful for treating certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating, such as anorexia nervosa, and disorders associated with over¬ eating, such as obesity and anorexia bulimia.

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

A— X (CH ₂ ) _n — O A — (CH ₂ ) _m CH< ₂ COR

(I)

or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein:

A* represents a substituted or unsubstituted aromatic heterocyclyl group;

A^ represents a benzene ring having three optional substituents;

R! represents a moiety CH2-R^ wherein R^ represents hydrogen, optionally substituted alkyl wherein optional substituents are selected from the list consisting of: alkox) . phenyl, phenoxy, aminoalkyl, alkylaminoalkyl and bisalkylaminoalkyl, or R3 represents optionally substituted alkenyl wherein optional substituents are selected from the list consisting of alkyl, phenyl and phenyl substituted with halogen, alkyl,

phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups or R^ represents an alkoxy group;

R represents OR^ wherein R^ represents hydrogen, alkyl, aryl or aralkyl, or R^ represents-NR5R5a wherein R^ and R^ ^a each independently represent hydrogen or alkyl or R^ and R^ ^a together with the nitrogen atom to which they are attached form a heterocyclic ring;

X represents O, S or NR wherein R represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group; m represents an integer in the range of from 1 to 6 and n represents an integer in the range of from 2 to 6.

Suitably, A* represents a substituted or unsubstituted, single or fused ring aromatic heterocyclyl group comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen.

Favourably, A* represents a substituted or unsubstituted single ring aromatic heterocyclyl groups having 4 to 7 ring atoms, preferably 5 or 6 ring atoms.

In particular, the A* aromatic heterocyclyl group comprises 1, 2 or 3 heteroatoms, especially 1 or 2, selected from oxygen, sulphur or nitrogen. Suitable values for A when it represents a 5- membered aromatic heterocyclyl group include thiazolyl and oxazolyl, especially oxazolyl.

Suitable values for A* when it represents a 6- membered aromatic heterocyclyl group include pyridyl or pyrimidinyl, especially pyridyl.

A particular pyridyl group is a 2-pyridyl group. Preferably, A* represents a moiety of formula (a), (b) or (c):

(a) (b) (c)

wherein:

R6 and R^ each independently represents a hydrogen or halogen atom, an alkyl or alkoxy group or a substituted or unsubstituted aryl group or when R*> and R? are each attached to adjacent carbon atoms, then R" and R^ together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom represented by R" and R^ together may be substituted or unsubstituted; and in the moiety of formula (a) X* represents oxygen or sulphur.

Aptly, A ¹ represents a moiety of the abovedefined formula (a). Aptly, A* represents a moiety of the abovedefined formula (b). Aptly, A* represents a moiety of the above defined formula (c). One favoured moiety (c) is that wherein the linking bond is attached to a ring carbon adjacent to the ring nitrogen atom.

In one favoured aspect R^ and R^ together represent a moiety of formula (d):

wherein R^ and R^ each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy. Suitably, R^ and R^ each independently represent hydrogen, halogen, alkyl or alkoxy. Favourably, R represents hydrogen. Favourably, R^ represents hydrogen. Preferably, R^ and R^ both represent hydrogen.

In a further favoured aspect R*> and R? each independently represent hydrogen, alkyl or a substituted or unsubstituted phenyl group and more favourably, R" and R each independently represent hydrogen, alkyl or phenyl.

Preferably, for the moiety of formula (a), R^ and R together represent the moiety of formula (d).

Preferably, for the moieties of formula (b) or (c), R*> and R? both represent hydrogen. Favoured optional substituents for A^ are selected from the group consisting of halogen, substituted or unsubstituted alkyl and alkoxy.

Favourably, A^ represents a moiety of formula (e):

(e)

wherein R 0 and R* 1 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.

Suitably, R 0 and R^ each independently represent hydrogen, halogen, alkyl or alkoxy. Preferably, R*0 and R * each represent hydrogen.

In one aspect, X represents O. In a further aspect, X represents S. In yet a further aspect, and preferably, X represents NR.

When R3 represents alkyl it is suitably C _j .g alkyl including methyl, ethyl, n- and iso propyl, n- and iso butyl and pentyl, especially n-pentyl.

Suitable optional substituents for any alkyl group represented by R^ include 1 to 3 substituents selected from the list consisting of: alkoxy, phenyl, phenoxy, aminoalkyl, alkylaminoalkyl and bisalkylaminoalkyl.

When R3 represents substituted alkyl, a favoured optional substituent is a phenyl group, generally substituted at the terminal position on the respective alkyl group.

Examples of substituted alkyl groups represented by R^ include benzyl, 2-phenylethyl, 3-phenylpropyl and 4-phenylbutyl, especially 2-phenylethyl and 4- phenylbutyl.

When R3 represents alkenyl it is suitably C2-6 alkenyl, a particular example is ethenyl.

Suitable optional substituents for any alkenyl group represented by R^ include 1 to 3 substituents selected from the list consisting of: alkyl, phenyl and phenyl substituted with halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy and alkylcarbonyl.

When R represents substituted alkenyl, favoured optional substituents include one or more C\_ alkyl groups, such as methyl, and phenyl: generally the substituents are at the terminal position on the respective alkenyl group.

Examples of substituted alkenyl groups represented by R^ include 2-phenylethenyl and 2,2-dimethylethenyl.

When R3 represents C _^ alkoxy, a particular example is methoxy.

Suitably, R^ represents alkyl or optionally substituted alkyl. Suitably, R ² represents OR ⁴ .

Suitably, R ⁴ represents hydrogen, alkyl or aryl, in particular hydrogen or alkyl.

Favourably R ⁴ represents hydrogen or Cj.g alkyl such as methyl.

Suitably, R represents hydrogen or alkyl. When R is acyl, suitable acyl groups include acetyl.

Suitably, m represents 1.

Suitably, n represents 2.

As indicated above, a compound of formula (I), and the pharmaceutically acceptable salts thereof, may exist in one of several tautomeric forms, all of which arc encompassed by the present invention as individual tautomeric forms or as mixtures thereof. The compounds of formula (I) may contain at least one chiral carbon, and hence they may exist in one or more stereoisomeric forms. The present invention encompasses all of the stereoisomeric forms of the compounds of formula (I) and the

pharmaceutically acceptable salts thereof, whether as individual stereoisomers or as mixtures of isomers, including racemates.

When used herein, unless otherwise stated, the term 'aryl' includes phenyl and naphthyl; any aryl group mentioned herein may be optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxyca-rbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.

When used herein the term Tialogen' refers to fluorine, chlorine, bromine and iodine; preferably chlorine. As used herein, alkyl groups, whether present alone or as part of other groups, such as alkoxy, aralkyl or alkylcarbonyl groups, are alkyl groups having straight or branched carbon chains containing up to 12 carbon atoms. Thus, suitable alkyl groups are Cj-12 alkyl groups, especially Cι_6 alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups. used herein, alkenyl groups, whether present alone or as part of other groups a... aikenyl groups having straight or branched carbon chains, containing up to 12 carbon atoms. Thus, suitable alkyl groups are C2-12 alkenyl groups, especially C2-6 alkenyl groups

Suitable substituents for any alkyl group, unless indicated to the contrary, include those indicated above in relation to the term "aryl".

Suitable acyl groups include alkylcarbonyl groups

Suitable pharmaceutically acceptable salts include salts of carboxy groups and acid addition salts.

Suitable pharmaceutically acceptable salts of carboxy groups include metal salts, such as for example alumir :um, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alky ^' Ines such as triethylamine, hydroxyalkylamines 1 -h as 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-β

-phenethylamine, dehydroabietylamine, N,N ^, -bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.

Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinr benzoate, ascorbate, methane-sulphonate, α-keto glutarate and α-glycerophospha

Suitable pharmaceutically acceptable solvates include hydrates. A compound of formula (I) may be prepared from a compound of formula (II) activated so as to react at the *CH2 carbon atom:

A-X— (CH-). —O — A ² (Chy _m Chi, —CO — R ^P

(ID

wherein A , A ² , X, m and n are as defined in relation to the compound of formula (I) and RP represents R ² or a protected form thereof, by reaction with a compound of formula (III):

R3-CH ₂ -Ll (HI) wherein R^ is as defined in relation to formula (I) and L represents a leaving group or atom; and thereafter if required carrying out one or more of the following optional steps:

(i) converting a compound of formula (I) into a further compound of formula (I);

(ii) removing any protecting group; and

(iii) preparing a pharmaceutically acceptable salt of a compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.

Preferably, L.1 represents a halogen atom such as chlorine or bromine.

A suitably activated form of a compound of formula (II) is an anionic form or a masked anionic form.

Suitable reaction conditions are the appropriate conventional conditions depending upon the nature of the compounds of formula (II) and (III). Thus the reaction between the activated form of a compound of formula (II) and the compound of formula (III) may be carried out in an aprotic solvent, such as tetrahydrofuran, under anhydrous conditions, at a temperature which provides a suitable rate of formation of the required product, being generally a low to medium temperature, such as in the range of from -90°C to 40°C, conveniently at ambient temperature; preferably the reaction is carried out in an inert atmosphere, for example under nitrogen or argon.

The activated form of the compound of formula (II) may be prepared by any appropriate conventional procedure, for example the anionic form of the compound of formula (II) may be prepared by treating the compound of formula (II) with a base, such as a metal hydride base for example sodium hydride, or a metal amide base, such as a lithium amide. One preferred base is the lithium amide, lithium diisopropylamide.

The masked anionic form of a compound of formula (II) may also be made by conventional procedures, for example, by treatment with a base in the presence of a chlorosilane such as chlorotrimetiiylsilane.

A compound of formula (II) may be prepared by reacting a compound of formula (IN):

R ^a A ² (CH.,)-,, CH ₂ — CO— R ^p

(IV)

wherein A ² , RP and m are as defined in relation to formula (II) and R ^a is a moiety capable of being converted into a moiety of formula (f):

Al-X-(CH ₂ ) _n -0- (f) wherein A*, X and n are as defined in relation to formula (I), with an appropriate reagent capable of converting R ^a into the said moiety of formula (f). Suitably, R ^a represents HX-(CH.2) _n -O- wherein X and n are as defined in relation to formula (I), or R ^a represents OH. Preferably, R ^a represents OH.

When R ^a is HX-(CH2) _n -O-. an appropriate reagent capable of converting R ^a to a moiety (f) is a compound of formula (N):

A1 - L2 (V)

wherein A is as defined in relation to formula (I) and L ² represents a leaving grc or atom. A suitable leaving group L ² is a halogen atom, preferably chlorine or bromine atom, or a thioalkyl group for example a thiomethyl group.

When R ^a is OH, an appropriate reagent is a compound of formula (VI):

A ¹ — X — (CH ₂ ) _n — OL ³ (VI)

wherein A*, X and n are as defined in relation to formula (I) and l represents hydrogen or a leaving group, such as a tosyiate or mesylate group.

The reaction between the compound of formula (IV) and the appropriate reagent may be carried out under conditions Jictated by the particular compound of formula (IV) and the reagent chosen:

For example, the above mentioned reaction between a compound of formula (IV) wherein R ^a represents HX-(CH2)n-O- and the compound of formula (V), may

be carried out in any suitable solvent, for example dimethylformamide, at a temperature which provides a suitable rate of formation of the compound of formula (II), for example at an elevated temperature in the range from 50°C to 120°C, preferably in the presence of a base such as sodium hydride. The reaction conditions for the reaction between a compound of formula (IV) wherein R ^a is OH and the compound of formula (VI) tend to vary with the nature of (VI): Thus when L 3 in the reagent of formula (VI) represents a leaving group, such as a tosylate or mesylate group, the reaction between the compound of formula (VI) and the compound of formula (II) wherein R ^a is OH may be carried out in an aprotic solvent, such as dimethylformamide, at a low to an elevated temperature, for example in the range from 50°C to 120°C, for example at 80°C, and preferably in the presence of a base, such as sodium hydride. However, when 1? in the reagent of formula (VI) represents a hydrogen atom, the reaction between the compound of formula (VI) and the compound of formula (IN) wherein R ^a is OH is conveniently carried out in the presence of a suitable coupling agent; a suitable coupling agent being provided by diethylazodicarboxylate and triphenylphosphine. The coupling reaction may be carried out in any suitable solvent at a low to medium temperature, for example in tetrahydrofuran at a temperature in the range of between 0 and 60°C, conveniently at ambient temperature. Preferably, R ^a represents a hydroxyl group and a particularly appropriate reagent is a compound of formula (VI).

A compound of formula (IV) may be prepared by reducing a compound of formula (VII):

R— A ² — CH=CH (CH,),,— CO— R

(vπ)

wherein A ² and RP are as defined in relation to formula (IV), q is zero or an integer 1, 2, 3, 4 or 5 and R^ represents R ^a or a protected form thereof; and thereafter, if required, removing any protecting group.

The reduction of a compound of formula (VII) may be effected by standard reduction methods, for example by catalytic reduction using platinum (IV) oxide catalyst and hydrogen.

A compound of formula (VII) may be prepared by reacting a compound of formula (VIII): b 2

R — A — CHO

(VIII)

wherein R ^D and A ² are as defined in relation to formula (VII) with a reagent capable of forming a moiety wherein RP and q are as defined above, from the -CHO group.

Suitably R* ⁵ represents a protected OH group, such as a benzylated OH group.

A suitable reagent capable of forming the above defined moiety CH=CH-(CH2) _q -CO-RP from the -CHO group is a Wittig reagent of formula (IX):

[Ph ₃ P - (CH ₂ ) _q+ i - CO - RP] ⁺ M" ^κ )

wherein RP and q are as defined in relation to the compound of formula (VII) and M" is a counter-ion, suitably a halogen, for example chloride or bromide.

The above mentioned reaction between the compound of formula (VIII) and the said reagent may be carried out under conventional conditions depending upon the particular nature of the reagent used: for example the reaction between a compound of formula (VIII) and the Wittig reagent of formula (IX) may be carried out under conventional Wittig reaction conditions in an aprotic solvent, such as tetrahydrofuran or, preferably dimethyl sulphoxide, at low to ambient temperature, such as in the range of fror-u - 10° to 25°C, generally at 0 - 10°C. The reaction is most effectively carried out under an inert atmosphere and under anhydrous conditions. Preferably, the Wittig reagent is activated prior to addition of the compound of formula (VIH) by addition of a base such as sodium hydride.

For compounds of formula (TV) wherein m is 1, the reagent is preferably a

Wadsworth Emmons reagent of formula (X):

(X)

wherein RP is as defined in relation to formula (VI) and R*2 represents a Cj.g alkyl group, preferably a methyl or ethyl group, for example for compounds of formula (IV) wherein R*2 i _s methoxy, the Wadsworth Emmons reagent of formula (X) is trimethyl phosphonoacetate.

The reaction between a compound of formula (VIII) and the Wadsworth Emmons reagent of formula (X) may be carried out under conventional Wadsworth Emmons reaction conditions, for example in an aprotic solvent, such as tetrahydrofuran, at low to ambient temperature, such as in the range of from -10° to 25°C generally at 0 - 10°C, and preferably in the presence of a base such as sodium hydride. The reaction is most effectively carried out under an inert atmosphere and

under anhydrous conditions. Preferably, the trimethyl phosphonoacetate is activated prior to addition of the compound of formula (VIII) by addition of a base such as sodium hydride.

A compound of formula (I) wherein m is 1 may be prepared by dehydroxylating a compound of formula (XI):

A ¹ — X— (CH ₂ ) _n — O— A ² — CH — CH

OOR' (XI)

wherein A*, A ² , X, Rl, R ² and n are as defined in relation to the compound of formula (I); and thereafter if required carrying out one or more of the following optional steps:

(i) converting a compound of formula (I) into a further compound of formula (I);

(ii) removing any protecting group; and

(iii) preparing a pharmaceutically acceptable salt of a compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.

The dehydroxylation of the compounds of formula (XI) may be carried out using any appropriate dehydroxylation procedure, in particular we have found that the dehydroxylation is conveniently carried out by using a trialkylsilane, for example triethylsilane, in the presence of an acid such as trifluoroacetic acid. The dehydroxylation reaction using the trialkylsilane is conveniently carried out in an inert solvent such as dichloromethane at any convenient temperature which provides a suitable rate of formation of the required product, for example at ambient temperature.

A compound of formula (XI) may be prepared by reacting a compound of formula (XII):

A ¹ -X-(CH ₂ ) _n -O-A ² -CHO (XII)

wherein A*, A ² , X and n are as defined in relation to the compound of formula (I), with a compound of formula (XIII):

Rl-*CH ₂ -COR ² P (XIII)

wherein Rl is as defined in relation to formula (I) and R ² P is R ² as defined in relation to formula (I), or a protected form thereof.

Generally, the compound of formula (XIII) is in an activated form, activated so as to react at the *CH2 carbon atom.

For compounds of formula (XI) wherein R ² is OR ⁴ , R P is usually R ² .

For compounds of formula (XI) wherein R ² is -NR^R5a wherein R^ and R^ ^a are as defined above and especially when R^ and R^ ^a each independently represent hydrogen, R ² P is usually a protected form of the required group R ² , such as a benzylated or silylated form.

A suitable activated form of a compound of formula (XIII) is provided by forming an ionic form [R -CH-COR ² ]- M ⁺ wherein R* and R ² are as defined above and Mtas a salting ion such as an alkaline metal ion for example a lithium ion.

The activated form of a compound of formula (XIII) may be prepared by any appropiate method, for example by treating the compound of formula (XIII) with a base, such as a metal hydride base for example sodium hydride, or a metal amide base, such as a lithium amide. One preferred base is the lithium amide, lithium diisopropylamide.

Favourably the reaction between the compounds of foumulae (XII) and (XIII) is carried out under conventional Aldol reaction conditions.

The reaction is conveniently carried out in an aprotic solvent, such as tetrahydrofuran, at any temperature which provides a suitable rate of formation of the required product, generally at a low to ambient temperature, such as a temperature in the range of from -80° to 25°C generally at -70°C. The reaction is most effectively carried out under an inert atmosphere, such as argon, and under anhydrous conditions.

A compound of formula (I) wherein m is 1 may also be prepared by reducing a compound of formula (XIV):

/

A ¹ -X— (CH ₂ ) _n — O A ² CH=CH

COR' (XIV)

wherein A*, A ² , X, R , R ² and n are as defined in relation to the compound of formula (I); and thereafter if required carrying out one or more of the following optional steps:

(i) converting a compound of formula (I) into a further compound of formula (I);

(ii) removing any protecting group; and

(iii) preparing a pharmaceutically acceptable salt of a compound of formula (I) and/or a pharmaceutically acceptable solvate thereof. The reduction of a compound of formula (XIV) may be carried out using conventional reduction procedures, in particular catalytic hydrogenation using for

example a 10% palladium on charcoal catalyst and hydrogen in an alkanol solvent such as methanol, at a temperature and pressure which provides a suitable rate of formation of the required product, for example at ambient temperature and conveniently using hydrogen at atmospheric pressure. A compound of formula (XIV) may be prepared by dehydrating a compound of the above defined formula (XI).

The dehydration of the compound of formula (XI) is suitably carried out under conventional dehydration reaction conditions, for example by treating the compound of formula (XI) with pαrα-toluenesulphonic acid in an inert, preferably water immisible solvent, such as toluene. The reaction is conveniently carried out at any temperature which provides a suitable rate of formation of the required product generally being an elevated temperature, conveniently at the reflux temperature of the solvent, preferably removing the water produced form the reaction, using for example a Dean and Stark apparatus. The compounds of formula (IV), wherein R ^a is OH and m is 1, are known commercially available compounds or they are compounds prepared by methods analogous to those used to prepare known compounds, for example those disclosed in Dictionary of Organic Compounds 5th Edition, Vol. 3, p.3222, Chapman & Hall, or D.H. Williams et. al. J.Chem.Soc., Section B, 1969, 439, or J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.

The compounds of formulae (IX), (X) and (XIII) are known compounds or they may be prepared according to methods used to prepare known compounds, for example those disclosed in J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience. The compounds of formula (V), (VI), (VIII) and (XII) are known compounds or they are prepared according to methods used to prepare known compounds, for example those methods disclosed in EP 0306228.

The abovementioned conversion of a compound of formula (I) into a further compound of formula (I) includes: a) converting one group R into another group R; b) converting one group CO.R ² into another group CO.R ² .

The abovementioned conversions may as appropriate be carried out on any of the intermediate compounds mentioned herein.

The conversion of a compound of formula (I) to a further compound of formula (I) may be carried out by using any appropriate conventional procedure.

Suitable conversions of one group R into another group R include converting a group R which represents hydrogen into a group R which represents an acyl group; such conversion may be carried out using an appropriate conventional acylation

procedure, for example treating an appropriately protected compound of formula (I) with an acylating agent. Thus acetic anhydride may be used to prepare the compound of formula (I) wherein R is acetyl.

Suitable conversions of one group CO.R ² into another group CO.R ² include: (i) hydrolysing one group CCR ³ wherein R^ is alkyl, aryl or aralkyl into a group CO.OH; and

(ii) aminating one group CO.R ² *' wherein R ² ° is alkoxy into a group CO.NR5R5a wherein R^ and R^ ^a are as defined in relation to formula(I).

Suite -5 hydrolysis methods for use in conveπ "^n b(i) are conventior-.il ester hydrolysis methods, for example using an alkali hydroxide in aqueous methanol. Suitable animation methods for conversion b(ii) include conventional methods, for example treatment with aqueous ammonia in tetrahydrofuran/methanol or treatment with an appropriate dialkylam^ - in a so! at such as tetrahydrofuran/methanol. It will be appreciated that in any of the abov. ioned reactions including the <-.-- vementioned conversions (a) and (b) any reac , . ; group in the substrate molecule may be protected, according to conventional chemical practice.

In the abovementioned procedures protecting groups will be used when and ss necessary in accordance with conventional procedures. Suitable protecting groups in any of the abovementioned reactions are those used conventionally in the art. Thus, for example, a suitable hydroxyl protecting group is a benzyl group. A suitable amino protecting group is a benzyl group or a silyl group.

The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected. Thus for example a benzyloxy group may be prepared by treatment of the appropriate compound with a benzyl halide, such as benzyl bromide, and thereafter, if required, the benzyl group may be conveniently removed using catab r hydrogenation or a mild ether cleavage reagent such as trimethylsilyl iodide or boron tribromide. An N-benzyl group may be inserted and removed by similar treatment of an appropriate amine compound and an N-silyl group may be prepared by treating the appropriate amine compound with a chloroalkyl silane, such as tert-butyl dimethylsilylchloride, in the presence of a base such as sodiur- hydride.

As mε- jned above the compounds of the invention are indicated as having useful therapeutic properties: The present invention accordingly provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use -s an active therapeutic substance.

Thus the present invention provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of hyperglycaemia. In a further aspect the present invention also provides a compound of formula

(I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment and/or prophylaxis of hyperlipidaemia.

As indicated hereinbefore the present invention also provides a compound of formula (I) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof for use in the treatment of hypertension, cardiovascular disease and certain eating disorders.

Cardiovascular disease includes in particular atherosclerosis.

Certain eating disorders include in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating ,such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia.

A compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/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 the general formula (I), or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.

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

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

Usually the pharmaceutical compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption 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 0.1 to 500 mg, and more especially 0.1 to 250 mg. The present invention further provides a method fo* the treatment and/or prophylaxis of hyperglycaemia in a human or non-human » ammal which comprises administering an effective, non-toxic, amount of a compound of the general formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/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 the treatment of hyperlipidaemia in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, to a hyperlipidaemic human or non-human mammal 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 the treatment and/or prophylaxis of hyperglycaemic humans, and/or the treatment and/or prophylaxis of hyperlipidaemic human, the compound of the general formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/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.

In the treatment and/or prophylaxis of hyperglycaemic 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. Similar dosage regimens are suitable for the treatment and/or prophylaxis of hyperlipidaemia in non-human mammals.

The dosages regimens for the treatment of hypertension, cardiovascular disease and eating disorders will generally be those mentioned above in relation to hyperglycaemia.

In a further aspect the present invention provides the use of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of hyperglycaemia.

The present invention also provides the use of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of hyperlipidaemia, hypertension, cardiovascular disease or certain eating disorders.

No toxicological effects have been established for the compounds of formula (I) in the abovementioned dosage ranges. The following Procedures and Examples illustrate the invention but do not limit it in any way.

Procedure 1

Methyl 3-(4-(2-(N-(2-benzoxazolyI)-N-methylamino)ethoxy)phenyl)prop anoate

Sodium hydride (60% dispersion in oil, 2.5 lg) was added portionwise to a stirred, ice cooled solution of methyl 3-(4-hydroxyphenyl)propanoate (10.25g) in dry N,N- dimethylforma-mide (100ml) under a nitrogen atmosphere. The mixture was stirred for 40 minutes at room temperature . ior to the addition of a solution of 2-[N-(2- benzoxazolyl)-N-methylamino]ethanol methanesulphony' ester (Eur. Patent Appl., Publication No. 0306228) (15.39g) in N,N-dimethylformamide (150ml). The mixture was heated at 80°C for 23.5 hrs, cooled and concentrated in vacuo, then diluted with water (11) and extracted with ethyl acetate (3x400ml). The combined organic extracts were washed with water (2x11) and brine (11), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel using 1.5% ethyl acetate in dichloromethane as eluent to afford the title compound, mp 51-2°C. !H NMR δ (CDCI3) 2.58 (2H,t), 2.88 (2H,t), 3.34 (3H,s), 3.65 (3H,s), 3.93 (2H,t), 4.23 (2H,t), 6.81 (2H,d) and 6.90-7.45 ppm(6H,complex).

Procedure 2

Methyl 3-(4-(2-(N-(2-benzoxazolyl)-N-methyIamino)ethoxy)phenyl)-3-h ydroxy-

2-(4-phenylbut-l-yl)propanoate

To a solution of diisopropylamine (0.90 ml) in tetrahydrofuran (THF, distilled from sodium and benzophenone, 5 ml) at 0°C was added n-butyllithium (1.6 M, 4.0 ml) under a dry argon atmosphere. After stirring for ten minutes, the mixture was cooled to -70°C and a solution of methyl 6-phenylhexanoate (1.2 g) in THF (5 ml) was added slowly. Stirring was continued for seventy five minutes at -70°C and then 4- (2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)benzaldehyde (1.72 g) in THF (5 ml) was added. The reaction was maintained at -70°C for a further 60 minutes and then allowed to warm to room temperature. Saturated aqueous ammonium chloride (20 ml) was added and the mixture was extracted with ethyl acetate (3 x 15 ml). The combined organic extracts dried over anhydrous magnesium sulphate. Filtration and removal of solvent gave an oil which was chromatographed on silica gel eluting with

5 to 30% (gradient elution) ethyl acetate in hexane to afford the title compound as a mixture of two diastereoisomers.

Procedure 3 Methyl 3-(4-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2-( 4- phenyIbut-l-yl)p

A solution of methyl 3-(4-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-3- hydroxy-2-(4-phenylbut-l-yl)propanoate (2.78 g), as a mixture diastereomers, and p-toluenesulphonic acid (10 mg) in toluene (100 ml) was heated at reflux using a Dean and Stark apparatus for 18 hours. The solvent was evaporated and the crude product dissolved in dichloromethane (100 ml). The organic phase was washed with saturated sodium hydrogen carbonate (2 x 50 ml) and dried over anhydrous magnesium sulphate. Filtration and removal of solvent gave the title compound, as an oil, as a mixture of geometric isomers.

^J H NMR δ (CDCI3) 1.63 (4H,m), 2.63 (4H,m), 3.34 (3H,s), 3.64 (3H,s), 3.97 (2H,t), 4.30 (2H,t), 6.82-7.37 (13H,m) and 7.58 (lH,s).

Procedure 4 Methyl 3-hydroxy-2-(3-phenylprop-l-yl)-3-(4-(2-(N-(2-pyridyl)-N-met hyl-

The title compound, as a mixture of diastereomers, was prepared from 4-(2-(N-(2- pyridyl)-N-methylamino)ethoxy)benzaldehyde and methyl 5-phenylpentanoate by a method similar to that described in Procedure 2.

Procedure 5

Methyl 2-(3-phenylprop-l-yI)-3-(4-(2-(N-(2-pyridyl)-N-methylamino)e thoxy)- phenyl)prop-2-enoate

The title compound, as a mixture of geometric isomers, was prepared from methyl 3- hydroxy-2-(3-phenylprop-l-yl)-3-(4-(2-(N-(2-pyridyl)-N-methy lamino)ethoxy)- phenyl)propanoate by a method similar to that described in Procedure 3.

^l H NMR δ (CDCI3) 1.86 (2H,m), 2.55 (2H,m), 2.69 (2H,t), 3.15 (3H,s), 3.79 (3H,s), 3.9 (2H,t), 4.20 (2H,t), 6.50-6.59 (2H,m), 6.79 (2H,d), 7.13-7.31 (7H,m), 7.43 (lH,m), 7.57 (lH,s) and 8.16 ppm (lH,d).

Procedure 6

Methyl 3-(4-(2-(N-(2-benzoxazolyI)-N-methylamino)ethoxy)phenyl)-3-h ydroxy- 2-(2-phenoxyethyl)proparιoate

The title compound, as a m xture of diastereomers, was prepared from 4-(2-(N-(2- benzoxazolyl)-N-methylamino)ethoxy)benzaldehyde and methyl 4-phenoxybutyrate by a method similar to that described in Procedure 1

Procedure 7

Methyl 3-(4-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-3-h ydroxy- 2-(5-phenylpent-

The title compound, as a mixture of diastereomers, was prepared from 4-(2-(N-(2- benzoxazolyi)-N-methylamino)ethoxy)benzaldehyde and methyl 7-phenylheptanoate by a method similar to that described in Procedure 2.

Example 1

Methyl 3-(4-(2-(N-(2-benzoxazolyI)-N-methylamino)ethoxy)phenyI)-2-( 3-propen- l-yl)propanoate

To a solution of lith um (LDA) (1.5 M, 2.26 ml) in tetrahydrofuran (THF, distilled from sodium and benzophenone, 5 ml) at -70°C under a dry nitrogen atmosphere was added methyl 3-(4-(2-(N-(2-benzoxazolyl)-N-methylamino) ethoxy)phenyl)propanoate (1 g) in THF (5 ml). The reaction was stirred at -70°C for 2 hours and then allyl bromide (0.41 g) in THF (5 ml) was added. After raising the temperature to ambient, stirring was continued for a further 16 hours and saturated

ammonium chloride (30 ml) was added. The organic phase was separated and the aqueous phase extracted further using ethyl acetate (2 x 15 ml). The combined organic extracts were dried over anhydrous magnesium sulphate and filtered. Removal of solvent on a rotary evaporator gave an oil. The crude product was chromatographed on silica gel eluting with 10 to 30% (gradient elution) ethyl acetate in hexane to afford the title compound as an oil.

^X H NMR δ (CDC1 ₃ ) 2.29 (2H,m), 2.69 (2H,m), 2.82 (lH,m), 3.35 (3H,s), 3.58 (3H,s), 3.93 (2H,t), 4.23 (2H,t), 5.01 (2H,m), 5.72 (lH,m), 6.78 (2H,d) and 6.98-7.37 ppm (6H,m).

Example 2

3-(4-(2-(N-(2-Benzoxazolyl)-N-methylamino)ethoxy)phenyI)- 2-(3-propen-I-yl)- propanoic acid

A solution of methyl 3-(4-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2- (3-propen-l-yl)propanoate (0.85 g) and sodium hydroxide (0.13 g) in methanol (3 ml) and water (3 ml) was heated at reflux for 4 hours. After cooling, the organic solvent was removed on a rotary evaporator and aqueous residue diluted with water (20 ml). The aqueous solution was acidified using dilute hydrochloric acid and then extracted using ethyl acetate (3 x 15 ml). After drying over magnesium sulphate and filtering, the filtrate was concentrated on a rotary evaporator to afford the title compound as a solid, mp 106-7°C (C22H24N2O4 requires C, 69.46; H, 6.36; N, 7.36; found C, 69.56; H, 6.38; and N, 7.49%). *H NMR δ (DMSO) 2.18 (2H,m), 2.65-2.75 (3H,m), 3.22 (3H,s), 3.87 (2H,t), 4.21 (2H,t), 4.99-5.06 (2H,m), 5.70-5.77 (lH,m), 6.82-7.39 (8H,m) and 12.15 ppm (lH,br).

Example 3

Methyl 3-(4-(2-(N-(2-benzoxazoIyl)-N-methylamino)ethoxy)phenyl)-2-( prop-I- yI)propanoate

A solution of methyl 3-(4-(2-(N-(2-benz»xazolylVN-methylamino)ethoxy)phenyl)-2- (3-propen-l-yl)propanoate (0.40 g) in methanol (20 ml), 10% palladium on charcoal (40 mg) and cyclohexene (1 ml) was heated at reflux for 2 hours and cooled. The catalyst was filtered off and the filtrate evaporated to afford the title compound as an oil.

!H NMR δ (CDC1 ₃ ) 0.87 (3H,t), 1.20-1.65 (4H,m), 2.60-2.90 (3H,m), 3.35 (3H,s), 3.58 (3H,s), 3.93 (2H,t), 4.23 (2H,t), 6.78 (2H,d) and 7.00-7.37 ppm (6H,m).

Example 4

3-(4-(2-(N-(2-Benzoxazolyl)-N-methylamino)ethoxy)phenyl)- 2-(prop-l-yl)- propanoic acid

A solution of methyl 3-(4-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2- (prop-l-yl)propanoate (0.39 g), sodium hy -oxide (79 mg) in methanol (2 ml) and water (2 ml) was heated at reflux for 3 hou: After cooling, the organic solvent was removed on a rotary evaporator and the aqueous residue diluted with water (20 ml).

The aqueous solution was acidified with dilute hydrochloric acid and then extracted using ethyl acetate (3 x 15 ml). The combined organic extracts were dried over anhydrous magnesium sulphate and filtered. The filtrate was evaporated to afford the title compound as a solid, mp 108-9° (C22H26 ^N 2°4 requires C, 69.09; H, 6.85; N,

7.32; found C, 69.08; H, 6.75; and N, 7.43%).

^X H NMR δ (CDCI3) 0.90 (3H,t), 1.30-1.49 (4H,m), 2.64-2.74 (2H,m), 2.86 (lH,m), .31 (3H,s), 3.88 (2H,m), 4.09 (2H,m), 6.76 (2H,d) and 6.97-7.36 ppm (7H,m).

Example 5

Methyl 3-(4-(2-(N-(2-benzoxazoIyl)-N-methylamino)ethoxy)phenyl)-2- (cinnamyl)propanoate

The title compound was prepared from methyl 3-(4-(2-(N-(2-benzoxazolyl)-N- methylamino)ethoxy)phenyl)propanoate and cinnamyl bromide as described in Example 1. The crude product was chromatographed on silica gel eluting with 10 to 30% (gradient elution) ethyl acetate in hexane to afford the product as an oil. ^l NMR δ (CDCI ) 2.39-2.50 (2H,m), 2.71-2.79 (2H,m), 2.91 (lH,m), 3.35 (3H,s), 3.59 (3H,s), 3.94 (2H,t), 4.24 (2H,t), 6.05-6.15 (lH,m), 6.39 (lH,d) and 6.78-7.38 ppm (13H,m).

Example 6

3-(4-(2-(N-(2-BenzoxazolyI)-N-methylamino)ethoxy)phenyl)- 2-(cinnamyI)- propanoic acid

The title compound, a white solid mp 95-6°C, was prepared from methyl 3-(4-(2-(N- (2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2-(cinnamyl)pr opanoate by a procedure similar to that described in Example 2 (C28H28N2O4 requires C, 73.66;

H, 6.18; N, 6.14; found C, 73.61; H, 6.17; and N, 6.25%). lH NMR δ (CDCI3) 2.55 (2H,m), 2.81 (3H,m), 3.30 (3H,s), 3.87 (2H,m), 4.08

(2H,m), 6.23 (lH,m), 6.45 (lH,d), 6.74 (2H,d), 7.00-7.35 (HH,m) and 10.50 ppm (lH,br).

Example 7

Methyl 3-(4-(2-(N-(2-benzoxazolyI)-N-methylamin)ethoxy)phenyI)-2-(3 - phenylprop-l-yl)propanoate

A solution of methyl 3-(4-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2- (cinnamyl)propanoate (0.40 g) in methanol (10 ml) was hydrogenated for 24 hours over 10% palladium on charcoal (40 mg) at atmospheric pressure and ambient

temperature. The catalyst was filtered off and the filtrate evaporated. The crude product was chromatographed on silica gel eluting with diethyl ether to afford the title compound as an oil.

*H NMR δ (CDCI3) 1.55-1.65 (4H,m), 2.55-2.70 (4H,m), 2.81-2.86 (lH,m), 3.35 (3H,s), 3.57 (3H,s), 3.94 (2H,t), 4.23 (2H,t), 6.77 (2H,d) and 7.00-7.37 ppm (1 lH,m).

Example 8

3-(4-(2-(N-(2-BenzoxazolyI)-N-methylamino)ethoxy)phenyi)- 2-(3-phenylprop-l- yl)propanoic acid

The title compound, a white solid mp 91-2°C, was prepared from methyl 3-(4-(2-(N- (2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2-(3-phenylpro p-l-yl)propanoate by a procedure similar to that described in Example 2 (C28H30N2O4 requires C, 73.34; H, 6.59; N, 6.11; found C, 73.34; H, 6.63; and N, 6.23%).

*H NMR δ (CDCI3) 1.55-1.70 (4H,m), 2.58-2.73 (4H,m), 2.82-2.91 (lH,m), 3.30 (3H,s), 3.39 (2H,m), 4.06 (2H,m), 6.74 (2H,d) and 6.97-7.50 ppm (12H,m).

Example 9

Methyl 3-(4-(2-(N-(2-benzoxazoIyI)-N-methyIamino)ethoxy)phenyI)-2- (methoxymethyl)propanoate

The title compound was prepared from methyl 3-(4-(2-(N-(2-benzoxazolyl)-N- methylamino)ethoxy)phenyl)propanoate and bromomethyl methyl ether by a procedure similar to that described in Example 1. The crude product was chromatographed on a silica gel eluting with 10 to 30% (gradient) ethyl acetate in hexane to afford the product as an oil.

*H NMR δ (CDCI3) 2.75-2.90 (3H,m), 3.31 (3H,s), 3.35 (3H,s), 3.40-3.56 (2H,m), 3.63 (3H,s), 3.93 (2H,t), 4.23 (2H,t), 6.80 (2H,d) and 6.97-7.38 ppm (6H,m).

Example 10

3-(4-(2-(N-(2-BenzoxazoIyl)-N-methyIamino)ethoxy)phenyI)- 2-(methoxymethyl)- propanoic acid

The title compound, white solid mp 107-8 was prepared from methyl 3-(4-(2- (N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)propanoate by a procedure similar to that described in Example 2 (C21H24N2O5 requires C, 65.61; H, 6.29; N, 7.29; found C, 65.87; H, 6.29; and N, 7.34%). !H NMR δ (CDCI3) 2.78-2.95 (3H,m), 3.32 (3H,s), 3.34 (3H,s), 3.46-3.56 (2H,m), 3.90 (2H,m), 4.15 (2H,m), 6.77 (2H,d) and 6.97-7.37 ppm (7H,m).

Example 11

Methyl 3-(4-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyI)-2-( 2- methy!but-2-ene-4-yl)propanoate

The title compound was prepared from methyl 3-(4-(2-(N-(2-benzoxazolyl)-N- methylamino)ethoxy)phenyl)propanoate and 4-bromo-2-methyl-2-butene as described in Example 1. The crude product was chromatographed on silica gel eluting with 5 to 20% (gradient elution) in hexane to afford the product as an oil. lH NMR δ (CDCI3) 1.56 (3H,s), 1.68 (3H,s), 2.25 (2H,m), 2.60-2.90 (3H,m), 3.34 (3H,s), 3.57 (3H,s), 3.93 (2H,t), 4.23 (2H,t), 5.06 (lH,m), 6.78 (2H,d) and 7.00-7.37 ppm (6H,m).

Example 12

3-(4-(2-(N-(2-Benzoxazolyl)-N-methylamino)ethoxy)phenyl-2 -(2-methylbut-2-en- 4-yI)propanoic acid

The title compound, a white solid mp 106-7°C, was prepared from methyl 3-(4-(2-

(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2-(2-met hylbut-2-ene-4-yl)- propanoate by a procedure similar to that described in Example 2 (C24H28N2O4 requires C, 70.59; H, 6.86; N, 6.86; found C, 70.81; H, 7.00; and N, 6.92%). !H NMR δ (CDCI3) 1.58 (3H,s), 1.70 (3H,s), 2.23-2.40 (2H,m), 2.65-2.87 (3H,m),

3.31 (3H,s), 3.88 (2H,m), 4.06 (2H,m), 5.14 (lH,m), 6.75 (2H,d) and 6.97-7.37 ppm

(7H,m).

Example 13

Methyl 3-(4-(2-(N-(2-benzoxazolyI)-N-methyIamino)ethoxy)phenyl)-2-( 3- methyIbut-l-yl)propanoate

The title compound was prepared from methyl 3-(4-(2-(N-(2-benzoxazolyl)-N- methylamino)ethoxy)phenyl)-2-(2-methylbut-2-ene-4-yl)propano ate by a procedure similar to tha; described in Example 7.

*H NMR δ (CDCI3) 0.90 (3H,s), 0.93 (3H,s), 1.23 (2H,m), 1.55 (3H,m), 2.58-2.96

(3H,m), 3.42 (3H,s), 3.65 (3H,s), 4.01 (2H,t), 4.37 (2H,t), 6.86 (2H,d) and 7.08-7.45 ppm (6H,m).

Example 14

3-(4-(2-(N-(2-Benzoxazolyl)-N-methylamino)ethoxy)phenyl)- 2-(3-methylbut-l- yl)propanoic acid

The title compound, a white solid mp 103-4°C, was prepared from methyl 3-(4-(2- (N-(2-benzoxa-zolyl)-N-methylamino)ethoxy)phenyl)-2-(methylb ut-l-yl)propanoate by a procedure similar to that described in Example 2 (C24H30N2O4 requires C, 70.22; H, 7.37; N, 6.82; found C, 70.06; H, 7.56; and N, 6.78%). *H NMR δ (CDCI3) 0.85 (6H,m), 1.23 (2H,m), 1.45-1.55 (3H,m), 2.55-2.75

(2H,m), 2.79 (lH,m), 3.30 (3H,s), 3.88 (2H,m), 4.10 (2H,m), 6.76 (2H,d), and 6.97- 7.37 ppm (7H,m).

Example 15 Methyl 3-(4-(2-(N-(2-benzoxazoIyl)-N-methyIamino)ethoxy)phenyl)-2-( 2- phenylethyl)propanoate

The title compound was prepared from methyl 3-(4-(2-(N-(2-benzoxazolyl)-N- methylamino)ethoxy)phenyl)propanoate and phenethylbromide by a similar method to that described in Example 1. The crude product was chromatographed on silica gel eluting with 10 to 30% (gradient elution) ethyl acetate in hexane to afford the product as an oil. lH NMR δ (CDCI3) 1.80 (lH,m), 1.97 (lH,m), 2.50-2.72 (4H,m), 2.90 (lH,m), 3.34

(3H,s), 3.59 (3H,s), 3.93 (2H,t), 4.27 (2H,t), 6.77 (2H,d) and 6.97-7.37 ppm (HH,m).

Example 16

Methyl 3-(4-(2-(N-(2-benzoxazolyl)-N-methyIamino)ethoxy)phenyI)-2-( hex-l- yl)propanoate

The title compound was prepared from methyl 3-(4-(2-(N-(2-benzoxazolyl)-N- methylamino)ethoxy)phenyl propanoate and 1-iodohexane by a similar method to that

described in Example 1. The crude product was chromatographed on silica gel eluting with 5 to 30% (gradient elution) ethyl acetate in hexane to afford the product as an oil.

*H NMR δ (CDCI ) 0.87 (3H,m), 1.24 (8H,m), 1.49 (lH,m), 1.65 (lH,m), 2.57-2.95 (3H,m), 3.34 (3H,s), 3.58 (3H,s), 3.94 (2H,t), 4.23 (2H,t), 6.78 (2H,d) and 7.02-7.35 ppm (6H,m).

Example 17

3-(4-(2-(N-(2-BenzoxazoIyI)-N-methylamino)ethoxy)phenyI)- 2-(hex-l- yOpropanoic acid

The title compound, a solid mp 63-64°C, was prepared from methyl 3-(4-(2-(N-(2- benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2-(hex- 1 -yl)propanoate by a procedure similar to that described in Example 2 (C25H32N2O4 requires C, 70.73; H, 7.60; N, 6.60; found C, 70.49; H, 7.86; and N, 6.23%).

^X H NMR δ ( DCI3) 0.86 (3H,m), 1.25 (8H,m), 1.50 (lH,m), 1.62 (lH,m), 2.59- 2.87 (3H,m), 3.31 (3H,s), 3.89 (2H,m), 4.12 (2H,m), 6.74 (2H,d) and 6.97-7.30 ppm (7H,m).

Example 18

Methyl 3-(4-(2-(N-(2-benzoxazoIyl)-N-methylamino)ethoxy)phenyl)-2- ethylpropanoate

The title compound was prepared from methyl 3-(4-(2-(N-(2-benzoxazolyl)-N- methylamino)ethoxy)phenyl)propanoate and iodoethane by a similar method to that described in Example 1. The crude product was chromatographed on silica gel eluting with 5 to 30% (gradient elution)ethyl acetate in hexane to afford the product as an oil.

*H NMR δ (CDCI3) 0.89 (3H,t), 1.73 (2H,m), 2.53 (lH,m), 2.68 (lH,m), 2.81 (lH,m), 3.34 (3H,s), 3.59 (3H,s), 3.93 (2H,t), 4.23 (2H,t), 6.79 (2H,d) and 6.97-7.37 ppm (6H,m).

Example 19

3-(4-(2-(N-(2-BenzoxazoIyl)-N-methylamino)ethoxy)phenyl)- 2-ethyIpropanoic acid

The title compound, a solid mp 106-107°C, was prepared from methyl 3-(4-(2-(N-(2- benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2-ethylpropanoate by a procedure similar to that described in Example 2 (C21H24N2O4 requires C, 68.46; H, 6.57; N, 7.60; found C, 68.39; H, 6.68; and N, 7.63%). lH NMR δ (CDCI3) 0.96 (3H,t), 1.62 (2H,m), 2.56-2.92 (3H,m), 3.30 (3H,s), 3.88 (2H,m), 4.10 (2H,m), 5.60 (lH,br s), 6.76 (2H,d) and 6.97-7.36 ppm (6H,m).

Example 20

Methyl 3-(4-(2-(N-(2-benzoxazoIyI)-N-methylamino)ethoxy)phenyI)-2-( 4-

A solution of a mixture of double bond isomers of methyl 3-(4-(2-(N-(2- benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2-(4-phenylbut-l- yl)prop-2-enoate (1.65 g) in methanol (25 ml) was hydrogenated for 24 hours over 10% palladium on charcoal (200 mg) at atmospheric pressure and ambient temperature. The catalyst was filtered off and the filtrate evaporated to afford the title compound as an oil. *H NMR δ (CDCI3) 1.33 (2H,m), 1.63 (4H,m), 2.56 (4H,m), 2.80 (lH,m), 3.34 (3H,s), 3.56 (3H,s), 3.93 (2H,t), 4.23 (2H,t), 6.79 (2H,d) and 7.00-7.37 ppm (HH,m).

Example 21 3-(4-(2-(N-(2-Benzoxazolyl)-N-methyIamino)ethoxy)phenyI)-2-( 4-phenylbut-l- yI)propanoic acid

The title compound, a solid, mp 103-104°C, was prepared from methyl 3-(4-(2-(N-(2- benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2-(4-phenylbut- 1 -yl)propanoate by a procedure similar to that described in Example 2 (C29H32N2O4 requires C, 73.71; H, 6.83; N, 5.93; found C, 73.79; H, 6.76; and N, 6.13%).

^X H NMR δ (CDCI3) 1.25-1.76 (6H,m), 2.55-2.72 (4H,m), 2.83-2.91 (lH,m), 3.30 (3H,s), 3.87 (2H,m), 4.09 (2H,m), 6.75 (2H,d) and 6.96-7.36 ppm (12H,m).

Example 22

Methyl 2-(3-phenylprop-l-yl)-3-(4-(2-(N-(2-pyridyl)-N-methylamino)e thoxy)- phenyl)propanoate

The title compound, an oil, was prepared from methyl 2-(3-phenylprop-l-yl)-3-(4-(2- (N-(2-pyridyl)-N-methylamino)ethoxy)phenyl)prop-2-enoate by a procedure similar to that described in Example 20.

*H NMR δ (CDCI ₃ ) 1.59 (4H,m), 2.59 (4H,m), 2.84 (lH,m), 3.14 (3H,s), 3.57 (3H,s), 3.96 (2H,t), 4.15 (2H,t), 6.52 (2H,m), 6.78 (2H,d), 7.01 (2H,d), 7.11-7.28 (5H,m), 7.44 (lH,d) and 8.14 ppm (lH,d).

Example ^Λ~

Methyl 3- .-*-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2-(2 - phenoxyethyl)propanoate

A solution of methyl 3-(4-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-3- hydroxy-2-(2-phenoxyethyl)propanoate (2.86 g) in trifluoroacetic acid (4.50 ml), triethylsilane (9.30 ml) and dichloromethane (10 ml) was stirred at ambient temperature for 18 hours. The organic phase was washed exhaustively with saturated sodium hydrogen carbonate and dried over anhydrous magnesium sulphate. Filtration and evaporation of solvent afforded the crude product which was chromatographed on silica gel eluting with 5 to 30% (gradient elution) ethyl acetate in hexane to afford the title compound as an oil. *H NMR δ (CDCI3) 1.90 (lH,m), 2.10 (lH,m), 2.73-2.95 (3H,m), 3.34 (3H,s), 3.59 (3H,s), 3.93 (4H,m), 4.23 (2H,t) and 6.78-7.37 ppm (13H,m).

Example 24

3-(4-(2-(N-(2-Benzoxazolyl)-N-methylamino)ethoxy)phenyl)- 2-(2-phenoxyethyI)- propanoic acid

The title compound, a white solid, mp 94-95°C was prepared from methyl 3-(4-(2-

(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2-(2-phe noxyethyl)propanoate

by a procedure similar to that described in Example 2 (C27H28N2O5 requires C, 70.42; H, 6.13; N, 6.08; found C, 70.35, H, 6.14; and N, 6.14%). *H NMR δ (CDCI3) 2.00 (lH,m), 2.17 (lH,m), 2.79-3.00 (3H,m), 3.29 (3H,s), 3.86 (2H,m), 4.03 (4H,m), 6.73-7.33 (13H,m) and 10.10 ppm (lH.br s).

Example 25

Methyl 3-(4-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2-( 5- phenyIpent-l-yI)propanoate

The title compound, an oil, was prepared from methyl 3-(4-(2-(N-(2-benzoxazolyl)- N-methylamino)ethoxy)phenyl)-3-hydroxy-2-(5-phenylpent- l-yl)propanoate by a procedure similar to that described in Example 23.

*H NMR δ (CDCI3) 1.23-1.75 (8H,m), 2.27-2.85 (5H,m), 3.34 (3H,s), 3.57 (3H,s), 3.93 (2H,t), 4.22 (2H,t), 6.78 (2H,d) and 6.97 -7.38 ppm (1 lH,m).

Example 26

3-(4-(2-(N-(2-Benzoxazolyl)-N-methylamino)ethoxy)phenyl)- 2-(5-phenylpent-l- y propanoic acid

The title compound, a solid mp 94-95°C, was prepared from methyl 3-(4-(2-(N-(2- benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2-(5-phenylpent- 1 -yl)propanoate by a procedure similar to that described in Example 2.

*H NMR δ (CDCI3) 1.26-1.75 (8H,m), 2.54-2.72 (4H,m), 2.83-2.91 (lH,m), 3.30 (3H,s), 3.87 (2H,m), 4.01-4.13 (2H,m), 6.75 (2H,d), 6.96-7.36 (HH,m) and 9.20 ppm (lH,br s).

DEMONSTRATION OF EFFICACY OF COMPOUNDS

The efficacy of the compounds of the invention is demonstrated using the following test procedure.

Obese Mice, Oral Glucose Tolerance Test.

C57bll 6 obese (ob/ob) mice were fed on powdered oxoid diet. After at least one week, the mice rontinued on a powdered oxoid diet or were fed powered oxoid diet containing the test compound. After 8 days on the supplemented diet all of the mice were fasted for 5 hours prior to receiving an oral load of glucose (3g/kg). Blood samples for glucose analysis were taken 0, 45, 90 and 135 minutes after glucose administration and the results appear below as the percentage reduction in area under the blood glucose curve where test compound treated groups are compared with the control group. 8 mice were used for each treatment.

Results

Example No. LevelinDiet %Reductionin

(μmol.kg" ¹ ofdiet) areaunderblood glucosecurve

2 30 26 4 30 44 6 100 33

8 100 50

3 25

10 30 27 12 30 21 14 1000 66 15 300 47 17 10 35 19 30 26 21 300 32 22 100 32 24 100 47 26 30 32