NZ299256A - Separating optical isomers of hydroxy carboxylic acid derivatives using enzymes - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £99256 2992 5 6 | Priority Date(s): 3|.!.)a2L j asls. las | CcTsp'its Specification Fiisclt .asMsa V lass: .^.feSa/osr, G.p-i&sn.. Is?.!? F jblication Dato: f-'.O. Journal No: 1 «... ,, . — NO DRAWINGS NEW ZEALAND PATENTS ACT, 1953 Divided out of No.: 253742 Dated: 29 June 1993 COMPLETE SPECIFICATION PROCESS FOR SEPARATING OPTICAL ISOMERS We, SMITHKLINE BEECHAM PLC, of New Horizons Court, Brentford, Middlesex TW8 9EP, England, a British Company, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement Under the precisions of Regu- Istion 2o j •) SpC-Ci'V; •. I-•••■ to io43t_ Wh.

Initials (followed by page la) 29925 -la 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.

European Patent Applications, Publication Numbers 0008203,0139421, 0155845,0177353,0193256,0207581,0208420,0306228 and International Patent Application Publication No. WO 9101337 relate to thiazolidinedione derivatives which are disclosed as having hypoglycaemic and hypolipidaemic activity. Chem. Phann. Bull 1982,30 (10) 3580-3600 relates to certain thiazolidinedione derivatives having hypoglycaemic and hypolipidaemic activities.

International Patent Application, Publication Number WO 91/19702 discloses compounds of formula (A) and (B): X R (A) Z OY (B) wherein A is or n is 0 cr 1; m is 0, 1 or 2; — represents a bond or no bond; R is (Ci-Cg)alkyl, (C3-C7>cycloalkyl, (C3-Cg)alkenyl, (C3-Cg)alkynyl, 29 92 ^ % IN 4 phenyl, (C7_Cg)phcnylalkyl, (C2-Cg)a^au:K>y^ or one of said groups mono- or disubstltuted with (Ci-C3>alkyl, trifluoromorocthyl, hydroxy, (Ci-C3>alkoxy, fluoro or chloro; W is O, CO. CH2. CHOH or -CH=CH-; X is S, O, NR2, -CH=CH-, -CH=N- or -N=CH-' R2 is hydrogen, (C]-C3)alkyl, phenyl or benzyl; Y is CH or N; Z is H, amino, (Cj-C7)alkyl, (C3-C7>cycloalkyl, phenyl, or phenyl mono- or disubstituted with (Ci-C3>alkyl, trifluoromethyl, (Ci-C3>alkoxy, phenyl, phenoxy, 10 benzyl, benzyloxy, fluoro or chloro; Z* is hydrogen or (Ci-C3>alkyl; X1 is O, S, SO or SO# and Y* is hydroxy, (C]-C3)alkoxy, phenoxy, benzyloxy, amino, (C j .(^alkanoylamino, (C j -C4)alkancsulfonyl-amino, benzenesulfonylamino, IS naphthalenesulfonylamino, di[(Cj-C3)alkyl]aminosulfonylamino, or one of said groups mono- or disubstituted with (Cj-C3)allcyl, trifluoromethyL, hydroxy, (Ci_C3)alkoxy, fluoro or chloro; the phanmceutically-acceptable cationic salts thereof when Y1 is hydroxy; and die pharmaceutical 1 y-acceptable acid addition salts thereof when the compounds contain a bask nitrogen atom. 20 The compounds of formula (A) are stated to be useful as hypoglycaemic and hypochlolesterolemic agents.

It has now surprisingly been discovered that certain novel compounds, structurally distinct from die abovementioned compounds, show particularly good blood-glucose lowering activity and are therefore of potential use in die treatment 25 and/or prophylaxis of hyperglycaemia and are of particular use in the treatment of Type n diabetes.

These compounds are also indicated to be of potential use for the treatment and/or prophylaxis of other diseases including hyperlipidacmia and hypertension. They are also indicated to be of use in die treatment and/or prophylaxis of 30 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 overeating, such as obesity and anorexia bulimia.

Accordingly, die present invention provides a compound of formula (I): a'—X—(CHjJjt-O—A2—A3 —Y.R2 (I) 29925 ft 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; A2 represents a benzene ring having three optional substituents; A^ represents a moiety of formula -(CH2)iii-CH(ORl)- wherein R* represents substituted or unsubstituted alkyl, aryl, aralkyl or alkylcarbonyl and m represents an integer in the range of from 1 to 5, or A^ represents a moiety of formula -<CH2)m-r CH^CCOR1)- wherein R1 and m are as defined above; R2 represents OR^ wherein r3 represents hydrogen, alkyl, aryl or aralkyl or R2 represents an aromatic heterocyclyl group or -NR^R^ wherein R* and R^ each independently represent hydrogen, alkyl or alkylcarbonyl or R^ and R^ together with the nitrogen atom to which they are attached form a heterocyclic ring, providing that R2 represents an aromatic heterocyclyl group only when Y as defined below represents a bond; X represents NR wherein R represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group wherein die aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aiyl group; Y represents 0=0 or OS or a bond providing that Y represents a bond only when R2 represents die above mentioned aromatic heterocyclyl group; and n represents an integer in the range of from 2 to 6.

Suitable aromatic heterocyclyl groups include substituted en- unsubstituted, angle or fused ring aromatic heterocyclyl groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen.

Favoured aromaiic heterocyclyl groups include substituted or unsubstituted single ring aromatic heterocyclyl groups having 5 to 7 ring atoms, preferably 5 or 6 ring atoms.

In particular, the 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 A1 when it represents a 6- membered aromatic heterocyclyl group include pyridyl or pyrimidinyl, especially pyridyl.

Preferably, A* represents a moiety of formula (a), (b) or (c): 29925 ^ ,X- a —*^v 7 N (a) (b) (c) wherein: R*> 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 caxbon atoms, then R*> and R? together with the carbon atoms to which they axe attached fonn a benzene ring wherein each caxbon atom xepresentcd by R^ and R? together is substituted or unsubstituted; and in the moiety of formula (a) X* represents oxygen or sulphur.

Aptly, A* 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 abovedefined formula (c).

A particular form of moiety (c) is a moiety (cO: 6 R <C) wherein R.6 and R? are as defined in relation to formula (c).

In one favoured aspect R*> and R? together represent a moiety of formula (d): (d) wherein R&a and R^b each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.

Suitably, R^ and R^b each independently represent hydrogen, halogen, alkyl or alkoxy. Favourably, R^a represents hydrogen. Favourably, R^b represents hydrogen. Preferably, R^a and R**b both represent hydrogen. 29925^ In a further favoured aspect R*> and R? each independently represent hydrogen, alkyl or a substituted or unsubstituted phenyl group and more favourably, r6 and R? each independently represent hydrogen, alkyl or phenyl.

Preferably, for tht moiety of formula (a), R*> and R? together represent the 5 moiety of formula (d).

Preferably, for the moieties of formula (b), (c) or (c*), R*> and R? both represent hydrogen.

Optional substituents for A2 axe selected from the group consisting of: halogen, substituted or unsubstituted alkyl and alkoxy.

Favourably, A2 represents a moiety of formula (e): -Q- (C) wherein RiO 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.

When RlO or R*1 represent alkoxy, a suitable alkoxy group is a methoxy group.

Preferably, R*0 and R* 1 each represent hydrogen.

Suitably, A 3 iv^^esents a moiety of formula -(CH2)m-CH(OR^)-.

Suitably, A^ represents a moiety of formula -CH=C(ORl)-.

When R1 represents alkyl, suitable alkyl groups are Ci_6 alkyl groups, for 25 example methyl, ethyl, propyl, such as n-propyl and uo-propyl, and butyl, such as t-butyl. A preferred alkyl group is an ethyl group.

When Rl is substituted alkyl, particular substituents for the alkyl group include halo, hydroxy, alkoxy or a moiety -NRSR1, wherein Rs and Rl each independendy represents hydrogen or alkyl or Rs and R( together with the nitrogen 30 atom to which they are attached form a 5- or 6- membered heterocyclic ring, or a moiety of formula -CO X2 wherein X2 represents OH, alkoxy or a moiety of the above defined formula -NRSR*.

Suitable haloalkyl groups include fluoroalkyl groups, such as txifluoioethyl groups.

Generally when R* is substituted alkyl, the substituent is attached to a terminal carbon atom of the alkyl group. 29925 « Whcn R* represents alkylcarbonyl, suitable alkylcarbonyl groups include Ci_£ alkylcarbonyl groups.

When R* represents aiyl, suitable aryl groups include phenyl or naphthyl groups.

When R1 represents aralkyl, suitable aralkyl groups include phenylalkyl groups for example benzyl and phenylethyl groups.

A preferred aralkyl group is a benzyl group.

Favoured substituents for any aryl group represented by R1 includes halo, alkyl and alkoxy groups; examples of such substituents include chloro, methyl and methoxy groups.

Suitably, R* represents substituted or unsubstituted alkyl or substituted or unsubstituted aralkyl Preferably, R* is unsubstituted alkyl or unsubstituted aralkyl.

Suitably, R2 represents OR3- Suitably, r3 represents hydrogen or alkyl.

When R3 is alkyl, examples of R3 include methyl and ethyl.

When R2 is an aromatic heterocyclyl group it is suitably a single ring aromatic heterocyclyl group having 5 ring atoms, which ring atoms comprise nitrogen and optionally 1,2 or 3 additional hetero atoms; examples include 1, 2,4-triazole; 1,2,4-oxadiazole and tetrazolyl; generally die aromatic heterocyclyl group is C-linkcd.

Suitable substituents on the aromatic heterocyclyl group include alkyl, aryl, alkoxy and halo, an example of a substituent is methyl.

When -Nr4r3 or -NRsRt represents a heterocyclic ring, favoured heterocyclic rings are saturated or unsaturated, fused or monocyclic heterocyclic rings comprising 5,6 or 7 ring atoms and optionally comprising 1 or 2 additional hetero-atoms, selected from O.S or N, in each ring. Favoured rings are saturated rings. Favoured rings are monocyclic rings. Favoured, additional hetero-atoms are N or O. Examples of such heterocyclic rings include N- pynolidinyl, N-piperidinyl and N-morpholinyl.

A further example of NR^p5 is NH2.

Suitably, R2 represents NR^R^.

Preferably R2 is OR3.

Suitably when R2 represents OR-* wherein R3 represents hydrogen, alkyl, aryl or aralkyl or R2 represents -NR^pA Y is CO or CS; preferably, Y is CO.

When R2 is an aromatic heterocyclyl group, Y is a bond.

Suitably, R represents hydrogen or alkyl.

When R is acyl, suitable acyl groups include alkylcarbonyl groups, such as acetyl. 2992 n -7 Suitably, m represents 1 or 2.

Favourably, m is 1.

Favourably, n is 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 are 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 stereoisomers forms. For example, when A3 10 represents a moiety of formula -(CH^m-CHCORl)- the CH(OR * )-carbon atom is a chiral carbon. In addition, when A3 represents a moiety of formula -(CH2)m-1 -CH=C(OR * y the compounds of formula (I) exist as geometric isomers. The present invention encompasses all of the isomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof, whether as individual 15 isomers or as mixtures of isomers, including racemates.

Suitable substituents for any heterocyclyl group inclu up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent caxixm atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a phenylene group, and wherein the 20 carbon atoms of the aryl group represented by die said two substituents may themselves be substituted or unsubstituted.

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, 25 haloalkyl, hydroxy, amino, nitro, caiboxy, alkoxycarbonyl, alkoxy caibonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.

When used herein die term "halogen1 refers to fluorine, chlorine, bromine and iodine; preferably chlorine.

As used herein, alkyl groups, whether present alone or as part of other groups 30 such as alkoxy or aralkyl groups, are alkyl groups having straight or branched carbon chains, containing up to 12 carbon atoms. Thus, suitable alkyl groups are alkyl groups, especially Cj_6 alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups.

Suitable substituents for any alkyl group include those indicated above in 35 relation to the term "aryl".

Favoured aralkyl groups axe phenylalkyl groups, optionally substituted on the aryl or alkyl moieties as defined herein.

Suitable acyl groups include alkylcarbonyl groups 29 92* 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 aluminium, 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 alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-anune or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-^-phcncthylamine, dehydroabietylamine, N,Nr-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, succinate, benzoate, ascorbate, methane-sulphonate, a-keto glutaratc and a-glyccrophosphatc.

Suitable pharmaceutically acceptable solvates include hydrates.

The salts and/or solvates of the compounds of formula (I) may be prepared and isolated according to conventional procedures for example sodium salts may be prepared by using sodium methoxide in methanol.

In a further aspect die present invention also provides a process for the preparation of a compound of formula (I), or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable hydrate thereof, which process comprises reacting a compound of formula (II): • 2 s r R—A—A —Y.R (ID wherein A2 and Y are as defined in relation to formula (I); A3' represents a moiety of formula -(CH2)m-CH(OR *')- wherein R1' represents R1 as defined in relation to formula (I) or a protected form thereof, and m is as defined in relation to formula (I), or A3 represents a moiety of formula i~CH=C(OR^ )- wherein R*' is as defined above; R2 represents R2 as defined in relation to formula (l)< or a protected form thereof and Ra is a moiety convertible to a moiety of formula (f): A*-X-(CH2)n-0- (0 29925 wherein A*, X and n are as defined in relation to formula (I); with an appropriate reagent capable of converting Ra to the said moiety (f) and thereafter. If required, carrying out one or more of die following optional steps: 0) converting a compound of fonnula (I) to a further compound of fonnula (I); (ii) removing any necessary protecting group; (iii) preparing a pharmaceutically acceptable salt of the compound of formula 0) and/or a pharmaceutically acceptable solvate thereof.

Suitably, Ra represents HX-(CH2)n-0- wherein X and n are as defined in relation to formula (I), or Ra represents OH.

Preferably, Ra represents OH.

When Ra is HX-(CH2)n-0-, an appropriate reagent capable of converting Ra to a moiety (f) is a compound of formula (HI): A* - Rx (HI) wherein A* is as defined in relation to fonnula (I) and Rx represents a leaving group.

A suitable leaving group Rx includes a halogen atom, preferably a chlorine or bromine atom, or a thioalkyl group for example a thiomethyl group.

Generally, R*' is R*. Preferably, R2, represents OR3' wherein R3' represents hydrogen, alkyl, aryl, aralkyl or R2 represents the above defined moiety -NR^R^. When Ra is OH, an appropriate reagent is a compound of formula (IIIA): Ai-X^CH^n-ORy (IDA) wherein A*, X and n are as defined in relation to formula (I) and Ry represents a leaving group, such as a tosylate or mesylate group.

The reaction between the compound of fonnula (II) and the appropriate reagent may be carried out under conditions suitable to the particular compound of formula (ED and the reagent chosen: For example the abovementioned reaction between a compound of formula (II) wherein Ra represents HX-(CH2)n-0- and the compound of fonnula (HI), may be carried out in any suitable solvent, for example dimcthylfoimamide, at a temperature which provides a suitable rate of formation of the compound of formula (I), for example at an elevated temperature in the range from 50°C to 120°C, preferably in the presence of a base such as triethylamine.

In a further example, the reaction between the compound of formula (II) wherein Ra is OH and the reagent of the abovedefined fonnula (MA) may be carried 29925R 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. In an alternative aspect, when Ry in die compound of formula (ECIA) represents H and Ra is OH in the 5 compound of formula (II), then a suitable reagent is 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.

A compound of formula (II), wherein A3' represents a moiety of formula -10 (CH^^-CHCORl')-, may be prepared by reacting a source of a carbene of fonnula (IV): R—A (CH2),j (IV) wherein A2, Y and m are as defined in relation to the compound of fonnula (I), R*3 is a moiety Ra or a moiety convertible to a moiety Ra and R^ is the above defined R2' or a protecting group, with a compound of fonnula (V): Rl'OH (V) wherein R*' is defined in relation to formula (II); and thereafter, if required, converting a moiety Rb into a moiety Ra and removing any protecting group. Preferably,Y is CO. Preferably, R9 is OR3' or -NR4rS-25 A suitable source of the carbene of formula (IV) is provided by reacting a compound of fonnula (IVA): R—A2 (CHJ. C—Y—R# N2 (IVA) wherein A2, R^ Rb, Y and m are as defined in relation to formula (TV), with a rhodium (II) salt, such as rhodium (II) acetate.

The conditions used in the preparation of the carbene of fonnula (IV) from (IVA) will of course depend upon the particular carbene chosen, but in general 35 conventional procedures are used, for example when (TV) is the carbene and (IVA) is the source of carbene then suitable conditions are analogous to those disclosed in 29925* Tetrahedron Lett 1973,2233.

The reaction between the carbene of formula (IV) and the compound of fonnula (V) may be carried out under conventional conditions, generally in an inert solvent, such as benzene, or when practicable in compound (V) as solvent, at any temperature providing a convenient rate of formation of the required product, generally at an elevated temperature, such as the reflux temperature of the solvent: Suitably, the conditions used are analogous to those disclosed in Tetrahedron Lett, 1973,2233.

When the source of the carbene is a compound of formula (IVA), the compound of formula (IVA) may be prepared by diazotizing a compound of formula (VI): R—h (CH2)„ CH—Y —RS NH2 (VI) wherein A2, R?, Rb Y and m are as defined in relation to the compound of formula (IV), with an appropriate diazotizing agent; and thereafter, if required, converting a moiety Rb into a moiety Ra and removing any protecting group.

A suitable diazotizing agent is an alkyl nitrite, such as iso-amyl nitrite.

Suitable diszotising conditions for preparing the compound of formula (IVA) are conventional conditions, for example those disclosed in Tetrahedron Lett., 1971, 4495.

Any moiety Rb may be converted into a moiety Ra by the appropriate conventional means, for example when Rb represents -OH and Ra represents HX-(CH2)n-0- die appropriate conversion may be carried out by coupling a compound of formula (VI) wherein Rb is OH with a compound of formula (g): RZ-X-(CH2)n-OH (g) wherein X and n axe as defined in relation to formula (I) and Rz is a protecting group and thereafter, if necessary, removing any protecting group.

The last abovementioned reaction is generally carried out in the presence of a suitable coupling agent; a suitable coupling agent being diethylazodicarboxylate and triphenylphosphine. The coupling reaction may be carried out in any suitable solvent at« tow to medium temperature, for example in tetrahydiofuran at a temperature in the range of between 0 and 60°C Generally, for the preparation of compounds of formula (II), wherein Ra is 299?-^ OH, from compounds of formula (TV), Rb in (IV) is either OH or a protected OH, such as a benzylated OH.

The compounds of fonnula (V) are known-commercially available compounds or they may be prepared using methods analogous to those used to prepare such 5 compounds.

The compounds of formula (VI) are known compounds or they may be prepared using methods analogous to those used to prepare known compounds, for example those disclosed in Tetrahedron Lett, 1971,4495, in particular the compound wherein R9 is OCH3, m is 1, A2 is 1,4-phenylene and Rb is OH is a commercially 10 available compound.

The compounds of formula (g) are known compounds or they may be prepared using methods analogous to those used to prepare known compounds, for example those disclosed in EP0356214.

A compound of formula (I), wherein A3 represents a moiety of formula -15 (CH2)m-CH(OR *)-, or a tautomeric fonn thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may also be prepared by reacting an activated form of a compound of fonnula (VII): A— x—(CH2)„ o—A—(CH2) —CH —Y -R OH (VII) wherein A*. A2, X, Y, m and n are as defined in relation to formula (I) and is as defined in relation to fonnula (TV) with a compound of formula (VIII); R1 - L* (Vm) wherein R* is as defined in relation to formula 0) and L* represents a leaving group or atom; and thereafter if required carrying out one or more of the following optional 30 steps: (i) converting a compound of formula (I) into a further compound of fonnula (I); (ii) removing any protecting group; and (iii) preparing a pharmaceutically acceptable salt .of a compound of formula (I) 35 and/or a pharmaceutically acceptable solvate thereof.

Suitably, L* is a halogen atom, for example a bromine atom.

A suitable activated form of a compound of fonnula (VII) is an anionic form such as a salted fonn and especially an alkali metal salted form, for example a sodium salt Hie activated form of the compound of formula (VII) may be prepared by any appropriate conventional procedure. Fen* example, the anionic form of the compound 5 of formula (VII) may be prepared by treating the compound of formula (VH) with a base, such as a metal hydride base, for example sodium hydride.

The reaction conditions for the reaction between the compounds of formulae (VII) and (VIH) are generally conventional alkylation conditions. For example the reaction between the salted form of a compound of formula (VII) and a compound of 10 formula (Vm) may be carried out in an aprotic solvent, such as dimethylformamide, at any temperature providing a suitable rate of formation of the required product, generally an elevated temperature such as in the range of 40°C to 100°C, for example 80°C Favourably, die formation of die activated form of (VII) from (VII) - for 15 example the formation of a salted form of (VII) - may be carried out in-situ prior to the reaction of the activated fonn of (VII) with the above defined compound of formula (VHI).

A compound of formula (VII) may be prepared by reacting a compound of formula (IX): R-—A-—(CH2)b CH —Y —R* OT (IX) wherein Ra, R?, A2, Y and m are as defined above and T is hydrogen or a hydroxyl 25 protecting group, with an appropriate reagent capable of converting Ra to a moiety of the above defined formula (f).

The reagent capable of converting Ra to a moiety of formula (f) is as defined above in relation to the formation of a compound of formula (I) from a compound of formula ;,IQ.

Suitable values for Ra include those described hereinbefore.

Suitable reaction conditions for the reaction of the compound of fonnula (IX) and die appropriate reagent include those described above in relation to the preparation of compound (II) with die said appropriate reagent Preferably, in the compound of fonnula (IX), Ra represents a hydroxyl group 35 and a particularly appropriate reagent is the above defined compound of formula (IDA).

The reaction between die compound of formula (IX), wherein Ra is an 29 925 hydroxyl group, and the reagent of the abovedefined fonnula (IIIA) may be carried out in an aprotic solvent; such as dimethylfannamide, at a low to an elevated temperature, for example in the range of from 50°C to 120°C, for example at 80°C, and preferably in the presence of a base, such as sodium hydride. 5 The compounds of formula (IX), wherein Ra is OH, are known 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 DJi. Williams et. al. J.Chcm.Soc., Section B. 1969,439, or J. March, Advanced Organic Chemistry, 3rd Edition (1985), 10 Wiley Interscience or for example those disclosed in International Application, Publication No. W092/02520.

A compound of fonnula (I), wherein A3 represents a moiety of fonnula -(CHjjWOKORl)-, or a tautomeric form thereof, and/or a pharaiaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may also 15 be prepared by reacting a source of a caibene of fonnula (X): A— X— (CHjJn 0—A-— C —Y —R* (X) wherein A*, A2, X, Y,m and n are as defined in relation to fonnula (I) andR9 is as defined in relation to fonnula (IV), with a compound of the above defined fonnula (V); and thereafter, if required, carrying out one or mote of the following optional steps: (i) converting a compound of formula (I) into a further compound of formula (I); 25 (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.

A suitable source of a caibene of formula (X) is provided be reacting a compound of fonnula (XI): A— x— (CH*),, O A" (CH2)„ C —Y —R* m2 (XI) wherein A*. A2, R9, X, Y, m and n are as defined in relation to fonnula (X) with a rhodium(II) salt, such as a rhodium (II) acetate.

The carbene of fonnula (X) may be prepared from the compound of formula 299256 (XI) by using an analogous procedure to that used for the preparation of the carbene of fonnula (IV) from the compound of fonnula (IVA).

The reaction conditions for the reaction between the compounds of formulae (X) and (V) are equivalent to those used in the reaction between the compounds of formulae (TV) and (V).

The compound of formula (XI) may be prepared by reaction between the compounds of formulae (IDA) and (VI) using an analogous procedure to thu used for the preparation of the compound of formula (I) from the compounds of formulae (II) and (EHA) and thereafter diazotized as described above for the conversion of (VI) to OVA).

A compound of formula (I) wherein A3 represents a moiety of fonnula -(CH2>m-1 -CH=CXOR *)- or ~(CH;2)m-CH(ORl)-, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may also be prepared by reacting a compound of formula (XII): A— X—(CH2)n O—A- (CH2)m..,—CHO (XID wherein A*, A2, X, m and n are as defined in relation to formula (I), with a reagent capable of converting the CHO carbon atom into a group of the above defined formula CH=C(ORl)-Y.R2; and thereafter, if required, reducing the group -CH=C(ORl)- to provide a compound wherein A3 represents a moiety of formula ~(CH2)nrCHORl- 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 (ii) preparing a pharmaceutically acceptable salt of a compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.

A suitable reagent capable of converting die GKO caibon atom into a group of the above defined formula -CH=C(OR^)-Y .R2 is a Wittig reagent or preferably a Wadsworth Emmons reagent of formula (XHI): ^ /OR' (R 0),P—CH^r (XIII) 2992 wherein R1', R2' and Y are as defined in relation to formula (II) and R10 represents a Ci_£ alkyl group, preferably a methyl or ethyl group.

The reaction between the compounds of formulae (XII) and (XDI) may be 5 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 0° to 2S°C, conveniently at ambient temperature, preferably in an inert atmosphere and under anhydrous conditions. Preferably the compound of fonnula (XIII) is suitably activated, for example by die addition of a base such as 10 sodium hydride or n-butyl lithium, prior to the addition of the compound of formula (XII).

The reduction of a compound wherein A3 represents a moiety of formula -(CH^m-1 -CH>=C(OR* )- to provide a compound wherein A3 represents a moiety of fonnula -(CH^m-CHCOR1)- may be carried out using conventional reduction IS methods, such as catalytic reduction using for example a 10% palladium-on-carbon catalyst in an alkanolic solvent such as ethanol, or by use of a metal/solvent system such as magnesium metal/methanol as described in Tet Lett. 19S6,22,2409.

A compound of formula (XII) may be prepared from a compound of formula (XIIA): A*— x-mx O— A— (CH^-CC^R (XIIA) wherein A *, A2, X, m and n are as defined in relation to formula (I) and Ra represents hydrogen or a Cj.g alkyl group, suitably a methyl group, by conventional 25 methods for converting an ester group into a caxbony 1 group; one convenient method involves reducing die ester group to give » primary alcohol using for example a metal hydride reducing agent such as lithium aluminium hydride in tetrahydrofuran, and thereafter oxidising the primary alcohol to give the required caibonyl group by use of an oxidising reagent such as pyridine-sulphur trioxide complex in 30 dimethylsulphoxide.

A compound of formula (XIIA) may be prepared from a compound of formula (XIIB): HO—A—(CH^-COfcR (XIIB) wherein A2, m and Ra ace as defined in relation to fonnula (XIIA), with a compound of the above defined formula (TIIA). 299256 Suitably reaction conditions for the reav lion between the compounds of formulae (EDA) and (XHB) arc those described above for the reaction between the compounds of formulae (II) and (HIA).

A compound of formula (II) wherein A3' represents a moiety of formula 5 -CH-CXORiy or -CH^-QHKORI')-, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be prepared by reacting a compound of formula (XIV): 0 2 R—A CHO (XIV) wherein Rb and A2 are as defined in relation to fonnula (TV), with a reagent capable of converting the CHO caxbon atom into a group of die above defined formula -CH=€(OR 1 *)-Y .R2'; and thereafter, if required, reducing the group -CH=C(OR^ )- to 15 provide a group of formula -CH2-CHOR *and thereafter, if required, removing any protecting group.

Preferably, Rb is a protected OH group.

A suitable reagent capable of converting the CHO carbon atom of compound (XIV) into a group of the above defined formula 20 -CH*=CH(OR*)-Y.R2, is a compound of the above defined formula (XHQ in optionally protested form as defined by die nature of R and R2' in the required compound of formula (II).

Suitable conditions for the reaction between the compound of fonnula (XIV) and the said reagent are analogous to those described above for the reaction between 25 the compounds of formulas (XII) and (XIII).

The compounds of fonnula (XH), in particular those wherein m is 1, may also be prepared by methods disclosed in EP0306228.

The compounds of formula (XHB) are known commercially available compounds or they are compounds prepared by analogous methods used to prepare 30 such compounds or they may be prepared from such compounds, for example by converting a commercially available caiboxylic acid into an alkyl ester.

The compounds of formula (XHI), are known compounds or they are compounds prepared by methods analogous to those used to prepare known compounds, for example those disclosed in Annalen Chcmie 1966,699,53 or J. Org. 35 Chem. 1983,48,3408.

The compounds of formulae (XIV) are known compounds or they are compounds prepared by methods analogous to those used to prepare known compounds, for example those disclosed in £P 0306228. 29 92* A compound of fonnula (I), wherein A3 represents a moiety of fonnula ■CHj - CH(OR1)- wherein R1 represent* alkyl, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may also be pteparcd by hydrolysing a compound of formula (XV): A1 -X-(CH2)n - O - A2 - CH2 - OTOR1) - CN (XV) wherein A', A2, X and n are as defined in relation to formula (I) and R" represents alkyl, to provide a compound of formula (I) wherein R2 represents OH; and thereafter, if required, converting R2 as OH into another R2; and thereafter, if required, carrying out one or more of the following optional steps: 0) converting a compound of fonnula (I) into a further compound of formula (I); (ii) removing any protecting group; and (ui) preparing a pharmaceutically acceptable saJ* of a compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.

The hydrolysis of the compound of formula (XV) may be canied our using conventional conditions and reagents for nitrile hydrolysis, for example basic hydrolysis using 10% sodium hydroxide in methanol.

The conversion of R2 as OH into another R2 may be effected by using any convenient method, such as those methods described hereinafter.

A compound of fonnula (XV) may be prepared from a compound of formula (XVI); Al - X - (CH2)n - O - A2 - CH2 - CH(ORl«) - ORlb (XVI) wherein A*, A2, X and n are as defined in relation to fonnula (I) and Rla = which represents alkyl; by reaction with trimethylsilylcyanide.

The reaction between die compounds of formulae (XVI) and trimethylsilylcyanide may be canied out in an inert solvent, such as dichkxomethane, at low to ambient temperature, conveniently at ambient temperature and preferably in the presence of a Lewis add catalyst, such as boron trifluoride etberate.

A compound of formula (XVI) may be prepared from a compound of formula (XVII): At -X-(CH2>n-°-A2-CH = CH-ORla 299256 (XVII) wherein A1, A2, Rla, X and n are as defined in relation to fonnula (XV); by reaction 5 with a compound of fonnula (XVIII): Rl*-OH (xvni) wherein Rl* is as defined above.

The reaction between the compounds of formulae (XVII) and (XV ill) is 10 suitably canied out using the compound of fonnula (XVIII) as solvent, generally at an elevated temperature such as the reflux temperature of the solvent and preferably in die presence of p-toluenesulphonic acid.

Preferably, Rla is methyl.

A compound of fonnula (XVII) may be prepared by reaction of the above IS defined compound of fonnula (XII), wherein m is 1, with a reagent capable of converting the CHO carbon atom of fonnula (XII) into a group of the above defined formula -CH*=CH - OR*, die reagent being suitably a Wittig reagent of fonnula (XIX): [Ph3PCH2 - OR1]+ CI' (XIX) wherein R* is as defined in relation to fonnula (I).

The reaction between the compounds of formulae (XII) and (XIX) may be carried out under conventional Wittig reaction conditions, fin- example in an aprotic 25 solvent, such as tetrahydrofuran, at low to ambient temperature, such as in die range of from -10° to 2S°C, conveniently at ambient temperature and, preferably, in an inert atmosphere under anhydrous conditions. Preferably, the compound of formula (XIX) is suitably activated by, for example, die addition of a base such as sodium hydride, n-butyl lithium or lithium diisopropylamide, prior to the addition of the compound of 30 fonnula (XII).

The compounds of fonnula (XVIII) and (XIX) are known compounds or they are compounds prepared by methods analogous to those used to prepare known compounds, for example those disclosed in J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Intersstence.

A compound of formula (I), wherein is (CH2)in-CH(OR1)- and R2 is a C-linked aromatic heterocyclyl group, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable hydrate thereof, may be prepared by reacting a compound of the above defined fonnula (XII) with an 29 925 6 activated fonn of a compound of fonnula (XX) het^^CH (XX) wherein het-CH is an aromatic heterocyclic group represented by R2 which contains at least 1 carbon atom and thereafter converting the compound wherein R* is hydrogen into another R1; and thereafter if required: (i) converting a compound of formula (I) to a further compound of fonnula (I); 10 (ii) removing any necessary protecting group; (iii) preparing a pharmaceutically acceptable salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.

A suitable activated form of a compound of formula (XX) is a salted form such as a lithium salted form.

IS The activated form of a compound of formula (XX) may be prepared by reacting an aromatic heterocyclic group Het-CH or Het-CL, wherein L is a leaving group such as halogen, with an appropriate, conventional activating agent such as a salting agent, for example an alkyl lithium, in an aprotic solvent such as tetxahydrofuran according to known methods and procedures for example those 20 disclosed in Adv. Heterocyclic chenu, 1993,56,1SS.

Compounds of formula (1) wherein is (CH2)m-CH(OR1)- and R2 is a C-linked tetrazolyl group or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable hydrate thereof, wherein the heterocyclyl group may be prepared by reacting a compound of formula (XXI) 1 2 /0R' A X (CH,). O—A (CHj).—CH<^ CN (XXI) wherein A*, A2, R*, X, m and n are as defined in relation to formula (I), with a source of azide ions such as an azide salt, suitably in alkali metal azide, for example sodium azide.

The compound of formula (XXI) may be prepared by dehydrating a 35 compound of fonnula (I) wherein A^ is (CH2)m-CH(OR*) and YR2 is CONHj using for example POCI3. 2992 5 The reaction between die compound of fonnula (XXI) and the source of azide ions may be canied out under conventional conditions for example when sodium azide is the source of azide ions the reaction may be effected in an aprotic solvent such as dimethylfonnanride generally at an elevated temperature, for example the 5 reflux temperature of die solvent; preferably in the presence of trimethylsilyl chloride.

The abovementioned conversion of a compound of formula (I) into a further compound of fonnula (I) includes: a) converting one group R into another group R; b) converting one group OR* into another group OR*; c) converting one group YH2 wherein Y is CO into another group Y.R2; d) converting one group COJR2 into a group CSJt2; and e) reducing a group-CH=C(OR^)-to a group-CH2^(OR1)-- The abovementioned conversions may as appropriate be carried out on any of 15 die intermediate compounds mentioned herein.

The conversion of a compound of formula (I) to a further compound of fonnula (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; 20 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 conversations of one group OR* into another group OR* include the convetson of one substituent into another substituent when R* represents substituted alkyl, for example die reduction of a COjRu substituent, wherein Ru is C\^ alkyl, to provide a CH2OH substituent The above mentioned reduction may be canied out using any conventional reduction method, for example using boronhydride reducing agents such as sodium 30 borohydride in a solvent such as methanol.

Suitable conversions of one group Y.R2 wherein Y is CO into another group Y.R2, include: (i) hydrolysing one group Y.OR^a wherein r3* is alkyl, aryl or aralkyl into a group Y.OH, wherein Y is CO; (ii) animating one group Y.R2** wherein R2b is alkoxy into a group YJNR^R^, wherein Y is CO; (iii) halogenating the above defined group Y.OH to provide the corresponding acid halide, and then aminating the halide to provide the abovementioned group 29 925 Y.NR4R5 wherein Y is CO; (iv) esterifying a group YOH to give a group Y-Oalkyl or Y-Oaralkyl, wherein Y is CO, and (v) convening one group Y.NH2 wherein Y is CO into a group Y-C-Hct wherein Y is a bond and C-Het is a Clinked aromatic heterocyclyl group.

Suitable hydrolysis methods for use in conversion c(i) are conventional ester hydrolysis methods, for example using an alkali hydroxide in aqueous methanol.

Suitable amination methods for conversion c(ii) or c(iii) include conventional methods, for example treatment with aqueous ammonia in tetrahydrofuran/methanol.

Suitable halogenation methods for conversion c(iii) include conventional methods, for example treatment with oxalyl chloride.

Suitable esterification methods for conversion c(iv) are conventional methods, thus alkyl esters may be prepared by using the appropriate alkanol, for example methanol, in the presence of an acid and aralkyl esters may be prepared by treatment of a salted YOH group, such as a sodium salt, with an appropriate aralkyl halide, for example benzyl bromide.

Suitable conversion of a group Y.NH2 wherein Y is CO into a group Y-C-Het wherein Y is a bond and C-Het is a C-linked aromatic heterocyclyl group includes: a) reaction with a hydrazine, for example hydrazine hydrate, and an amide acetal, such as dimethylformamide dimethyl acetal, to provide a 1,2,4-triazole; or b) reaction with a hydroxy lamine, for example hydroxy lamine hydrochloride, and an amide acetal, such as dimethylformamide dimethyl acetal, to provide a 1,2,4-oxadiazole.

Suitable conversions of one group COJl2 into another group CS.R2 may be effected using conventional methods .for example by using Lawes son's reagent in a solvent such as toluene, at any temperature providing an acceptable rate of formation of the required product, conveniently at the reflux temperature of the solvent Suitable reductions of one group -CH=C(OR1)- to a group -CHjCHCOR1)-may be carried out using any convenient reduction procedure, such as the catalytic reduction or metal/solvent reduction methods as described hereinbefore.

It will be appreciated that in any of the abovementioned reaction including the abovementioned conversions (a), (b), (c), (d) and (e) any reactive group in the substrate molecule may be protected, according to conventional chemical practice.

Suitable protecting groups in any of the abovementioned reactions are those used conventionally in the art. Thus, fen* example, suitable hydroxyl protecting groups include benzyl or trialkylsilyl groups.

The methods of formation and removal of such protecting groups are those 299255 conveational methods appropriate to the molecule being protected. Thus for example . a benzyloxy group may be prepared by txeatment of the appropriate compound with a benzyl halide, such as benzyl bromide, and thereafter, if required, the benzyl group may be conveniently removed using catalytic hydrogenation or a mild ether cleavage 5 reagent such as trimethylsilyl iodide or boron tribromide.

Where appropriate the isomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof may be prepared as individual isomers using conventional chemical procedures.

However for certain compounds of fonnula (I) there is provided a novel 10 process for separating optical isomers of such compounds. Indeed the newly discovered process is considered to be capable of separating optical isomers of any compound providing the chiral carbon of such compound is attached to a carboxy ester group and a group OZ* wherein Z* is alkyl, aryl or aralkyl.

Accordingly, the present invention provides a process for separating optical IS isomers of a compound (the substrate ester) which comprises a moiety of formula (H): ./C0*Z —HC >)Z (H) wherein C* is a chiral carbon, Z is a Ci_i2 alkyl group and Z1 is a C\.\2 alkyl, aryl or an aryl C\.\2 alkyl group, which process comprises enantioselectively hydrolysing the ester group CO2Z of one enantiomer into a carboxyl group with a lipase from Rhizopus delemar, Rhizopus 25 axxhizus or Rhizopus LIP F4 or a lipase from Mucor miehei; and thereafter, as necessary, isolating either die enantiotnerically enriched product carboxylic acid or the enanatiomerically enriched substrate ester.

The enantiomerically enriched product carboxylic acid and/or die enanatiomerically enriched substrate ester may be isolated using conventional ' 30 extraction methods, such as phase separation and/or extraction into a suitable solvent, and thereafter, if required it may be chromatographed.

In an alternative isolation procedure, prior to isolation, the enantiomerically enriched substrate ester, may be converted by hydrolysis into the respective carboxylic acid which may then be isolated in the usual way. In one convenient 35 aspect of the invention the enantiomerically enriched substrate ester may be hydrolyssd by treatment with the abovementioned lipases to give the respective carboxylic acid. 29925 f The compounds of fonnula (I) which foil within formula (H) are those compounds wherein Z represents r3 and Z1 represents R1: Thus the novel process may be used to prepare enantiomerically enriched compounds of formula (I) wherein A3 represents (CH2)m-CH(OR *)-, Y represents CO, R2 is OR3 and A1, A2, R1, r3 X, m and n are as defined in relation to fonnula (I)- (hereinafter referred to as compounds of formula (IA».

The microbial lipase enzymes may be obtained by conventional culturing techniques such as those disclosed in J. BacterioL, 1982, Vol.150 498-505. H. Gilbert and M. Tully, European Patent Application No. 0198440 and British Patent No. 1,474,519. The lipase may be isolated as a pure enzyme or, in the alternative a suitable source of the lipase may be incorporated into the reaction.

Preferably, die microbial lipase enzymes are obtained commercially as purified or partially purified enzyme preparations.

The hydrolysis of the compound of formula (H) may be canied out in any suitable aqueous solvent having controlled pH, for example in an aqueous buffer en* in a solvent wherein thepH is controlled by the addition of aqueous sodium hydroxide, at a pH which provides a suitable rate of formation of the required product, which is generally a pH in the range of from 5 to 9, such as in the range of from 6 to 8, for example at pH7.

The hydrolysis may be carried out at any temperature which provides a suitable rate of formation of die required product, being generally at a low to ambient temperature, such as a temperature in die range of from 5°C to 40°C, such as in die range of from 20°C to 40°C and preferably in die range of from 20°C to 30°C, for example 23°C Generally, the substrate mixture is introduced into the reaction system as a solution in an organic solvent which may be a water miscible solvent such as acetone, tetrahydrofuran, dimethylsulphoxide, dimethylformamide or acetonitrfle.

The stereoselective process selectively hydrolyses the compound (IA) having the same stereochemistry at the asterisked carbon atom as the equivalent carbon atom in (-) 3-(yK2-[N-(2-bcnzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-methoxypropanoic add.

The reaction conditions, such as the particular acidic pH and the reaction temperature which provide optimum enrichment for any particular enantiomerically enriched compound (H) may be determined by routine experimentation.

Suitably, the stereoselective reaction provides enantiomerically enriched compound (IA) in the form wherein the required enantiomer is present in greater than 70% w/w, and favourably greater than 80% w/w. Most favourably, the product from the stereoselective process provides enantiomerically enriched compound (IA) in the form wherein the required enantiomer is present as 80-100% w/w, preferably 90- 299256 100%, such as 90-95%, and most preferably 95-100%, for example 95%, 96%, 97%, 98%, 99% or 100% w/w.

The above mentioned enantiomerically enriched compound (IA) is considered to form a further aspect of the present invention. Accordingly the present invention 5 provides enantiomerically enriched compound (IA) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof.

The present invention also provides enantiomerically enriched compound (IA) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or 10 a pharmaceutically acceptable solvate thereof, wherein the required isomer is present in greater than 50% w/w; suitably greater than 70% w/w and favourably greater than 80% w/w. Most favourably, the enantiomerically enriched compound (IA) is in a form wherein 80-100% w/w, preferably 90-100%, such as 90-95%, and most preferably 95-100%, for example 95%, 96%, 97%, 98%, 99% or 100% w/w is in the 15 form of the required isomer of a compound of formula (IA).

In one preferred aspect there is provided a compound of formula (IA) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, preferably in optically pure form.

The absolute stereochemistry of compounds may be determined using 20 conventional methods, such as X-ray crystallography.

As mentioned above the compounds of the invention are indicated as having useful therapeutic properties: The present invention accordingly provides a compound of formula 00, or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active 25 therapeutic substance.

Thus the present invention provides a compound of fonnula (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 35 fonnula (I) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof for use in die treatment of hypertension, cardiovascular disease and certain eating disorders.

Cardiovascular disease includes in particular atherosclerosis. 29 9 Ccrtain eating disorders include in particular the regulation of appetite and food intake in subjects suffering from disordeis associated with under-eating ,such as anorexia nervosa, and disorders associated with over-caring, 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 pharmaceutical^ acceptable solvate thereof, may be administered pa: SS. or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.

Accordingly, the present invention also provides a pharmaceutical 10 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 acceptable1 embraces compounds, compositions and ingredients for both human and veterinary use: for example the IS 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 20 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 die carrier may 25 comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant Typical earners include, for example, microczystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypynolidone, magnesium stearate or sodium lauryl sulphate.

Most suitably th«. 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.SOO mg, and more especially 0.1 to 250 mg.

A method for the treatment and/or prophylaxis of hyperglycaemia in a human or non-human mammal comprises 35 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. 299256 A method for the treatment of hyperlipidaemia in a human or non-human mammal 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 or non-human mammal in need thereof.

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

In die 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 die treatment and/or prophylaxis of hyperglycaemic non-human mammals, especially dogs, the active ingredient may be adminstered by mouth, usually <mce or twice a day and in an amount in die range of from about0.025 mg/kg to 25 mg/kg, for example 0.1 nag/kg to 20 mg/kg. Similar dosage regimens arc 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 fonn thereof and/or a pharmaceutically acceptable salt thcroof and/or a pharmaceutically acceptable solvate thereof, for die 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. 29925 Example 1 Ethyl 3-[4-l2-[N-(2-benzoxazoIyl)-N-mefhylaniino]ethoxy]pheny!]-2-methoxypropanoate CO^CHjCHJ Sodium hydride (60% dispersion in oil; 0.47g) was added portionwise to a stirred, ice-cooled solution of ethyl 3-(4-hydxoxyphenyl)-2-methoxyprop-10 anoate (2.38g) in dry N,N-dimethylformamide (50mL) under a nitrogen atmosphere. The mixture was stirred for 30 minutes at room temperature prior to the addition of a solution of 2-[N-(2-benzoxazolyl)-N-methylamino]ethanol methanesulphonyl ester (Eur. Patent Appl.. Publication No: 03062281 (2.86g) in N,N-dimethylformanude (90mL). The mixture was heated for 17 hrs at 80°C, cooled and concentrated in 15 vacuo. The residue was diluted with water (200mL) and extracted with ethyl acetate (3x200mL). The combined organic solutions were washed with water (3xl00mL), brine (200mL), dried (MgSC>4) and evaporated to afford a gum. This was chromatographed on silica gel using 10% ethyl acetate in dichloromethane as eluent to afford the title compound as a gum. lHNMR5(CD03) 1.22 (3H, t); 2.95 (2H, complex); 3.33 (3H, s); 3.34 (3H, s); 3.89 (1H, dd); 3.93 (2H, t); 4.17 (2H, q); 4.24 (2H, t); 6.81 (2H, d); and 6.90-7.40 (6H, complex).

Example 2 3-[4-[2-[N-(2-Benzoxazolyl)-N-niethylamino]ethoxy]phenyI]-2-methoxypropanoic add A mixture of ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]-phenyl]-2-methoxypropanoate (1.5g), 10% aqueous sodium hydroxide solution (7 JmL) and methanol (23mL) was stined for lJhis at room temperature and then 35 diluted with water (600mL), washed with dichloromethane (300mL) and acidified to 290256 pH2 with concentrated hydrochloric add. The mixture was extracted with ethyl acetate (3x300mL) and the confined ethyl acetate solutions washed with water (2x200mL) and brine (200mL), dried (MgSC>4) and evaporated. The residue was crystallised from ethyl acetate-dichloromethane-hexane to afford the title compound, 5 rop 150-153°C *H NMR 8 (CDC13) 2.80 (IH, dd); 2.91 (IH, dd); 325 (3H, s); 3.27 (3H, s); 3.83 (IH, dd); 3.90 (2H, t); 4.22 (2H, t); 6.75-7.40 (8H, complcx); and 12.60 (IH, broad, exchanges with D2O).

Example 3 Methyl 3-[4-[2-[N-(2-benzoxaw>IyI)-N-inethylamino]ethoxy]phenyI]-2-methoxypropanoate The tide compound, a gum, was prepared from methyl 3-(4-hydroxyphenyl)-2-methoxypiopanoate by a method similar to that described for Example 1.

NMR 6 (CDCI3) 2.95 (2HUcomplex); 3.33 (3IU); 3.34 (3H^); 3.70 (3H,s); 3.90 (3H,complex); 4.24 (2H,t); 6.80 (2H,d); and 7.00-7.40 (6H,complex).

Example 4 Methyl 2-methoxy-3-[4-[2-[N-methyl-N-(2-pyridyl)ainino]ethoxy]-phenyQpropanoate A mixture of 2-methoxy-3-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]-phenyQpropanonitrile (1.15 g), sodium hydroxide solution (10% w/v; 10 mL) and methanol (20 mL) was heated at reflux for 2.5 hrs, cooled and neutralised to pH7 35 with dilute HCL The mixture was evaporated in vacuo and the residue rcdissolved in methanol presaturated with hydrogen chloride gas. The mixture was allowed to stand at room temperature for 7 days, then evaporated. Saturated sodium bicarbonate solution (100 mL) was added and the suspension extracted with ethyl acetate (3 x 200 29925 mL). The combined ethyl acetate solutions were washed with water (2 x 500 mL) and brine (500 mL), dried (MgS(>4) and evaporated. The resulting gum was chrotmtographed on silica gel with 1% methanol in dichloromethane to afford the title compound, a gum.

*H NMR 6 (CDCI3) 2.94 (2H,complex); 3.14 (3IU); 333 (3HU); 3.71 (3H^); 3.94 (lH4d); 3.96 (2H,t); 4.15 (2H,t); 6.55 (2H,complex); 6.81 (2lid); 7.11 (2H,d); 7.45 (lH^omplcx); and 8.15 (lEMd).

Example 5 3-[4-[2-[N-(2-B«nzoxazolyl)-N-methylaminolethoxy]phenyI]-2-methoxylpropauamide A mixture of methyl 3-{4-[2-[N-(2-benzoxa2olyl)-N-methylaniino]ethoxy]-phenyl]-2-roethoxypropanoate (1.00 g), tctrahydrofuran (20 mL), methanol (20 mL) and 20 aqueous ammonia (specific gravity 0.88; 20 mL) was stirred at room temperature for 4 hrs. A further portion of aqueous ammonia (20 tnL) was added and the stirring continued at room temperature foe* a total of 50 hrs. The mixture was concentrated in vacuo, die residue diluted with water (500 mL) and extracted with e ihyl acetate (3x200 mL). The combined ethyl acetate solutions were washed with water (500 25 mL), brine (500 mL), dried (MgS(>4) and evaporated. The residue was crystallised from dichloromethane-hexane to afford the title compound, mp 133-5°C *H NMR 5 (CDCI3) 2.88 (llidd); 3.07 (lH,dd); 3.33 (3H,s); 3.34 (3H,s); 3.80 (lH,dd); 3.94 (2H,t); 4.24 30 (2H,t); 5.41 (lH,br,exchanges with D2O); 6.33 (lH,br,exchanges with D2O); 6.80 (2H,d); 7.00 (lH,t); 7.13 (2H4); 7.14 (llUpp. t); 7.25 (lH,d); and 7.33 (1H4). 29925 Example6 Ethyl (E/Z)-3-[4-[2-[N-(2-benzoxa»>lyl)-N-metIiyUminojethoxy]-pbeftyIl-2-ethoxypropenoate CHj OCH,CH, A solution of tricthyl 2-ethoxyphosphonoacet&te (W. Grell & H. Machleidt, Annalen. Chemie, 1966,699,53) (1.98 g) in dry tetnhydrofuran (25 mL) was added slowly to 10 a stirred, ioe-cooled suspension of sodium hydride (60% dispersion in oil; 0.33 g) in dry tcttahydiofurau (5 mL) under a nitrogen atmosphere. The mixture was stirred at 0°C for 30 minutes prior to the addition of a solution of 4-[2-[N-(2-bcnzoxazolyl)-N-methylamino]cthoxy]bcnzaldchyde (2.19 g) in dry tetrahydrofuran (15 mL). The mixture was allowed to warm to room temperature, and stirred for a further 20 hrs. 15 The solvent was evaporated and die residue suspended in water (300 mL) and extracted with ethyl acetate (3x250 mL). The combined ethyl acetate layers were washed with water (2xlL), brine (1L), dried (MgSC>4) and evaporated. The residue was chromatogrsphed on silica gel with 23% ethyl acetate in dichloromethane as eluent to afford die tide compound, a gum, as a 62:38 Z:E mixture of double bond 20 isomers (by NMR integration of die olefinic signals).

*H NMR 6 (CDCI3) 1.10-130 (6H,complex^nixture of isomeric OCH2CH3 signals); 3.35 OELs.NMc): 3.85-430 (8H,complex, mixture of isomeric OCH2CH3 and NCH2CH2O signals); 25 6.02 (0.38H*;sJE-olefimc proton); 6.75-7.70 (8H^omplex4someric aromatic protons); and 6.91 (0.62H* ^Z-olefinic proton).

The two signals H* together constitute the olefinic proton signal. The assignment of the major isomer as Z (Z:E ratio is 62:38) is by analogy with reported chemical shifts of similar olefinic protons (cf R. A Aitken and G. L. Thom, 30 Synthesis, 1989,958). 29 92 5 Exampie 7 Ethyl (E/Z)-3-[4-[2-[N-(2-b€nzoxazolyl)-N-methylaniino]ethoxy]-phenyI]-2-phenoxypropenoate The title compound, a 1:1 mixture of double bond isomers (ratio determined by *H NMR) was obtained as a gum when triethyl 2-pheitoxyphosphonoacetate (0.94 g) was reacted with 4-[2-[N-(2-bcnzoxazolyl)-N-methylamino]ethoxy]benzaldehydc (0.89 g) in a manner similar to that described for Example 6.

NMR 8 (CDC13) 1.05 and 1.18 (combined 3H, isomeric OCH2QI3 triplet signal r.). 3.31 and 3.35 (combined 3H, isomeric NMe singlets); 3.85-4.30 (6H, complex, isomeric OCH2CH3 and NCH2CH2Q signals); and 6.70-7.70 (14H,complex, aromatic and olefinic signals).

Emnple8 Ethyl 3-[4-[2-[N-(2-bens50xazoiyl)-Nmethyiamino}ethoxy]phenyI]-2-pbenoxypropanoate Ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-Nf-methylaniino]ethoxy}phenylJ-2-phenoxypropenoate (0.97 g) was dissolved in dioxan (100 mL) and hydrogenated over 10% Palladium on charcoal (200 mg) at room temperature and 22 psi for a total of 7 hrs. The solution was filtered through filter aid and evaporated. The residue was chromatographed on silica gel using 5% ethyl acetate in dichloromethane as eluent to afford die title compound as a gum.

NMR 8 (CDCI3) 1.18 (3H,t); 3.17 (2H,appd); 3.33 (3H,s); 3.93 (2H,t); 4.13 (2K,q); 4.25 (2H,t); 4.71 2992 (lH,dd); 6.81 (2H,c); snd 6.90-7.40 (llH^omplex).

Example 9 3-[4-[2-[N^2-BenzoxaioljI)-N-iiw*hylaiffllno)ethoxy]phenyl-2-pheiioxypropai»ic add The title compound, mp 162-4°C (methanol) was obtained from ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-pherioxypropanoate (0.88 g) by a method analogous to that described for Example 2. 1*1 NMR 6 (DMSO-d^) 3.10 (2H,complex); 3.21 (31UK 3.87 (2H,i); 4.21 (2H,t); 4.83 (lJidd); 6.75-7.40 (13Eicomplex); and 13.00 (lH,br,exchang6S with D2O).

Example 10 Methyl 3-[4-[2-[N^2-benxoxazolyl>~N-methyUmir»olethoxy]!phrml]-2-ethoxypropanoate Rhodium (II) acetate dimer (33 mg) was added to a mixture of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-metbylamino]edJoxy]phenyl;-2-d542opropaiioate (2.80 g), ethanol (2.16 mL) and benzene (50 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 15 minutes, heated at reflux lor a further 15 minutes, dten cooled and evaporated in vacuo. Thr residue was chromatographed on silica gel 30 using 1.5% methanol in dichlororocumnc as eluent to afford the title compound as a gum.

*H NMR 5 (CDO3) 1.14 (3H,t); 2.93 (2IUpp d); 331 (lH^omplex); 3.32 (3H,s); 3.57 (lH.complex); 35 3.69 (3H,s); 3.93 (3Rcomplex). *.23 (2H,t); 6.79 (2H,d); 7.00 (lH,t); 7.14 <3H,complex); 73.5 (1H4); and 7.36 (lH,d). 299? Example II Methyl 3-[4-[24N-(24>eiiaoxazolyl)-N-raettaylainitio}ethoxy]pbenyU-2'* 5 iaopropaxy propanoate The title compound, a gum, was prepared from methyl 3-(4-hydroxypbenyl)-2-10 isopropoxypropanoate (134 g) by a method analogous to that described in Example 1.

*H NMR 5 (CDCI3) 094 (3Hwd); 1.13 (3HLd); 2.87 (2IUomptex); 3.34 (3FU); 3.47 (lH^omplex); 3.70 15 (3H,s); 3.93 <2H.t)*, 4.00 (lUdd); 4.23 (2H.0; 6.79 (2H,d); 7.00 (lH,t); 7.17 (3H^oroplex); 7.25 (lHvd); and 736 (lHvd).

Example 12 Methyl 3-[4-[2-[N-(2-ben»oxa»olyi)-N-methylainino]etboxy]phenyt1'2-proposypropanoate The title compound. an oil, was prepared from methyl 3-(4-hydroxyphenyl>2- piopoxypropanoate (0.88 g) by a mediod analogous to that described in Example 1. lHNMR8(CDCl3) 0.83 (3H4); 132 C2H^complex); 2.93 (2H^omplex); 3.17 (lH,complex); 3.34 (3IU); 30 3.50 OH^omplex); 3.69 (3H,s); 3.85-4.00 (3H^omplex); 4.22 (2H.t); and 6.75-7.40 (8H^omplex). 29 93 * * Example 13 3-[4-[2-[N-(2-B«nmxaioly|>N-«etliylaroiiio)ethoxy]phenyl-2-propoxypropen3ic The title compound, a gum, was prepared from methyl 3-[4-[2-[N~(2-benzoxazolyl>-N-methylamino]ethoxy}phenyl]-2-propoxypropanoate (1.05 g) by a method 10 analogous to that described in Example 2. This material was used in the salt forming step without further purification.

*H NMR 6 (CDO3) 0.85 (3H,t); 1.53 (2H,t); 3.00 (21Lcomplex); 3.29 (lH^omplex); 3.32 (3H,s); 332 15 (llicomplex); 3.91 (2H,t); 4.02 (llidd); 4.18 (2H,t); 5.80 (lH,br,cxchanges with D2O); 6.77 (2H4); and6.95-7.40 (6H,complex).

Example 14 3-{4-[2-[N-C^-B«mwtaaolyi)»N«inethyhMnino]ethoxy]phenyn-2-prupttxypropanofc add, sodium salt Sodium medxuride (0.11 g) was added to a stirred solution of 3-[4-[2-{N-(2- betusoxazolyl)-N-methylaniino]ethoxy]phenyl}-2-prjpoxypropanoic acid (0.81 g) in methanol (10 mL). After stirring for 5 minutes the mixture was evaporated and then re-evaporated twice from ether (10 mL each time). The resulting gum was triturated with boiling ethyl acetate, filtered, and die filtrate concentrated and diluted with ether.

The resulting solid was filtered and dried in vacuo to afford die tide compound, mp 210-4°C *11 NMR S (DMSO-d*) 0.67 (3H,t); 1.35 (2H^omplex); 2.65 (lH,dd); 2.85 (lH,dd); 3.02 (lJLcomplcx); 3.25 35 (3H,s); 3.35 (lH,complex); 3.70 (lH^d); 3.90 (2H,t); 4.27 (2H,t); 6.80 (2H4); and 7.00-7.40 (6Hvcomplex). add 2992** Example 15 Ethyl (E/Z)-3-t4-[2-{N-(2-beiixoxazolyl)-N-roeUiytamino]eth<ncy]phe«iyl]-2-(4-5 methoxyphenoxjr)propenoate The title compound, a 1:1 mixture of double bond isomers (ratio determined by 10 NMR), was obtained as a gum when triediyl 2-{4-iiiethoxyphenoxy)phosphonoacetatc (2.00 g) was reacted with 4-[2-[N-(2-benzoxazolyl)-N-methylamino]cthoxy]~ benzaldehyde (1.71 g) in a manner similar to that described in Example 6.

*H NMR 8 (CDCI3) 1.08 and 1.19 (combined 3H4someric OCH2CH3 triplet signals); 3.32 and 3.34 (combined 3H»NMe singlets); 3.75 and 3.77 (combined 3H,OMc singlets); 3.95 (2H^otnplex); 4.05-4.35 (4H^xxnpkx); 6.55 (0.5H,sJE-isomer olefinic proton); and 6.75-7.70 (125H, complex).

Example 16 Ethyl 3-{4-[2-[N-(2->benxoxa20lyl)-N-methytamino]eUioxy] phenyl}-2*(4-metboxyphenoxy)propanoate The title compound, a gum, was ptepared from ethyl (E/Z)-3-[4-[2-[N-(2-benroxarolyl)-N-mcthylanrino]ethoxy}phenyl]-2-{4-rocthoxyphcnoxy)propcnoate by a procedure similar to that described for Example 8, using ethanol as solvent lH NMR 6 (CDC13) 1.18 (3H,t); 3.15 (2H*pp. d); 333 (3H,s); 3.72 (3H,s); 3.93 (2H,t); 4.15 (4Htcomplex); 4.62 (lH,t); 6.75 (4H,s); 6.81 (2H4); and 6.95-7.40 (6H,complex). 2992 <% Example 17 3-[4-[2-[N-(2-BenzoxazoIyl)-N-n>etliylainino}ethoxy]phenyl]-2-(4-methoxyphenoxy)propanoic add ll The title compound, mp 148-50°C (methanol), was obtained from ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylaimno)ethoxy]phenyl)-2-(4-methoxyphenoxy)propanoate 10 (1.62 g) by a method analogous to that described for Example 2.

*H NMR S (CDC13) 3.20 (2H4); 3.27 (3H,s); 3.71 (3H,s); 3.85 (2H,t); 4.07 (2H,t); 4.72 (lH,t); 6.70-7.30 (12H^omplex); and 9.05 (lH,br,exchanges with D2O).

Example 18 Ethyl (E/Z)-3-[4-[2~(N-(2-benzoxazolyl)-N-inethylainino]ethoxy]phenyl*2-(4-methylphenoxy)propenoate CH, x-w^^C01CHtCH, The tide compound, a 1:1 mixture of double bond isomers, was prepared from triethyl 2-(4-mcthylphcnoxy)phosphonoacctate by a method analogous to that 25 described for Example 6, and was obtained as a gum. lHNMR8(CDCl3) 1.07 and 1.19 (combined 3H4someric OCH2CH3 triplet signals); 227 and 229 (combined 3H,Me singlets); 331 and 3.34 (combined 3HJiMe signals); 3.90 30 (2H,complex); 4.05-435 (4H,complex); 6.64 (0.5H,s,E-olefin isomer); and 6.75-7.70(125H*omplex). 29 925 6 Example 19 Ethjrl (E/Z)-3-[4«[2»[N-<2-bfnroTiTOlyl)-N-inethylamino]ethoxy]pheny^2-(4-methylphenoxy)propanoate CH, —v^OOjCHJCH, The title compound, a gum, was prepared firom ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylainino}ethaxy}phenyl]-2-(4-methylphenoxy)propenoate by a procedure similar to that described for Example 8, using ethanol as solvent *H NMR 6 (CDC13) 1.18 (3H,s); 2J2A (3H,s); 3.15 (2H^omplex); 3.33 (3H,s); 3.93 (2H,t); 4.17 (2H,q); 4.23 (2H,t); 4.67 (lH,t); 6.71 (2H4); 6.81 (2H,d); and 6.95-7.40 (8H,complex).

Example 20 3-[4-[2-[N«(2-Benzoxazolyl)-N-methylaniino]ethoxy]phenyl]-2-(4-metbylphenoxy)propanoic add The dde compound, mp 150-151°C (methanol), was obtained from ethyl 3-[4-[2-[N-(2-benzQxazolyl)-N-methylamino}ethoxy]phenyl]-2-(4-methylphenoxy)propanoate by a method analogous to that described for Example 2.

NMR 5 (CDCI3) 2.33 (3lis); 3.21 (2H4); 3.26 (3IU); 3.84 (2H,t); 4.06 (2H,t); 4.77 (lH,t); 6.75 (4Iicomplsx); 6.95-7.30 (8H,cooqiiex); and 7.35 (lH,br,exchanges with D2O). « 299256 Example 21 Ethyl (E/Z)-3-[4-[2-[N-<2-benzoxazolyl)-N-metbylamino]ethoxy]phenyl}-2-(2-methyiphenox., )propenoate -v™' rrY0'^' JO The title compound, a gum, was obtained as a 44:56 ratio of double bond isomers (as measured by NMR) from triethyl 2-(2-methylphenoxy)phosphonoacetate by a 10 method analogous to that described for Example 6.

*H NMR 8 (CDCI3) 1.06 and 1.14 (combined 3H,isomeric OCH2CH3 triplet signals); 2.32 and 2.42 (combined 3H,methyl singlets); 3.31 and 334 (combined 3H,NMe singlets); 3.95 15 (2H^omplex); 4.14 (2H,complex); 4.26 (2H,compiex); 6.48 (0.44H,E-olefinic proton); 72% (0.56H,Z-olefinic proton); and 6.70-7.65 (12H,complex).

Example 22 Ethyl 3-[4-[2-lN-(2-betizoxaz0lyI)-N-methylainino]ethoxy]phenyI}-2-(2. methylphenoxy)propanoate «. ™' u^y-Y00.".0*.

Oy CH The tide compound, a gum, was prepared from ethyl (E/Z)-3-[4-[2-[N-(2- benzoxaxolyl)-N-methylamino]cthoxy]phenyl]-2-(2-methylphenoxy)propcr?ontc by a procedure similar to that described for Example 8, using ethanol as solvent *H NMR 8 (CDCI3) 1.18 (3H,t); 2^1 (3H,s); 3.18 (2H,d); 333 (3H,s): 3.93 (2H,t); 4.16 (2H,q); 4.23 (2H,t); 4.72 (lH,t); 6.57 (IHA); and 6.70-7.40 (1 lH,complex). 299256 Example 23 3-[4-[2-[N-(2-B«nzo%azolyl)-N-inethylainino]ethoxy]pbenyl]-2-(2-methylphenoxy)propanoic add The title compound, mp 142-3°C (dichloromethane-hexane), was prepared from ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]cthoxy]phenyl]-2-{2-methylphenoxy)propanoate by a method analogous to that described for Example 2. lHNMR5(CDCI3) 2.25 (3H,s); 3.25 (2H4); 3.27 (3H,s); 3.83 (2H,t); 4.04 (2H,t); 4.82 (lH,t); 6.65-7.40 (12H^omplex); and 7.88 (lH,br,exchanges with D2O).

Example 24 Methyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyI)-N-methylainino]elhoxy]phenyl}-2-(4-chlorophenoxy)propenoate The tide compound, a gum, was obtained as a 1:1 mixture of double bond isomers when methyldLret&yl 2-(4-chlorophenoxy)phosphoncsceiate was reacted with 4-[2-[N-(2-benzoxa2»iyi> N-methylaniino]ethoxy]benzaldeh}7ic in a manner analogous to that described for Example 6.

*H NMR 5 (CDCI3) 331 and 335 (combined 3HJ4Me singlets); 3.65 and 3.74 (combined 3H,OMe singlets); 3.93 (2H,complex); 4.25 (2H,complcx); and 6.70-7.70 (13Iicomplex). 299256 Example 25 Methyl 3-[4-[2-[N*(2-benzoxazolyl)-N-inethylaiiiino]ethoxy]phenyl}-2-(4-chlorophenoxy)propanoate Magnesium turnings (0.5 g) were added to a mixture of methyl (E/Z)-3-[4-[2-rN-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(4-chlorophenoxy)propeno: 0.98 10 g) and a crystal of iodine dissolved in methanol (50 mL) at room temperature. The mixture was wanned gently with a heat gun until reaction ensued, at which point die heating was stopped and the mixture stirred at room temperature during the addition, over n 5 minutes, of a further portion of magnesium (2.00 g). The reaction mixture was immersed in a cold water bath and stirring continued until all the metal had 15 dissolved (~ 4 hrs), then the mixture was evaporated in vacuo. The residue was suspended in water (100 mL) and stirred vigorously during the addition of concentrated hydrochloric add, to give (once all the suspension had dissolved;•«. anal pH of 1.5. The mixture was extracted with ethyl acetate (2 x 100 mL) and die combined ethyl acetate layers then washed with water (500 mL), brine (300 mL), 20 dried (MgSO>4) and evaporated. The resulting gum was chroroatographed on silica gel with 3% ethyl acetate in dichloromethane as eluent to afford the title compound, mp 88-90°C.

*H NMR 5 (CDCI3) 3.15 (2Hvd); 3.33 OH*); 3.69 (3H,s); 3.93 (2H,t); 4.23 (2H,t); 4.69 (lH,t); 6.73 (2H4); 6.81 (2H4); tnd 6.95-7.40 (8H,complex).

Example 26 3-[4-[2-[N-(2-Benzoxazolyl)-N-inethylamino]ethoxy]phenjl]-2-(4-chlorophenoxy)propanoic add The title compound, mp 164-5°C (methanol), was prepared from methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(4-chlorophenoxy)propanoateby 299256 a procedure analogous to that described for Example 2.

*H NMR 8 (CDCI3) 3.22 (2H,cotnplex); 3.26 (3H,s); 3.84 (2H,umesolvcd t); 4.02 (2H,unresolved t); 4.79 (lH,t); 6.75 (2H,d); 6.83 (2H,d); and 6.95-7.30 (9H,complex; reduces to 8H on shaking with D2O).

Example 27 Methyl 3-[4-[2-[N-(2-benzoxaxoIyl)-N-methyEainino]ethoxy]phenyl]-2-(phenylmethoxy)propanoatc Sodium hydride (60% dispersion in mineral oil; 0.14 g) was added portionwise to a stirred solution of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-hydroxypropanoate (1.20 g) in dry NJNf-dimethyl formamide (20 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes prior to the addition of benzyl bromide (0.6 mL). Stirring was continued at room temperature for 3 hrs, then at 80°C for 17 hrs before the mixture was cooled, diluted with water (500 mL) and extracted with ethyl acetate (3 x 200 mL). The combined ethyl acetate layers were washed with water (4 x 500 mL) and brine (SOO mL), dried (MgSC>4) and evaporated. The residue was chromatographed on silica gel with 1% methanol in dichloromethane to afford the title compound, a gum, which was ustd in the next stage without further purification.

*H NMR 8 (CDCI3) 2.98 (2H,complex); 336 (3*is); 3.70 (31Ls); 3.95 (2H,t); 4.07 (lH,dd); 4.25 (2H,t); 4.35 (lH,d); 4.64 (1H4); 6.80 (2H4); and 6.95-7.45 (llH,complex). 299256 Example 28 3-[4-[2-[N-(2-BenzoxazoIyi)N-methyIamino]ethoxyJphenyl]-2- (phenylmethoxy)propanoic add The title compound, a foam, was prepared from methyl 3-[4-[2-[N-(2-benzoxazoIyl)-N-mcthylami'io]ethoxy]phcnyl]-2-(phenylmcthoxy)propanoatc by a procedure analogous to Aiat described for Example 2. This material was used directly in the salt forming step without fanner purification.

Iff NMR 8 (CDCI3) 3.00 (lH,dd); 3.10 (lH^d); 3.32 (3H,s); 3.90 (2H,t); 4.16 (3H,complex); 4.45 (lH,d); 4.67 (1H4); 4.75 (lH,broad,exchanges with D2O); 6.78 (2H,d); and 6.95-7.45 (llH^omplex).

Example 29 3-[4-[2-[N-(2-BenzoxazoIyI)-N-inethylamino]ethoxy]phenyI]-2-(phenylmethoxy)propanoic add, sodium salt Sodium tnethoxide (0.031 g) was added to an ice-cooled, stirred solution of 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(phenylmethoxy)propanoic acid (0.26 g) in methanol (5 mL). The mixture was stirred at 0°C for 10 minutes then diluted with ether (10 mL) and evporated. The residue was stirred and re-evaporated several times from ether (10 mL each time) until a solid was obtained. The solid was filtered from ether and dried under vacuum at 60°C for 1 week to afford the title compound, a free-flowing powder.

*H NMR 8 (DMSO-dg) 2.67 (lH,dd); 2.90 (lH,dd); 3.23 (3H,s); 3.62 (lH,dd); 3.88 (2H,t); 4.15 (lH,dd); 29 925 6 4.18 (2H,t); 4.63 (1H4); 6.81 (2H,d); and 6.95-7.45 (llftcomplex).

Example 30 Ethyl (E/Z)-4-[4-[2-[N-(2-ben7X)xnzolyl)-N-inelhylatninolethoxy]phenyl]-2-ethoxybut-2-enoate The title compound, a gum, was prepared from 4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenylethanal by a method analogous to that described for Example 6, and was isolated as a 1:1 mixture of double bond ison?crs *H NMR 8 (CDCI3) 1.25-1.50 (6H,complex); 3.34 (3I^s); 3.50 <0.5 x 2H,d); 3.72 (2H,t); 3.90 (3H,complcx); 4.20-4.35 (4H,complex); 5.29 (0.5H,t); 6.36 (0.5H,t); 6.78 (2H4); and 6.90-7.40 (6HUcomplex).

Example 31 Ethyl 4-[4-[2-[N-(2-benzoxazolyI)-N-inethylamino]ethoxy]phenyl]-2-ethoxybutanoate The title compound, a gum, was prepared from ethyl (E/Z)-4-[4-[2-[N-(2-benzoxazolyiy-N-methylamino]ethoxy]phenyl]-2-cthoxybut-2-enoate by a method similar to that described for Example 8, using ethanol as solvent lH NMR 8 (CDCI3) 1.26 (6H,complex); 1.97 (2H,q); 2.68 (2H,complex); 335 (3HUs); 3.37 (IH,complex); 3.63 (lH,complex); 3.75 (lH,t); 3.94 (2H,t); 4.154.25 (4H,complex); 6.81 (2H,d); and 6.95-7.40 (6H .complex).

OCH,CH, 0CH,CHj 2992f Example 32 Ethyl (E/Z)-3-(4-[2-[N-(2-beiwoxazolyl>-N-niethylainino]ethoxy]phenyIJ-2-(2-napthyloxy)propenoate The title compound, a gum, was isolated as a 1:1 mixture of double bond isomers when triethyl 2-napthyloxyphosphonoacetate was reacted with 4-[2-[N-(2-10 b&nzoxazolyl)-N-methylamino]ethoxy]benzaldehyde in a manner analogous to that described for Example 6.

*H NMk 8 (CDC13) 1.02 and 1.15 (combined 3H;OCH2CH3 triplet signals); 3.27 and 3.33 (combined 3H; 15 NMe singlets); 3.90 (2H,complex); 4.05-4.30 (4H,complex); and 6.75-7.80 (16H,complex).

Example 33 Methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-mefhylamino]ethoxy]phenyl]-2-(2-napthyloxy)propanoate The title compound, a sticky form, was obtained from ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-napthyloxy)pit)penoate by a procedure analogous to that described for Example 25.

*H NMR 8 (CDCI3) 3.23 (2IUpp d); 3.31 (3H,s); 3.70 (3H,s); 3.90 (2H,t); 4.21 (2H,t); 4.91 (lH,dd); 6.81 (2H,d); and 6.90-7.80 (13H^omplex). • 29925 Example 34 3-[4-[2-[N-(2-Bemoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2- napthyloxy)propanoic add CH, cXvJ^xjVq The tide compound, mp 162-4°C (methanol), was prepared from methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-mcthylamino]ethoxy]phenyl]-2-(2-napthyloxy)propanoaie in a 10 manner analogous to that described for Example 2.

*HNMRS(DMSO'd«) 3.17 (2H^omplex); 3.19 (3H,s); 3.87 (2H,t); 4.21 (2H,t); 5.03 (lH,dd); 6.85 (2H,d); 6.90-7.50 (lOH^omplex); 7.72 (1H4); 7.79 (2H4); and 13.10 (lH,br,exchanges with 15 D2O).

Example 35 Ethyl (Z)-2-ethoxy-3-l4-[2-tN-methyl-N-(2-pyridyl)amino]ethoxy]phenyi]-20 propenoate CO,CHfCH, CH, Triethyl 2-cthoxyphosphonoacetate (3.44 g) was dissolved in dry tetrahydrofuran (25 25 mL) and the solution added slowly to an ice-cooled, stirred suspension of sodium hydride (60% dispersion in mineral oil; 0.56 g) in tetrahydrofuran under an argon atmosphere. The mixture was stirred at 0°C for 30 minutes prior to the addition of a solution of 4-[2-[N-methyl-N-(2-pyridyl)anuno]cthoxy)benzaldehyde (Eur. Patent Appl. Publication Number EP 0306228) (3.29 g) in tetrahydrofuran (30 mL). The 30 mixture was allowed to wann to room temperature, with stirring, over 22 hours, then concentrated in vacuo. The residue was suspended in water (300 mL), extracted with ethyl acetate (2 x 300 mL) and the combined ethyl acetate solutions washed with water (500 mL) and brine (500 mL), dried (MgSC>4) and evaporated. The residual gum was chromatographed on silica gd using 20% ethyl acetate in hexane as eluent 35 to afford the title compound as an oil. '◦ntinued elution of the chromatography column afforded a mixture comprising 2992 5 6 vaotc of the (ZHsomer along with the isomeric (E)-alkene (see Example 36). lHNMR8(CDCI3) 1.35 (6H,t); 3.14 (3IU); 3.95 (4H,cotnplex); 4.21 (2H,t); 4.28 (2H,q); 6.50 5 (2H,conaplex); 6.88 (2H,d); 6.95 (1H^); 7.44 (lH^omplex); 7.72 (2H,d); and 8.15 (lH^omplex).

Example 36 Ethyl (E)-2-ethoxy-3-[4-l2-[N-methji-N-(2-pyridyl)amino)ethoxy]phenyI]-propenoate The mixture of double bond isomers obtained from the chromatography column in Example 35 was rc-chromatographed, this time using 10% ethyl acetate in hexane as eluent Mae of die (Z)-isomer eluted first, followed by the desired (E)-isomer, an oiL *H NMR 6 (CDCI3) 1.13 (3H,t); 1.40 (3H,t); 3.14 (3H.S); 3.90 (2H,q); 3.97 (2H,t); 4.15 (4H,complex); 6.06 (lH,s); 655 (2H,complex); 6.81 (2H,d); 7.10 (2H,d); 7.45 (lH^omplex); and 8.15 (lHvcomplex).

Example 37 Methyl 3-[4-[2>[N-(2-benzoxazolyl)-N-niethylamino]ethoxy]phenyi]-2-(2,2^-trifluoroethoxy)propanoate The tide compound, a gum, was prepared firom methyl 3-(4-hydroxyphenyl)-2-(2.2.2-trifluoroethoxy)propanoate by a mediod similar to that described for Example 1 NMR 5 (CDCI3) 3.00 (2H^omplex); 3.34 (3H,s); 3.65 (lH,complex); 3.72 (3H,s); 3.94 (2H,t); * ^ (IH,complex); 4.15 (lH,dd); 4.24 (2H.t); 6.81 (2H.d); and 6.95-7.40 (6H,co- Mass spectrum (FAB,glycerol) shows MH+ at 453.1647. [C22H23F3N205jn'i* 29 9? M requires 453.1637.

Example 38 Methyl 2-ethoxy-3-[4-[2-[N-methyI-N-(2-pyridyI)araino]ethoxy]phenyl]-propanoate CH, CUXXT& The tide compound, a gum, was prepared from ethyl (Z)-2-ethoxy-3-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]propanoate by a method similar to that described for Example 25.

*H NMR 8 (CDCI3) 1.15 (3H,t); Z93 (2H,d); 3.14 (3H^); 3.33 (lH^omplex); 3.56 (lH.complex); 3.69 (3lia); 3.95 (3H,cotnplex); 4.15 (2H,t); 6.52 (2H,complex); 6.81 (2H,d); 7.11 (2H,d); 7.42 (lH4t); and 8.13 (lUdd).

Example 39 Ethyl 3^[4-[2-[N-(2-bcnzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-etboxypropanoate CH, ^^^.CO.CH.CH, OCH,CH, The title compound, an oil, was prepared from ethyl (E/Z>-3-[4-[2-(N-(2-benxoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxypropenoate by a procedure: simiUr to that described for Example 8, using c-ianol as solvent *H NMR 6 (CDCI3) 1.15 (3H,t); 1.22 (3H4); 292 (2H4); 3.33 (lFUomplex); 3.34 (3H,s); 3.55 (lH,ccmplex); 3.94 (3H£omplex); 4.15 (21L,q); 4.24 (2H,t); 6.80 (2H,d); and 6.95-7.40 (6Hvcomplex). 40 Example 40 3-[4-[2-rN-(2-B«mjxx:tNyl)-N-OTethylamino}ethoxy]pheflj'l)-2-ettJOxypropanoic add The title compound, mp 109-110°C (dichloromethane-bcxane), was prepared from ethyl 3-(4-[2-{N-(2-benzoxazolyl)-N-inethyUniino]ethoxy]phenyl]-2-cthoxy 10 propanoate by a procedure similar to that descaribe for Example 2.

*H NMR S (CDQ3) 1.18 (3H,t); 2.98 (lH,d'); 3.04 (llidd); 3.32 (3H,s); 3.45 (lH.complex); 3.61 (lH«complex); 3.91 <2&t); 4.04 (llidd); 4.18 (2lit); 5.00 (lH,br,exchanges with 15 D2O); 6.80 (2H4); and 6.95-7.40 (6H,c©mplex).

Example 41 3-(442-[N-(2-Eteiumxazofyi}-N-methylamitto]etlioxy]phenyt]-2-20 eihoxypropanamide A solution of oxalyi chloride and 3-(4-[2-[N-(2-bcnzoxazolyI)-N-25 methylaminojethoxy]phcny!]-2-cthoxyprop3incHc acid in dichloromethane (5 ml) was rdloxed for l'/^h then concentrated. The residue was dissolved in dichloromethane and sdired with aqueous ammonia for 30 min. After extraction with chloroform (x4) the extracts were dried and concentrated. Chromatography (diethyl ether/ dichloromethane) gave a white foam which was crystallised from diethyl ether m.p. = 30 94-95°C.

*H NMR 5 (CDCI3) 1.12 (3H,U=7); 2.85 (lH4tU»14,75); 3.07 (UiddJ-14.35); 3.35 (3H,$); 3.37-355 (2Iim); 3.87 (lH,ddJ^7.5,3.5), 3.94 (2H,U»5); 4.24 (71iU=5); 5.54 (lH,br s); 6.43 35 (IH, br s); 6.79 (2H,<U®8-5); 7,00 (lRdU=8,1); 7.15 (2lidJ»8.5); 7.1-7.2 (llim); 7.24 (lliddJMU); 7.36 (lH,dJ«8,l). 29 0 WCJL V / v.' • Example 42 3-[4-l2-[N-(2-BenzoxazolyI}-N-methylaniino)ethoxy]pheny1]-2-eihoxythiopropanamide s 3-(4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxypropanamide (428 mg, 1.1 mmol) was suspended in toluene and Lawcsson's reagent (l.l eq) added.

After 3 h at refluxed the suspension was cooled and poured into water. After extraction with chloroform (x 3) the extracts were washed with aqueous ammonia, dried and concentrated. Chromatography (methanol/dichlorome thane) gave the product as a white solid m.p. = 46-48°C.

*H NMR 5 (CDCI3) 1.14 (3H,U=7); 2.91 (lH^JdJ=14,7); 3.25 (lH,dcU=143); 3.35 (3H,s); 3.35-3.51 (2H,m); 3.94 (2H.U=5); 424 (2H,U=5); 430 (lH,dd J=7,35); 6.79 (2H4J=8 5); 7.01 (lH,app tj=75); 7.16 (2H,cU=83); 7.13-7.2 (lH,obs,ra); 7.25 (1H4J=7.5); 7.35 (lH,dJ=7-3); 7.44 (lH.br s); 7.72 (lH,br s).

Example 43 -[2-[4-[2-IN-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-l-ethoxy]ethyl-lf2,4>triazole 03-^ 3-[4-[2-[N~(2-Benzoxazolyl)-N-niethylaniino]eihoxy]phenyl]-2-ethoxypropanamide (0562 g, 15 mmol) in dimethylformamide dimethyl acetal was heated to 120°C for 30 l'/jh then cooled and concentrated. The residue was dissolved in acetic acid (4 ml) and hydrazine hydrate (1.1 eq) added. After 1 !/2 h at 100°C the solution was cooled, diluted with ethyl acetate and washed with water (x 2) and sodium bicarbonate solution. After the solution was dried and concentrated the residue was chromatographed (methanol/dichloromethane) to give the product as a white solid 35 m.p.=127-129°C. 29925 -51 ■ 1-H NMR fi (CDCI3) 1.13 (2H^J»7); 3.09 3.31 (3HU); 3.46 (2H/jjr«=7); 3.8* 3.95 (2HUm); 4.20 (2H,U«5); 4.75 (HMd.I-6.5.5.5); 6.72 (2H4J=8-5); 6.96 (2H4J-85); 7.01 (1H^1U-8,1); 7.16 (lH,duI«8,l); 7.26 (1H4<U-UK 7.33 5 (1H4<U«8,1); 8.00 (lH,s).

Example 44 -[2-[4-[2-(N-2-Benzoxazo(yl)-N-methylanuno]ethoxy]phenyl]-I-ethoxy}ethyl- l^ondluoie 3-[4-[2-[N-(2-Bcnzoxazolyl>N-mcthylainino)ethoxy]phcnyl]-2-cthoxypropanamide 15 (0.7 g, 1.8 mmol) in dimethylfonnamide dimethyl acetal (0.6 ml, 4.6 mmol) was heated to 120°C for l1^ h. After cooling die residue was concentrated and dissolved in 70% aqueous acetic acid (2 an?). To this solution was added 5 N potassium hydroxide (0.44 m) and hydioxylaraine hydrochloride (152 mg) and it was then stirred for 15 minutes. After dilution with water the reaction was extracted with 20 dichloromethane (x 2) and the extracts washed with water, dried (MgS(>4) and concentrated. This residue was dissolved in glacial acetic acid/dioxane (2/2 ml) and heated to 90°C for 1 hour. After dilution with water the product was extracted with chloroform (x3), the extracts washed with water (x2), dried and concentrated. Chromatography (diethyl ethexVhexane) gave die product as a yellow solid 25 m.p. = 89-90°C *H NMR 5 (CDCI3) 1.16 (3H,U-7); 3.14 (lliqj-14); 3.18 (lH,qJ=14); 3.34 (3H^); 3.40-356 (2am); 3.94 (2H4J-5); 4.23 (2H,U«5); 4.75 (lH^dJ=8,6); 6.79 (2H4J=9); 7.00 30 (1H4U=75,1); 7.07 (2H4J-9); 7.16 (lH.dU=7.5,l); 7.31 (lH,ddJ=7J;05); 7.35 (lHddJ«7.5,05); 8.37 (lH,s). 29 09 R * \J L:a < Exampk*45 Emmloncdcally enhanced methyl M4-[2-[N-(2-benzoxazolyI)-N-methylamino]etlioxy]piKnyl]-2Hnethaxypropanoate.

CH, Lipase from Rhixopus delemar (680 mg, ex Biocatalysts Ltd.) was stirred in deionised water (380 ml) and the pH of the mixture adjusted to 7.0. To this mixture, at ambient 10 temperature (23°Q, was added a solution of raceraic methyl 3-{4-[2-[N-(2- bcnroxazolyl)-N-roethyiamino)ethoxy]phenyl]-2-mcthoxypropanoatc (1 g) in acetone (20 ml). The resulting reaction mixture was stirred and the pH maintained at 7.0 by antotitration with 0.1M sodium hydroxide solution. After a 66% molar equivalent of base had been added to the reaction, hydrochloric acid was added to bring the solution 15 to pH 2.0 and the products extracted into dichloromethane. Extraction of the organic phase with 50% saturated sodium bicarbonate solution removed the acid product and the water washed, dried (magnesitm sulphate), organic phase, on evaporation, yielded 350 mg of methyl 3-[4-{2-(N-{2-bcnzoxazolyl)-N-rocthylamino]-cthoxy]phcnyl]-2-soethuxyp*upagoatc as an oil with an enantiomer ratio of 3:95 as 20 determined by chiral HPLC assay. The basic aqueous extract was acidified by the addidon of hydrochloric acid and re-extracted into dichloromethane to yield, after drying and evaporation, 3-{4-{2-(N-(2-benzoxazolyl)-N- methylamino]etho<xy]phenyl}-2-aiethoxypropanoic acid as a white solid. This acid was strixred, at ambient tempera tare, for 3 hours, in methanol which had been 25 presaturated with HO, and die resulting methyl 3-[4-[2-[N-(2-bemoxazolyl)-N-melhylamino}ethaxy}phenyl}-2-fnethoxypropanG ate with an enantiomer ratio of 7(h30, as determined by HPLC, was recovered by extraction. Enantiomer ratios of methyl 3-[4-[2-[N-(2-ben20xazolyl)-N-methylam]i»o]ethoxy]phenyl}-2-methoxypropanoate were dcicrra'incri by HPLC on a chiral AGP column eluting with 30 12% acetonitrile in 0.01M sodium dihydrogen phosphate solution at pH 7.0 and detecting products by UV monitoring ax 245nm. Enantiomer ratios are quoted in the order of eludon. 299256 Example46 (+) - 5-[4-[2-[N-(2-benxox»Mlji)-N-ineth3flaiittno]cthoxy]phenylJ-2-medMmypropanoic add.

Lipase from Rhizopus delemar (300 mg, ex Biocatalysts Lid.) was stirred in deionised water (125 ml) and the pH of the mixture adjusted to 7.0. To this mixture, at ambient temperature (23°Q, was added a solution of methyl 3-[4-[2-[N-(2-bcnroxazolyl)-N-methylanrino]ethoxy]phcnyl]-2-roethoxypropanoate (69G mg) (enantiomer ratio 8:92 as prepared ,in example 1) in acetone (5 ml). The resulting reaction mixture was stirred at ambient temperature and pH 7.0 was maintained by autotitrarion with 0.1M sodium hydroxide solution until hydrolysis was complete. 0.1M Sodium hydroxide solution was added to bring die reaction mixture to pH °.5 after which it was washed with dichloromethane. The aqueous phase was addir with hydrochloric add to pHl and the add exnacwd into dichlotomethane. washed, dried (magnesium sulphate), and evaporated. The resulting solid was triturated wnh hexane to yield 490 mgo: >) 3-(4-[2-[N-(2-benzoxazolyl)-W-methylamino]eth >henyl]-2-methoxypropanoic acid as a white solid; m.p. 121-123°C; enuitiomer ratio 92:8 (by HPLC assay); [al£>25 +13°, MeOH, c 05. Enantiomer ratios of 3-[4-{2-[N-(2-benaoxirolyl)-N-roethylamino]cthoxy]phcnyl]-2-roethoxypr - noic acid were determined by HPLC on a chiral AGP column eluting with 4.8% acetonitrile in 0.01M sodium dihydrogen phosphate solution at pH 7.0 and detecting products by UV monitoring at 245nm. Enantiomer ratios are quoted in the order of elunoo.

Example 47 (•) • 3-[4-[2-[N-(2-benzoxazolyI)-N-ratthylainino]cthoxy]phenyl]-2-methoxypropanok add.

Lipase from Rhizopus delemar (500 rag, ex Biocatalysts Ltd.) was stirred in deionised water (380 ml) and the pH of the mixture adjusted to 7.0. To this mixture, at ambient temperature (23°Q, was added a solution of methyl 3-{4-[2-{N-(2-benzoxazolyI)-N- 299256 methylamino]ethoxy]phenyl)-2-inethoxypropanoate (950 mg) (recovered by re-esteriiication of acid as prepared in example 1) in acetone (20 ml). The resulting reaction mixture was stirred at ambient temperature and pH 7.0 was maintained by autotitratkxi with 0.1 M sodium hydroxide solution until a 32% molar cqivalent of base had been added to the reaction then hydrochloric acid was added to bring the solution to pH 2.0 and the products extracted into dichloromethane. Extraction of the organic phase with 50% saturated sodium bicarbonate solution removed the acid product and the water washed, dried (magnesium sulphate) organic phase, on evaporation, yielded 543 mg of recovered ester. The aqueous phase was acidified with hydrochloric acid to pHl and the add extracted into dichloromethane, washed, dried (magnesium sulphate), and evaporated. The resulting solid was triturated with hexane to yield 256 mg of (-) 3-(4-[2-[N-P. benzoxs?olyl)-N-methylamino]-ethoxy]phenyl]-2-methoxypropanoic acid as a white solid; m.p. 116-119*C; enantiomer ratio 7:93 (by HPLC assay); [ajp25 -10°, MeOH, c 0.55. Determination of enantiomer ratio by HPLC w» , as described for Example *t6.

Example 48 Ethjrl (E/Z)-3-[4-(2-[N-(2-benzoxaxoIyl)-N<niethylamino]ethoxy]-2-metboxyphenyf]-2-etlioxypropenoate OCHj The title compound, a gum, was obtained as a 66:34 mixture of double bond isomers when triethyl 2-ethaxyphospbonoacetafie was reacted with 4- [2-{N- (2-benzoxazo!yl)-N-methylamino]ethoxy]-2-methoxybenzaldehyde in a manner similar to that described far Example 6.

*H NMR 5 (CDCI3) 1.09 and 1.25-1.45 (combined,6H,OGH2C//3 triplets); 3.35 (3H,s); 3.75 and 3.80 (combined 3H,OMe singlets); 3.87-4.40 (8H,complex); 6.06 (0.34H^-olcfin singlet) and 6.40-8.18 (7.66H,complex,axomatic protons and Z-olefin). 2982 Example 49 Ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-niethylanuno}ethoxy]-2-niethoxyphenyl]-2-ethoxypropanoate The title compound, a gum, was prepared firom ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylaInino]ethoxy]-2-Inethoxyphenyl]-2-ethoxypropenoa, manner similar to that described for Example 8. iH NMR 5 ! CDCI3) 1.10-1.40 (6H,complex); .194 (2H,complex); 3.34 (3H,s); 3.35 (IH,complex); 3.55 (lH,complcx); 3.76 (3H,s); 3.93 (2H,t); 4.10(lH,dd); 4.13 (2H,q); 4.24 (2H,t); 6.39 (2H,complex) and 6.95-7.40 (5H/x>mplex).

Example 50 Ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazoIyl)-N-methylanuno]et!ioxy]phenyI'~ *rt-butoxypropenoate OC(CH,», The title compoond, a gum, was obtained as a 76:24 mixture of Z and E double bond isomers when triethyl 2-zsrr-butoxyphosphonoacetate was reacted with 4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]benzaldehyde in a manner similar to that described for Example 6.

*H NMR 8 (CDCI3) 1.18 and 1-35 (combined 3H, OCH2CH3 triplet signals); 1.27 and 134 (combine. 9H, OBu1 singlets); 3.34 and 335 (combined 3H, NMe singlets); 3.95 (2H, complex); 4.10-4.28 (4H, complex); 653 (0.24H, s, E-olefin) and 6.75-7.80 (8.76H, complex, Z-olcfin and aromatic protons). 299256 Example 51 Ethyl 3-[4-[2-tN-(2-benxoxazolyl)-N-inethylamino]ethoxy]pheRyi]-i-tert-butoxypropanoate The title compound, a gum, was prepared from ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-inethylaimno]ethoxy]phenyl]-2-ferr-butoxypiopenoate by a method 10 analogous to that described for Example 25. Tbis material was contaminated with some of the corresponding methyl ester and the mixture was used directly in the next stage without further purification.

*H NMR 8 (CDCI3) 0.91 (9H^); 1.24 (3H,t); 2.85 (2H*omplex); 3.34 (3H,s); 3.93 (2H,t); 4.03 (lH,dd); 4.16 (2H,q); 4.23 (2H,t); 6.79 (2H,d) and 6.95-7.40 (6H,complex).

Example 52 3-[4-[2*tN-(2-Bcnzoxazolyl>-N-methytamino]ethoxy]phenyl]-2-(erf-butoxypropanoic add The title compound, a gum, was prepared from ethyl 3-[4-[2-[N-(2-bcnzoxazolyl)-N-methylamino]ethoxy]phenyl}-2-terr-butoxypropanoate by a method similar to that described for Example 2.

*H NMR 8(CDQ3) 1.04 (9H^); 2.84 (lH,dd); 2.98 (lH,dd); 3.34 (3H,s); 3.93 (2H,t); 4.13 (lH,dd); 4.21 (2H,t); 6.79 (2H4); 6.95-7.40 (6H£omplex) and 7.45 (lH,broad,exchanges with D2O). 2s) 92 5 6 Example 53 3-[4-[2-[N-(2-BenzoxazolyI)-N-methylamino]etbox¥]phenyl]-2-tert-butoxypropanoic add, sodium salt ^.CO, Na OCqCH^ Sodium hydride (60% dispersion in mineral oil, SO mg) was added to a stirred, ice-cooled, solution of 3-[4-[2-[N-(2-benzoxazolyl>N-methylanuno]ethoxy]phenyl]-2-10 terr-butoxypropanoic add (0.496 g) in methanol (10 mL). The mixture was stirred at 0°C for 10 minutes, concentrated in vacuo and iediluted with diethyl ether (40 mL). The resulting solid was filtered and dried to afford the title compound, mp > 250°C.

*H NMR 5 (DMSO-d^) 0.85 (9H,s); 2.43 (lH,dd); 2.73 (lH,ad); 3.21 (3H,s); 3.55 (lH,dd); 3.86 (2H,t); 4.19 (2H,t); 6.77 (2H,d) and 6.95-7.40 (6H,complex).

Example 54 Ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylainino]ethoxy]phenyI]-2-(2-phenylethoxy)propenoate The tide compound, a 71:29 Z:E mixtuie of double bond isomers, was obtained from triethyl 2-(2-phenylethoxy)phosphonoacetate by a method similar to that described for Example 6.

% NMR 8 (CDC13) 1.14 and 1.34 (combined 3H,OCH2^"3 triplet signals); 3.05 (2Ii,cotxtf>I&x); 3.33 and 334 (combined 3HJNMe signals); 3.95-4.30 (8H,complex); 6.07 (0.29H,E-olefin ringlet) and 6.70-7.55 (13.71H,coinplex^£-olefin and aromatic protons). • 2992 PS I Example 55 Methyl 3-[4-[2-[N-(2-benzoxazolyl}-N-inethylamIno]eihoxj]phenyI]-2-(2- phenylethoxy)propanoate The title compound, a gum* was obtained from ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methyU2nino]ethoxy]phenyl]-2-(2-phenylethoxy)propenoate by a 10 method similar to that described for Example 25.

*H NMR 8 (CDCI3) 2.84 (2H,t); 2.93 (2H,complex); 334 (3H,s); 3.43 (lILco&plex); 3.68 (3H,s); 3.77 (llicomplex); 3.94 (3H,complex); 4.23 (2H.0; 6.77 (2H^J and 6.95-7.40 15 (UH,complex).

Example 56 3-[4-[&[N-(2-Benzoxa£olyl)-N-methylammo]ethoxy]phenyl]-2-(2-20 phenyieUMny)propanoic add The title compound, mp 131-3°C (dichloromethane-hexanc), was obtained from 25 methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-mcthylanuiK>]cthoxy]phenyl]-2-(2- phenylethoxy)propanoaie by a method similar to that described (or Example 2.

*H NMR 8 (CDCI3) 2.85 (2H,t); 2.93 (llidd); 3.04 (lH,dd); 3.32 (3Iis); 3.57 (llicomplex); 3.77 30 (lH,complex); 3.91 (2H,t); 4.02 (llidd); 4.17 (2H.0; 6.10 (lH,broad^xchanges with D2O); 6.77 (2Iid) and 6.95-7.40 (lllicomplex). 29 92 5 6 ExampSe 57 Ethyl (E/Z)-3-[4-[2-[N-(2-bcngoxayolyl)-N-methylamino]ethoxy]phenyI]-2-(2-methoxy^hoxy)propenoate CH.

The title compound, a gum, was obtained as a 76:24 7zE tnixture of double bond isomers firom triethyl 2-(2-methoxyethoxy)phosphonoacetate by a method similar to 10 that described for Example 6.

*H NMR 5 (CDQ3) 1,12 and 1.35 (combined 3H,OCH2C//3 triplets); 3.35-3.45 (combined,6H,complex NMe and OMe singlets); 3.67 and 3.72 (combined 2H,complex,OCH2Cf/20Me 15 signals); 3.90-4.35 (3H,complcx); 6.15 (0.24H,E-olcfin singlet) and 6.80-7.80 (8.76H^omplex).

Example 58 Methyl 3-[4-(2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyI>2-(2* methoxyethoxy)propanoate The title compound, a gum, was prepared from ethyl (E/Z)-3-[4-[2-[N-(2- bcnzoxazolyl)-N-mcthylamino]ethoxy]phenyI]-2-(2-mcthoxyethoxy)propcnoatc by a method similar to that described for Example 25.

*H NMR 5 (CDQ3) 2.95 (2H,cotnplex); 3.29 (3H^); 3.34 (3H,s); 3.47 (3H,complex); 3.68 (lH,complex); 3.69 (3H,s); 3.93 (2H,t); 4.06 (lH,dd); 4.23 (2H,t); 6.79 (2H,d) and 6.95-7.40 (6H,complex). 299?5 6 Example 59 Methyl (Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyI]-2-(carbo^ymethoxy)propenoate 02 A mixture of sodium hydride (60% dispersion in mineral oil, 0.30 g). dimethyl diglycolate (0.81 g) and 4-[2-[N-(2-benzoxazolyl)-N-mcthylamino]ethoxy]-10 benzaldehyde (2.22 g) in dry benzene (50 mL) was stirred at room temperature overnight Acetic acid (1 mL) was added, the mixture was poured onto iced water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried (MgS(>4) and evaporated. The resulting oil was chromatographed on silica gel using 2% methanol in dichloromethane, and the product crystallised from 15 ethyl acetate, mp 111-112°C *H NMR 5 (CDCI3) 3.34 (3H,s); 3.83 (3H*s); 3.95 (2H,t); 4.25 (2H,t); 4.51 (2H,s); 6.85-750 (9H^omplex) and 9.40 (lH,bioad,exchanges with D2O).

Example 60 Methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-inethylamino]ethoxy]phenyl]-2-(carboxymethoxy)propanoate The title compound, mp 154-155°C, was prepared from methyl (Z)-3-[4-[2-[N-(2-bcnzoxazolyl!)-N-methylamino]ethoxy]phenyl]-2-(carboxymethoxy)prof>cnoate by a 30 method similar to that described for Example 8.

*H NMR 8 (CDCI3) 2.95 (lH,dd); 3.09 (lH,dd); 3.31 (3H,s); 3.7; (3H,s); 3.93 (2H,complex); 4.07 (2H^); 4.20 (3H,complex); 6.79 (2H4) and 6.95-7.40 (7H,coaiplex^educes to 6H on 35 shaking with D2O). 299256 Example 61 -[2-[4-[2-[N-(2-Bemoxazolyl)-N-meihyUimino]ethoxy]phenyI]-l-ethoxyethyI]-3-methyI-l,2t4-oxadiazole The title compound, mp 61-62°C, was prepared in a manna analogous to that described for Example 44 using N,N-dimethyIacctamide dimethyl acetal in place of 10 N,N-dimethylformamide dimethyl acetal.

NMR 5 (CDCI3) 1.15 (3H,t); 2.39 (3H,s); 3.12 (lH,q); 3.14 (lH,q); 3.35 (3H,s); 3.35-3.60 (2H,m); 3.94 (2H,t); 4.23 (2H,t); 4.65 (lH,dd); 6.79 (2H,d) and 7.00-7.36 (6H,complex).

Example 62 -[2-[4-[N-(2-Benzoxaz©lyl)-N-mcthylamino]ethoxy]phenyl]-l-ethoxyethyl]-l,23,4-(lH)-tetrazole Sodium azide (0.76 g) and trimethylsilyl chloride (1 mL) were added to a solution of 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phcnyl]-2-cthoxypropanonitrile 25 (0.85 g) in N,N-dimethyl formamide (30 mL). The mixture was refluxed for 4 days, cooled, poured into water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried and evaporated. The residue was purified by chromatography on silica gel using 1% methanol in ether as solvent to afford the title compound, a white foam.

Ill NMR 5 (CDCI3) 1.13 (3H,t); 3.13 (2Hdd); 3.22 (3H,s); 3.51 (2H,dq); 3.88 (2H.0; 4.15-4.20 (2H,m); 4.99 (lH,t); 632 (2H,d); 6.80 (2H,d); 7.04 (lH,dt); 7.16 (lH,dt) and 7.25-7.31 (2H^n). 2992 Procedure1 Ethjl 3-(4-hydroxyphenyl)-2-methoxypropanoate [CHjCH, A solution of ethyl 2-diazo-3-(4-hydroxyphenyl)propanoate (c.f. N. Takamura and T. Mizoguctu, Tetrahedron Lett.. 1971,4495) (8.3g) in benzene (40mL) was added over 30 minutes to a stirred, refluxing mixture of rhodium (II) acetate dimer (lOmg), methanol (7.9tnL) and benzene (50mL). The mixture was heated at reflux for a further 30 minutes, then allowed to cool to room temperature overnight and washed with water (2x200mL). The benzene solution was dried (MgSC>4) and evaporated and the residual oil chromatographed twice on silica gel, firstly with 20% ethyl acetate in hexane as eluent and subsequently with 4% ethyl acetate in dichloromethane as eluent to afford die tide compound as an oil.

*H NMR 8 (CDCI3) 1-22 (3H, t); 2.94 (2H, d); 335 (3H, s); 3.94 (IH, t); 4.20 (2H, q); 5.73 (IH, exchanges with D2O); 6.75 (2H, d); and 7.15 (2H, d).

Procedure 2 Methyl 3-(4-hydroxyphenyl)-2-inethoxypropanoate A solution of methyl 2-diaz0-3-(4-hydroxyphcnvl)propanoate (cf Tetrahedron Lett., 1971,4495) (8.58 g) in methanol (120 mL) was added over 10 minutes to a mixture of rhodium (II) acetate dimer (0.18 g) in methanol (50 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was heated at reflux for 5 hrs, allowed to stand at room temperature for 15 hrs, then concentrated in vacuo. The residue was dissolved in ethyl acetate (500 mL), washed with water (3 x 300 mL) and brine (500 mL), dried (MgSO>4) and evaporated. The resulting gum was chromatographsd on silica gel with a gradient of 4% ethyl acetate to 6% ethyl acetate in dichloromethane as eluent to afford the title compound, mp 61-3°C 29925'=; *H NMR 5 (CDCI3) 2.95 (2lid); 3.40 (3H,s); 3.75 (3H,s); 4.00 (lH,t); 6.30 (IH.broad, exchanges with ^ D20); 6.80 (2H,d); and 7.15 (2H,d).

Procedure 3 (E/Z)-l-Methoxy-2-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]-phenyl]ethene OCH, Methoxyinethyltriphenylphosphonium chloride (12.34 g) was suspended in dry tetrahydrofuran (200 mL), cooled to -10°C and stirred under a nitrogen atmosphere during the addition of a solution of lithium diisopropylamide (2.0 M in heptane/tetrahydrofuran/ethyl benzene; 13.5 mL) over ca 5 minutes. The resulting 15 mixture was allowed to warm to 10°C, and stirred at this temperature for 1 hr. A solution of 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzaldehyde (Eur. Patera Appl. Publication No. 0306228) (4.60 g) in dry tetrahydrofuran (75 mL) was added at 10°C and the mixture then stirred at room temperature for 4JS hrs. The solvent was evaporated, the residue suspended in water (600 mL) and extracted with 20 dichloromethane (3 x 250 mL). The combined dichloromethane solutions were washed with water (3 x 1L) and bine (1L), dried (MgSC>4) and evaporated. The residue was chromatographed on silica gel with 1.5% methanol in dichloromethane as eluent to afford the title compound, a gum, as a 1:1 mixture of double bond isomers.

*H NMR 5 (CDCI3) (Z)-alkene: 3.12 (3H^); 3.72 <3*is); 3.94 (2H,t); 4.14 (2H,t); 5.14 (1HAJ=7.0 Hz); 6.01 (1HAJ«7.0 Hz); 6.48 (2H,complex); 6.80 (2H,d); 7.11 (2H,d); 7.45 (IH,complex); and 8.15 (lH4d).

(E)-alkene: 3.12 (3H,s); 3.63 (3H*); 3.94 (2H,t); 4.15 (2H,t); 5.74 (1H,<U=12.9 Hz); 6.49 (2H,complex); 6.80 (2Rd); 6.88 (lH,dJ=12.9 Hz); 7.45 (3H,complex); and 8.15 (lH,dd). 299 f r. ,- - I Procedurc 4 l,l-Dimethoxy-2-[4-[2-[N-methy!~N-(&-pyridyl)amino)ethoxy}-phcnyi]ethane ■" jx^c A mixture of (E/Z)-l-raethoxy-2-[4-[2-[N-mcthyl-N-(2-pyridyl)arnino]-ethoxy]phenyl]ethene (2.80 g), p-toluenesulphonic acid monohydrate (1.90 g) and methanol (ISO mL) was heated at reflux for 20.75 hrs, cooled and evaporated. The 10 residue was dissolved in ethyl acetate (200 mL), washed with saturated sodium bicarbonate solution (200 mL) and brine (200 mL), dried (MgSC>4) and evaporated. The title compound, a gum, was used in the next stage without purification. lHNMRS(CDCt3) 2.85 (2H4); 3.15 (3H,s); 3.33 (fi&s); 3.98 (2H.I); 4.20 (2H,t); 4.49 (lH,t); 6.50-7.50 (7H,complex); and 8.20 (IHLdd).

Procedures 2-Methoxy*3-[4-[2-[N-meUiyl-N-(2-p3rridyl)amino]ethoxy]-plienj1]propanofutriIe Trimethylsilyl cyanide (3.4 mL) was added drop wise to a solution of 1,1-dimethoxy-25 2-[4-[2-[N-mcthyl-N-{2-pyridyl)aniino]ethoxy]phenyl]ethanc (2.64 g) in dicfaloromcthaiie (70 mL) at room temperature. The mixture was scored during the addition of boron trifluoride etherate (0.3 mL), and stirring continued at room temperature for 1.5 hrs prior to the addition of a further portion of boron trifluoride etherate (1 mL). After a further 2 hours the mixture was diluted with 30 dichloromethanc (100 mL) and washed with saturated sodium bicarbonate solution (2 x 300 mL), water (2 x 300 mL) and brine (300 mL), dried (MgSCty and evaporated. The residue was chrocnatographed on silica gel with 1% methanol in dichloromethane as eluent to afford the title compound, a gum, which was used without further purification.

Ifl NMR $ (CDQ3) 3.04 (2FLd); 3.14 (3FU); 3.46 (3H,s); 3.96 (2H,t); 4.16 (3H,complex); 6.55 299 (2Iiconiplcx); 6.84 Gttid); 7.15 (2H*d); 7.45 (lH,ld); and 8.15 (llidd).

Procedure 6 Methyl 2-atnlno-3-[4.[2~lN-(2-ben3toxazolyi)-N-ra«thylamino]-etlroxy]ptienyl]propanoate ccvC^cor Sodium hydride (60% dispersion in oil; 1.00 g) was added portion wise to stirred solution of tyrosine methyl ester (3.90 g) in dry N,N-dimethylfonnamide (70 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 30 minutes prior to the addition of a solution of 2-[N-(2-benzoxazolyl)-N-methylaxnino]eshanol methanesulphonyl ester (Eur. Patent Appl., Publication No. 03G622E) (5.90 g) in dry N,N-diroethylformamide (30 mL). The tnixture was heated at 100®C for 6 hrs, cooled, diluted with iced water (500 mL) and extracted with ethyl acetate (3x250 mL). The combined ethyl acetate layers were washed with brine (2xIL), dried (MgSO*) and evaporated. The residue was chromatographed on silica gel with 5% methanol in dichloromethane as eluent to afford an oil. This was crystallised from ethyl acetate to afford the title compound, mp 95-6°C 1H NMR 8 (CDCI3) 1.45 (2H,br,exchanges with D20); 2.81 (lH,dd); 3.01 (llidd); 3.33 (3H,s); 3.67 (llidd); 3.70 (3fis); 3.95 (2H,t); 4.25 (2H,t); 6.83 (21id); and 6.95-7.40 (6?icomplex).

Procedure 7 Methyl 3-[4-[2-[N-{2-benzoxazolyi)-N-niethylamino]ethoxy]phenyl]-2-diazopropanoate A mixture of methyl 2-amino-3-[4-[2-tN-(2-beniOxazolyl)-N-methylasmiK>]ethoxy]phenyl]propanoate (5.00 g), acetic acid (4.4 mL) and chloroform (160 mL) was treated drop wise with isoamyl nitrite (3.2 mL). The 299256 mixture was heated at reflux for IS hrs cooled, dilated with chloroform (200 mL) and washed successively with dilute hydrochloric acid (200 mL), water (2x200 mL) and brine (200 mL). The chloroform solution was dried over Mg504, evaporated and the residue chromatcgraphed on silica gel using 3% etfiyl acetate in dichloromethane as eluent to afford the title compound, a itur?..

*H NMR 5 (CDQ3) 3.34 (3H,s); 3.56 (2H,j); 3.77 (3Rs); 3.94 (2H,t); 4.7,5 and 6.80-7.40 (8H,complex).

Procedure8 Methyl 3-(4-hydroxyphenyl)-2~is©propoxypropanoate The title compound, a gum, was prepared firom methyl 2-diazo-3-(4-hydroxyphenyl)propanoa!e (3.00 g) by a method similar to that described in Procedure 2.

*H NMR 6 (CDCI3) 0.97 (3H4); 1.14 (3ILd); 2.91 (2Iicomplex); 351 (lH^ocaplex), 3.71 (3H,s); 4.05 (llidd); 6.02 (llibr.exchanges with D2O); 6.75 (2EUd); and 7.08 (2Iid).

Procedure9 Methyl 3-(4-hydroxypbenyl>*2~propoxypropanoate The title compound, an oil, was prepared from methyl 2~diazo-3-(4-hydroxyphenyi)propanoate (256 g) by a method similar to that described in Procedure 2.

CH, NMR 5 (CBCI3) 0.83 Qat); 1.54 (2Hconjpkx); 2.93 (2H,app. d); 3.22 (IH,complex); 3.51 29 92 5( 67 (lH,complex); 3.71 (3H^); 3.99 (IH,t); 534 (lH,br,excha«ges with D2O); 6.74 (2FM); and 7.08 (2HW).

Procedure 10 Methyl 2-hydroxy-3-(4-hydroxyphenyl)propanoatf A solution of methyl 3-(4-benzyloxyphenyl)-2-hydroxypropanoate (c.f. In: . ition&l Patent Appl.. Publicarion No. WO 9101337) (S.72g) in methanol (120mL) was added to an ice cooled suspension of 10% Palladium charcoal (1.90g) in methanol (30aaL) under a nit- . sn atmosphere. Solid ammonium formate (6.4g) was added and the mixture heated at reflux for 15 minutes, then allowed to cool to room temperature. IS Thecatal* was removed by filtering the reaction mixture through diatomaceous earth and solvent evaporated. The residue was suspended in dilute hydrochloric acid (2M, lOOmL) and extracted with ethyl acetate (2x400mL). The combined ethyl acetate solutions were washed with water (400mL), brine (400mL), dried (MgS04) and evaporated. The resulting gum was chxomatographed on silica gel with 1.5% 20 methanol in dichloromethane as eluent to afford the ride compound, mp 42-43°C 1H NMR d (CDCI3) 2.85 (IH, broad, exchanges with D2O); 2.90 (IH, dd); 3.05 (IH, dd); 3.77 (3H, s); 4.42 (IH, m, collapses to dd on washing with D2O); 5.36 (IH, broad, exchanges with 25 D20); 6.70 (2H,d); and 7.05 (2H,d).

Procedure 11 Methyl 3-(4-(2-[N-(2-benzoxazolyi)-N-inethylamino]ethoxy]phenyl]-2* 30 hydroxypropanoate The title compound, mp 1©»-112°C, was prepared from methyl 2-hydroxy-3-(4-35 hydroxyphenyl)propanoate by a procedure similar to that described in Example 1.

*H NMR d (CDCI3) 2.68 (IH, d, exchanges with D20); 2.90 (IH, dd); 3.05 (IH, dd); 3.35 (3H, s); 3.76 299256 (3H, s); 3.95 (2H, t); 4.25 (2H, t); 4.41 (IH, m, collapses to dd on washing with l>20); 6.81 (2H,d); and 6.95-7.40 (6H, complex).

Procedure 12 Methyl 2-[4-[2-[N-(2«beiutnauolyt)-N-raethylatnino]ethoxy]phenyl]ethanoate Sodium hydride (60% dispersion in mineral oil, 2J2Q g) was added portionwise to a stirred solution of methyl 4-hydroxyphenylethanoate (830 g) in diy N,N-dimethyl foimamide (100 mL) at room temperature under a nitrofen atmosphere. The mixture was sdired at this temperature for 30 minutes prior to the addition of a solution of 2-[N-(2~benz»xazolyl)-N-niethylamino]ethanol methanesulphonyl ester (13.50 g) in 15 N,N-dimethyl formamide (150 mL). The mixture was heated at 80°C for 18 hours, cooled and concentrated in vacuo. The residue was diluted with water (1L), extracted with ethyl acetate (3 x 400 mL) and the combined ethyl acetate solutions washed with water (4 x 1L). brine (1L), dried (MgS04) and evaporated. The residue was chromatographed on silica gel using 15 % methanol in dichloromethane as solvent to 20 afford the title compound as & gam which was used without further purification.

*H NMR 5 (CDCI3) 3.35 (3KU); 357 (2HU); 3.70 (3KU); 3.93 (2H.0; 4.28 (2H,t); and 6.85-7.45 (8Hvcocnplex).

Procedure 13 2-[4-[2-[N-{2-Be«tzDxazo*yt)-!N-nvtthyiamino]ethoxy]pheny1}€thanol A solution of methyl 2-[4-[2-[N-(2-benzoxazolyl)-N-mcthylainino]echaxy}-phcnyVjcthanoate (11.60 g) in dry diethyl ether (200 mL) was added slowly to an ice- under a nitrogen atmosphere. The mixture was stirred at 0°C for 20 minutes, then water (10 mL) and hydrochloric acid (2 M; 10 mL) were added dropwise with caution. The mixture was diluted with water (200 mL) and the solution adjusted to pH 4 prior to extraction with ethyl acetate (3 x 200 mL). The combined ethyl acetate cooled, stined suspension of lithium aluminium hydride (1.36 g) in ether (50 mL) 29925 R solutions were washed with water (2 x 500 mL), brine (50C mL), dried (MgSC>4) and evaporated to afford the title compound, mp 95-97°C *H NMR 5 (CDG3) 2.15 (lH,broad.exchanges with D2O); 2.75 (2H,t); 3.30 (3Rs); 3.80 (2H,t); 3.97 (2H,t); 422 (2H,t); and 6.80-7.45 (8ILcomplex).

Prooedure 14 4-[2-[N-(2-B«igo»axolyl)-N-n»ethylainipo]ethoxy]phenylethanal CH, A solution of pyridine-sulphur trioxide complex (1.53 g) in dimethylsulphoxide (5 15 mL) was added to a stirred, ice cooled mixture of 2-[4-[2- [N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyI] ethanol (1.00 g), triethylamine (2.25 mL) and dichloromethane (30 mL) under a nitrogen atmosphere. The mixture was stirred at 0°C for 10 minutes, then at mom temperature for 5 hours before being dilated with dichloromethane (100 mL) and washed with water (2 x 100 mL), hydrochloric acid 20 (05M; 100 mL), water (2 x 100 mL) and brine (100 mL), dried (MgSCXj) and evaporated. The residue was chromatographed on silica gel with 5% ethyl acetate in dichloromethane as solvent to afford die title compound, a gum.

NMR fi (CDCI3) 3.29 (3ILs); 353 (2H4); 3.86 (2H,t); 4.19 (2H,t); 6.80-750 (8H,complex); and 9.68 (1H.I).

Procedure 15 Methyl 3-(4-hydroxyphenyl)-2-(2^2-trifluoroethoxy)propanoate OCH.CF.

A sedation of methyl 2-diazo-3-(4-hydroxyphenyl)propanoate (3.00 g) in 122-35 triflnoroethanol (10 mL) was slowly added, over 15 minutes, to a stirred mixture of rhodium (II) acetate dinner (0.064 g) and i^2-trifluoroethanol (5 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at temperature for 15 minutes, then heated at reflux for 4 hours, cooled and evaporated. The residue was chromatogiaphed on silica gel with 4% ethyl acetate in dichloromethane to afford 29925 8 the title compound, a gum, which was used without further purification.

*H NMR 5 (CDCI3) 3.00 (2H,complex); 3.6S (llicomplex); 3.74 (3Iis); 4.00 (lH^omplex); 4.17 5 (l!idd); 5.20 (lH,broad,exchanges with D2O); 6.75 (2Fid); and 7.08 <2Iid).

Mass spectrum (EI) shows M+ at 278.0763 amu; C12H13F3O4 requires 278.0766.

Procedure 16 3-[4-[2-[N-(2-Bcnzoxazolyl)-N-inetliylanuno]ethoxy]phenyl]-2-etboxypropanonitrile A mixture of 4-[2-[N-(2-benzoxazolyl)-N-methylamino)ethoxy]phcnylethanal (1.5 g), p-toluenesulphonic acid mcoohydrate (100 mg), 3A molecular sieves (2 g) and ethanol (30 ml) was heated at reflux for 18 hours, cooled and stirred with potassium carbonate (5 g) for 30 minutes. The mixture was filtered through celite and 20 evaporated to afford 3-{4-[2-[N-(2-bcnzoxazolyl)-N-methylamino]ethoxy]phcnyl]-ethanal diethyl acetai which was used without Anther purification (below).

Boron trifiuoride etherate (0.05 ml) was added to a cold (4°C) solution of the above acetal (15 g) and trimethylsilyl cyanide (05 mL) in dichloromethane (20 mL). The 25 mixture was wanned to room temperature and stirred for 24 hrs before being poured into aqueous sodium bicarbonate solution. The organic phase was separated, dried (MgS04> and evaporated. The residual oil was chromatographed on silica gel using 20% ether in dichloromethane as eluent to afford the tide compound as an oiL NMR 8 (CDCI3) 1.20 (3H,t); 3.05 (2H4); 330 (3Iis); 33-4.8 (2H,complex); 3.87 (2H,t); 4.10-4.30 (3Iicomplex); 6.82 (2Iid) and 6.90-7.40 (6H .complex). 299256 DEMONSTRATION OF EFFICACY OF COMPOUNDS Obese Mice, Oral Glucose Tolerance Test C57M1/6 obese (ota/ob) mice were fed on powdered oxoid diet After at least one week, die mice continued 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 fen- each treatment. 2992 -72-Table % Reduction in Level in diet area under blood Example OimoL kg"* of diet) glucose curve 1 3000 54 49 2 3000 51 58 3 100 53 4 300 55 49 100 51 6 1000 50 26 9 100 49 100 53 56 11 100 51 49 14 30 54 17 100 52 100 58 23 100 58 26 100 51 29 100 60 55 31 30 41 34 100 36 1000 59 37 30 61 38 10 56 40 10 62

Claims (2)

-73-Table (continued) Example 41 42 43 44 46 47 49 61 Level in diet Ounol. kg*1 of diet);30;30;100;300;30;30;30;10;29925;% Reduction in area under blood glucose curve;61 69;56 37;57 61 53 37;29 92 5 P;-74-;WHAT WE CLAIM IS:;

1. A process for separating optical isomers of a compound (the substrate ester) which comprises a moiety of formula (H):;5;.^CC^Z —HC;1;QZ;<H);10 wherein C* is a chiral carbon, Z is a C,.,2 alkyl group and Z1 is a C,.12 alkyl, aryl or an aryl CM2 alkyl group, which process comprises enantioselectively hydrolysing the ester group C02Z of one enantiomer into a carboxyl group with a lipase from Rhizopus delemar, Rhisopus arrhizus or Rhizopus LIP F4 or a lipase from Mucor miehei; and thereafter, as necessary, isolating either the 15 enantiomerically enriched product carboxylic acid or the enantiomerically enriched substrate ester. 20 25

2. A process according to claim 1, substantially as hereinbefore described with particular reference to any one of the Examples 45, 46 and 47 herein. rrH^kiMir ^?(c By the authorised agents A J PARK & SON Per v (LsoXoi C\ V (J 30 END OF CLAIMS 35