OA10470A

OA10470A - Benzoxazoles and pyridine derivates useful in the treatment of the type ii diabetes

Info

Publication number: OA10470A
Application number: OA60957A
Authority: OA
Inventors: Harshad Kantilal Rami
Original assignee: Smithkline Beecham Plc
Priority date: 1994-07-29
Filing date: 1997-01-29
Publication date: 2002-04-08
Also published as: IL114759A; FI970357A0; CZ25497A3; NO970373L; WO1996004261A1; WO1996004260A1; FI970357A; CA2196079A1; HUT76637A; IL125525A0; EP0772605A1; NO970373D0; SK12297A3; MA23632A1; IL114759A0; AP9700918A0; MX9700763A; IL125525A; PL318766A1; AP776A

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein R<o> represents 2-benzoxazolyl or 2-pyridyl and R<1> represents CH2OCH3 or CF3; a process for the preparation of such compounds, a pharmaceutical composition containing such compounds and the use of such compounds and compositions in medicine.

Description

w ·>' -#1(1470

BENZOXAZOLES AND PYRIDINE DERIVATIVES USEFUL IN THE TREATMENT OF THE TYPE IIDIABETES

This invention relates to certain novel compounds, to a process for preparingsuch compounds, to pharmaceutical compositions containing such compounds and to 5 the use of such compounds and compositions in medicine.

International Patent Application, Publication Number WO 94/01420 discloses compounds of formula (A): A1 '-X'-(CH2)n’-O-A2'-A3'-Y.R2' (A) 10 or a pharmaceutically acceptable sait thereof, and/or a pharmaceutically acceptablesolvaté thereof, wherein: ΑΓ represents a substituted or unsubstituted aromatic heterocyclyl group; A2 represents a benzene ring having three optional substituents; 15 A3' represents a moiety of formula -(CH2)nrCH(ORl )- wherein Rl' represents substituted or unsubstituted alkyl, aryl, aralkyl or alkylcarbonyl and m represents aninteger in the range of from 1 to 5, or A3 represents a moiety of formula -(CH2)m'.j[-CH=C(ORl')- wherein R^' and m'are as defined above; R2' represents OR3' wherein R3' represents hydrogen, alkyl, aryl or aralkyl or R2' 20 represents an aromatic heterocyclyl group or -NR^ R3 wherein R^ and R3 each independently represent hydrogen, alkyl or alkylcarbonyl or R^ and R3 together withthe nitrogen atom to which they are attached form a heterocyclic ring, providing thatR2' represents an aromatic heterocyclyl group only when Y' as defined belowrepresents a bond ; 25 X' represents NR' wherein R’ represents a hydrogen atom, an alkyl group, an acylgroup, an aralkyl group wherein the aryl moiety may be substituted or unsubstituted,or a substituted or unsubstituted aryl group; Y' represents C=O or C=S or a bond providing that Y' represents a bond only whenR2 represents the above mentioned aromatic heterocyclyl group; and 30 n' represents an integer in the range of from 2 to 6.

These compounds are stated to hâve inter alla good blood-glucose lowering activity and are therefore of potential use in the treatment and/or prophylaxis ofhyperglycaemia and to be of particular use in the treatment of Type II diabètes.

It has now surprisingly been discovered that a particular group of compounds 35 falling within the generic scope of the compounds of formula (A) hâve particularlygood blood-glucose lowering activity combined with freedom from adversehaematological and cardiac effects. These compounds are therefore considered tohold potential to be of particular use in the treatment and/or prophylaxis ofhyperglycaemia and to be of particular use in the treatment of Type Π diabètes. 2 010470 10 10 15 15 20 20 25 25 30 30 35 35

These compounds are aiso indicated to be of potential use for the treatmentand/or prophylaxis of other diseases including hyperlipidaemia and hypenension.They are also indicated to be of use in the treatment and/or prophylaxis ofcardiovascular disease, especially atherosclerosis. In addition these compounds areconsidered to be useful for treating certain eating disorders, in particular therégulation of appetite and food intake in subjects suffering from disorders associatedwith under-eating, such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia.

These compounds are also indicated to be of of potential use in the treatmentand/or prophylaxis of rénal disease, especially rénal disease associated with thedevelopment of Type Π diabètes including diabetic nephropathy, glomerulonephritis,glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stagerénal disease. The prophylactic action of an insulin sensitiser upon nephropathy isalso indicative that an insulin sensitising agent can be expected to prevent, reverse,stabilise or retard the progression of microalbuminuria to albuminuria. This isbecause microalbuminuria is considered to be a predictor of future nephropathy,especially in patients with ciinical evidence of pre-diabetic insulin résistancesyndrome, altematively referred to as Syndrome X.

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

or a pharmaceutically acceptable sait thereof, and/or a pharmaceutically acceptablesolvaté thereof, wherein R° represents 2-benzoxazolyl or 2-pyridyl and Rl representsCH2OCH3 or CF3.

Preferably, R° represents 2-benzoxazolyl.

Suitably, R^ represents CH2OCH3.

Preferably, R^ represents CF3

As indicated above, a compound of formula (I), and the pharmaceuticallyacceptable salts thereof, may exist in one of several tautomeric forms, ail of which areencompassed by the présent invention as individual tautomeric forms or as mixturesthereof.

Suitable pharmaceutically acceptable salts include salts of carboxy groups andacid addition salts.

Suitable pharmaceutically acceptable salts of carboxy groups include métalsalts, such as for example aluminium, alkali métal salts such as lithium, sodium orpotassium, alkaline earth métal salts such as calcium or magnésium and ammonium WO 96/0- - 3 - 010470 or substituted ammonium salts, for example those with lower alkylamines such astriethylamine, hydroxy alkylamines such as 2-hydroxyethylamine,bis-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine, cycloalkvlamines such asbicyclohexylamine, or with procaine, dibenzylpiperidine, 5 N-benzyl-P-phenethylamine, dehvdroabietylamine, N,N'-bisdehydroabietylamine,glucamine, N-methylglucamine or bases of the pyridine type such as pyridine,collidine, quinine or quinoline.

Suitable acid addition salts include pharmaceutically acceptable inorganic saltssuch as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and, 10 where feasible, pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methanesulphonate,α-keto glutarate and oc-glycerophosphate.

Suitable pharmaceutically acceptable solvatés include hydrates.

The salts and/or solvatés of the compounds of formula (I) may be prepared 15 and isolated according to conventional procedures, for example sodium salts may beprepared by using sodium methoxide in methanol.

In a further aspect the présent invention also provides a process for thepréparation of a compound of formula (I), or a pharmaceutically acceptable saitthereof, and/or a pharmaceutically acceptable hydrate thereof, which process 20 comprises hydrolysing a compound of formula (U):

wherein R° and R1 are as defined in relation to formula (I) and L1 represents a25 hydrolysable group; and thereafter, if required, preparing a pharmaceutically acceptable sait of the compound of formula (I) and/or a pharmaceutically acceptablesolvaté thereof. A suitable hydrolysable group is a group of formula (a) or an epimer thereof: 30

A suitable hydrolysable group iJ is an Evans chiral auxillary, for example agroup of formula (b) or an epimer thereof: - 4 - 010470 wc

A suitable hydrolysable group iJ is a Cj.£ alkoxy group. 5 The hydrolysis of the compound of formula (II) is cairied out using conditions appropriate for hydrolysing the particular group M chosen, for example when L1 is agroup of formula (a) or a Cj_6 alkoxy group, the hydrolysis is suitably carried outunder acidic conditions, for example using dilute sulphuric acid, conveniently in awater/dioxan mixture, for example a 1:1 mixture, at any température which provides 10 a suitable rate of formation of the required product, generally at an elevated température, such as in the range of from 50°C to 120°C, for example 90°C; or whenLl is a group of formula (b) the hydrolysis is generally carried out using lithiumhydroperoxide in an aqueous solvent, such as aqueous tetrahydrofuran, at anytempérature which provides a suitable rate of formation of the required product, 15 generally at a reduced température, such as in the range of from -10°C to 0°C, forexample 0°C. Altematively, when iJ is a group of formula (b) the hydrolysis maybe effected under basic conditions, using for example aqueous sodium hydroxide, inan appropriate solvent such as aqueous tetrahydrofuran usually at ambienttempérature. 20 A compound of formula (II), wherein is a moiety of the above defined formula (a) or (b), may be prepared from a compound of formula (III) : ÇH3 R-N\ JÎ J OCH.R1 0 (III) 25 wherein R° and R1 are as defined in relation to formula (I) and represents a leaving group; (i) for compounds of formula (II) wherein iJ is a moiety of the abovedefined formula (a), by reaction with (S)-phenylglycinol; or (ii) for compounds of formula (II) wherein L1 is a moiety of the above definedformula (b), by reaction with (5)-4-benzyloxazolidin-2-one, preferably an activated 30 form thereof; and thereafter separating the required isomer from the mixture ofdiastereoisomers produced. A suitable leaving group L“ is a halogen atom, for example a chlorine atom. - 5 - W-ù -6Λ- / UÎÜ470

The réaction between the compounds of formula (III) and (S)-phenylglycinolmay be carried out under conventional amidation conditions, for example in an inertsolvent such as dichloromethane at a température which provides a suitable rate offormation of the required product, suitably at ambient température and preferably in 5 the presence of a base such as triethylamine. A suitable activated form of (5)-4-benzyloxazolidin-2-one is a salted form, forexample an alkali métal salted form, preferably a lithium sait.

The activated form of (S)-4-benzyloxazolidin-2-one may be prepared by anyappropiate conventional method. Thus when the activated form is a lithium sait, it 10 may be prepared by treating (S)-4-benzyloxazolidin-2-one with a source of lithiumions in the presence of a base, suitably provided by n-butyllithium, in an aproticsolvent such as tetrahvdrofuran, usually at a low température, for example in therange of from -78° to 0°C.

The reaction between the compound of formula (III) and the activated form of 15 (J)-4-benzyloxazolidin-2-one may be carried out in an aprotic solvent, such as tetrahydrofuran, at a température which provides a suitable rate of formation of therequired product, conveniently by allowing the reaction mixture to slowly warm from-78° to 0°C.

Preferably, the activated form of (S)-4-benxyloxazolidin-2-one is prepared 20 and then reacted in-sùu with the compound of formula (III). A compound of formula (ΙΠ) may be prepared by hydrolysing the carboxylic ester COOR2 of a compound of formula (IV):

25 wherein R° and R1 are as defined in relation to formula (I) and R2 represents an alkylgroup, and thereafter converting the carboxylic acid group so formed into a moietyCO.L2. A suitable alkyl group R2 is a alkyl group, especially a methyl group. 30 The hydrolysis of the carboxylic ester may be effected by use of any conventional hydrolysing agent, such as an alkaline métal hydroxide, for examplesodium hydroxide.

The hydrolysis of the compound of formula (IV) may be carried out in anysuitable solvent such as a methanol/water mixture, conveniently a 1:1 mixture, at a 35 température which provides a suitable rate of formation of the required product, suitably at an elevated température and conveniently at the reflux température of thesolvent.

V/O 10 15 20

~ 6 " •'io-iZO

The conversion of the carboxylic acid group into the moiety CO.L^ may becarried oui using any appropiate conventional procedure, depending upon theparricular nature of the group chosen, thus when L“ is a halogen a suitableprocedure involves treatment of the carboxylic acid with an oxalyl halide, forexample oxalyl chloride when is chlorine.

The reaction conditions for the conversion of the carboxylic acid group intothe moiety CO.L^ will be dictated by the particular nature of L- and the source of L-chosen, for example when is halogen and the source of is oxalyl chloride thenthe reaction may be carried out in an inert solvent such as dichloromethane orbenzene at a température which provides a suitable rate of formation of the requiredproduct, suitably at ambient température or at an elevated température such as thereflux température of the solvent.

It will be appreciated that the préparation and séparation of a compound offormula (II) wherein iJ is an epimer of the above defined moiety (a) or (b) and itssubséquent hydrolysis to afford a compound of formula (I) can be achieved byemploying analogous methods to those described above for the préparation,séparation and hydrolysis of a compound of formula (II) wherein lU represents theabove defined moiety (a) or (b). A compound of formula (II) wherein is a moiety of formula (b) may alsobe prepared by dehydroxylation of a compound of formula (V):

25 30 (V) wherein R° and R1 are as defined in relation to formula (I) and X is a moiety of theabove defined formula (b).

The dehydroxylation of the compound of formula (V) is conveniently carriedout by treatment with a trialkylsilane, for example triethylsilane, preferably in thepresence of trifluoroacetic acid and conveniently using trifluoroacetic acid as solvent,at any température providing a suitable rate of formulation of the product, forexample at a température in ±e range from 0°C to room température.

It will be appreciated that a compound of formula (Π) wherein iJ is a moietyof formula (b) would also be obtained by dehydroxylation of a compound of formula(V) in which the hydroxy bearing stereocentre is epimerised. A compound of formula (V) may be prepared by reacting a compound offormula (VIA): 35 WO 96/0 ί"6" - 7 -

çh3 010470 R-N. (VIA) wherein R° is as defined in relation to formula (I), with a compound of formula5 (VIB):

(VIB) wherein RJ is as defined in relation to formula (I); and thereafter separating the 10 required isomer from the mixture of diastereoisomers produced.

Suitably in the above mentioned reaction, the compound of formula (VIB) is in an activated form, which is preferably provided by treating the compound offormula (VIB) with an alkylboron triflate, for example dibutylboron triflate,preferably in the presence of an amine base such as triethylamine. 15 The activated form of the compound of formula (VIB) may be prepared by the appropriate conventional method depending upon the spécifie nature of the activatedform chosen, for example the compound of formula (VIB) is reacted withdibutylboron triflate and triethylamine in an inert solvent such as dichloromethane ata température in the range of from -78° to 0°C. 20 The reaction between the compounds of formulae (VIA) and (VIB) may be carried oui in an in an inert solvent such as dichloromethane, at a température whichprovides a suitable rate of formation of the required product, conveniently byallowing the reaction mixture to slowly warm from -78° to 0°C.

Preferably, the activated form of the compound of formula (VIB) is prepared 25 and then reacted in-situ with the compound of formula (VIA).

For compounds of formula (I) wherein R° represents 2-benzoxazolyl, a suitable compound of formula (VIA) is 4-[2-[N-(2-benzoxazolyl)-N-methylaminojethoxyjbenzaldehyde. A suitable means for separating any required single isomer from a mixture of 30 diastereoisomers is chromatography, such as préparative high pressure liquidchromatography or silica gel column chromatography. - 8 - V? .: · ' .,0 ΰί0470

One convenient method for preparing a compound of formula (II) wherein iJis a Ομ6 alkoxy group is the basic alcoholysis of a compound of formula (II) whereiniJ is a moiety of formula (b). A suirable base is an alkali métal alkoxide, for example when iJ is methoxy5 the compound of formula (II) wherein iJ is moiety (b) is treated with sodium methoxide in methanol. A compound of formula (I) may also be prepared by resolving a racemiccompound of formula (VII): 10 15 20 25 30

2H l1 (VII) wherein R° and R1 are as defined in relation to formula (I); and thereafter, ifrequired, preparing a pharmaceutically acceptable sait of the compound of formula (I)and/or a pharmaceutically acceptable solvaté thereof.

The resolution of a compound of formula (VU) may be carried oui usingknown resolution procedures, for example by reacting the compound of formula (VU)with a resolving agent, such as an optically active acid or base, to provide a mixtureof diastereoisomeric salts which may then be separated by fractional crystallisationand thereafter the compound of formula (I) may be regenerated from the separateddiastereoisomer sait by conventional means, such as hydrolysis.

It will be appreciated that the compounds of formula (VII) comprise thecompounds of formula (I) admixed with other optical isomers. A compound offormula (VII) or a pharmaceutically acceptable sait thereof and/or a pharmaceuticallyacceptable solvaté thereof, forms a further aspect of the présent invention. Theseparated isomers of the compounds of formula (VII), in addition to the compoundsof formula (I), or a pharmaceutically acceptable sait thereof and/or a pharmaceuticallyacceptable solvaté thereof, also comprise the présent invention.

Suitable acids or bases for resolving the compounds of formula (VII) are asdescribed in Enandomers, Racemates and Resolurion, J Jaques et al. 1981, WileyInterscience, especially at pages 255 and 256. Suitable methods for effecdng theresolution are also disclosed by Jaques et al.

The compounds of formula (II) and (III) form a further aspect of the présentinvention.

The compounds of formula (IV) and (VIA), for example 4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]benzaldehvde, are known compounds or theymay be prepared using methods analogous to those used to préparé knowncompounds, for example those disclosed in International Patent Application,Publication Number W094/01420.

35 - 9 “ WÛ : *0 ÜÏ0470

The compounds of formula (VIB) are known compounds or they may beprepared using methods analogous to those used io préparé known compounds, forexample those disclosed in Organic Synthesis Vol, 68, p83, 1990 Ed. J.D. White ormethods analogous thereto, in combination with conventional methodology for the 5 préparation of acid chlorides.

It will be appreciated that in any of the abovementioned reactions any reactivegroup in the substrate molécule may be protected, according to conventional Chemicalpractice. Suitable protecting groups in any of the abovementioned reactions are thoseused conventionally in the an. The methods of formation and removal of such 10 protecting groups are those conventional methods appropriate to the molécule beingprotected.

It will be appreciated that the above mentioned préparation of the compoundsof formula (I), or a pharmaceutically acceptable sait thereof and/or a pharmaceuticallyacceptable solvaté thereof, is a stereoselective procedure and that the compound of 15 formula (I) is a single stereoisomer. The présent invention also includes a compoundof formula (I) when présent in admixture with less than 50% w/w of its racemicisomer, that is when it is greater than 50% optically pure, suitably 80-100% andpreferably 90-100% pure, such as 90-95%, most preferably 95-100%, for example95%, 96%, 97%, 98%, 99% or 99.9% optically pure. 20 In one preferred aspect there is provided a compound of formula (I) or a pharmaceutically acceptable sait thereof and/or a pharmaceutically acceptable solvatéthereof, in optically pure form.

The absolute stereochemistry of compounds may be determined usingconventional methods, such as X-ray crystallography. 25 As mentioned above the compounds of the invention are indicated as having useful therapeutic properties: The présent invention accordingly provides a compoundof formula (I), or a pharmaceutically acceptable sait thereof and/or a pharmaceuticallyacceptable solvaté thereof, for use as an active therapeutic substance.

Thus the présent invention provides a compound of formula (I), or a 30 pharmaceutically acceptable sait thereof and/or a pharmaceutically acceptable solvatéthereof, for use in the treatment of and/or prophylaxis of hyperglycaemia.

In a further aspect the présent invention also provides a compound of formula(I), or a pharmaceutically acceptable sait thereof and/or a pharmaceutically acceptablesolvaté thereof, for use in the treatment and/or prophylaxis of hyperlipidaemia. 35 As indicated hereinbefore the présent invention also provides a compound of formula (I) or a pharmaceutically acceptable sait thereof and/or a pharmaceuticallyacceptable solvaté thereof for use in the treatment of hypertension, cardiovasculardisease, certain eating disorders and/or the treatment and/or prophylaxis of rénaldisease. - -10 ύ10470

In addition, the présent invention also provides a compound of formula (I) ora pharmaceutically acceptable sait thereof and/or a pharmaceutically acceptablesolvaté thereof, for use in the prévention, reversai, stabilisation or retardation of theprogression of microalbuminuria to albuminuria. 5 Cardiovascular disease includes in particular atherosclerosis.

Certain eating disorders include in particular the régulation of appetite andfood intake in subjects suffering from disorders associated with under-eating ,such asanorexia nervosa, and disorders associated with over-eating, such as obesity andanorexia bulimia. 10 Rénal disease includes rénal disease associated with the development of Type H diabètes including diabetic nephropathy, glomerulonephritis, glomerular sclerosis,nephrotic syndrome, hypertensive nephrosclerosis and end stage rénal disease. A compound of formula (I), or a pharmaceutically acceptable sait thereofand/or a pharmaceutically acceptable solvaté thereof, may be administered per $e or, 15 preferably, as a pharmaceutical composition also comprising a pharmaceuticallyacceptable carrier.

Accordingly, the présent invention also provides a pharmaceuticalcomposition comprising a compound of the general formula (I), or a pharmaceuticallyacceptable sait thereof, or a pharmaceutically acceptable solvaté thereof, and a 20 pharmaceutically acceptable carrier therefor.

As used herein the term 'pharmaceutically acceptable’ embraces compounds,compositions and ingrédients for both human and veterinary use: for example theterm 'pharmaceutically acceptable sait' embraces a veterinarily acceptable sait.

The composition may, if desired, be in the form of a pack accompanied by25 written or printed instructions for use.

Usually the pharmaceutical compositions of the présent invention will beadapted for oral administration, although compositions for administration by otherroutes, such as by injection and percutaneous absorption are also envisaged.

Particularly suitable compositions for oral administration are unit dosage30 forms such as tablets and capsules. Other ftxed unit dosage forms, such as powders presented in sachets, may also be used.

In accordance with conventional pharmaceutical practice the carrier maycomprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourantor other conventional adjuvant. 35 Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinvlpyrrolidone, polyvinylpolypyrrolidbne,magnésium stéarate or sodium lauryl sulphate. ν·\ % - 11 010470

Most suitably the composition will be formulated in unir dose form. Such unitdose will normally contain an amount of the active ingrédient in the range of from 0.1to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg.

The présent invention further provides a method for the treatment and/or5 prophylaxis of hyperglycaemia in a human or non-human mammal which comprises administering an effective, non-toxic, amount of a compound of the general formula(I), or a pharmaceutically acceptable sait thereof and/or a pharmaceutically acceptablesolvaté thereof to a hyperglycaemic human or non-human mammal in need thereof.

The présent invention further provides a method for the treatment of10 hyperlipidaemia, hypertension, cardiovascular disease, certain eating disorders, the treatment and/or prophylaxis of rénal disease and/or the prévention, reversai,stabilisation or retardation of the progression of microalbuminuria to albuminuria in ahuman or non-human mammal, which comprises administering an effective,non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable 15 sait thereof and/or a pharmaceutically acceptable solvaté thereof, to a human ornon-human mammal in need thereof.

Conveniently, the active ingrédient may be administered as a pharmaceuticalcomposition hereinbefore defined, and this forms a particular aspect of the présentinvention. 20 In the treatment and/or prophylaxis of hyperglycaemic humans, and/or the treatment and/or prophylaxis of hyperlipidaemic human, the compound of the generalformula (T), or a pharmaceutically acceptable sait thereof and/or a pharmaceuticallyacceptable solvaté thereof, may be taken in doses, such as those described above, oneto six rimes a day in a manner such that the total daily dose for a 70 kg adult will 25 generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500mg.

In the treatment and/or prophylaxis of hyperglycaemic non-human mammals,especially dogs, the active ingrédient may be adminstered by mouth, usually once ortwice a day and in an amount in the range of from about 0.025 mg/kg to 25 mg/kg, 30 for example 0.1 mg/kg to 20 mg/kg. Similar dosage regimens are suitable for thetreatment and/or prophylaxis of hyperlipidaemia in non-human mammals.

The dosages regimens for the treatment of hypertension, cardiovasculardisease and eating disorders hypertension, cardiovascular disease, certain eatingdisorders, the treatment and/or prophylaxis of rénal disease and/or the prévention, 35 reversai, stabilisation or retardation of the progression of microalbuminuria to albuminuria will generally be those mentioned above in relation to hyperglycaemia.

In a further aspect the présent invention provides the use of a compound offotmula (I), or a pharmaceutically acceptable sait thereof and/or a pharmaceutically ·~ Π 2 ·*

C ‘ . C· 0 jO 010470 acceptable solvaté thereof. for the manufacture of a médicament for the treatmentand/or prophylaxis of hvperglycaemia.

The présent invention also provides the use of a compound of formula (I), or apharmaceutically acceptable sait thereof, and/or a pharmaceuticallv acceptable solvaté 5 thereof, for the manufacture of a médicament for the treatment and/or prophylaxis ofhyperlipidaemia, hypertension, cardiovascular disease or certain eating disordersand/or the prophylaxis of rénal disease and/or in the prévention, reversai, stabilisationor retardation of the progression of microalbuminuria to albuminuria.

No toxicological effects hâve been established for a compound of formula (I) 10 or a pharmaceutically acceptable sait thereof and/or a pharmaceutically acceptable solvaté thereof, in the abovementioned dosage ranges.

The following Procedures and Examples illustrate the invention but do not limir it in any way. 15 - ·.% _ , , >»10470

Example 1 (5)-3-[4-[2-[N-(2-BenzoxazolyI)-N-methyiamino]ethoxy]phenyl]-2-(2-methoxy-ethoxy)propanoic acid

OCH3 A solution of [2S, N(lS)]-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]-phenyl]-2-(2-methoxyethoxy)-N-(2-hydroxy-l-phenylethyl)propanamide (1.846 g) ina mixture of IM sulphuric acid (45 mL) and dioxan/water (1:1, 150 mL) was heated 10 at 90°C for 56 hours and then the pH of the mixture was adjusted to pH 3 by additionof aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetateand the organic extracts washed with water, brine, dried (MgSO4) and evaporared togive an oil. Purification by chromatography on silica gel using a gradient of 1-5%methanol in dichloromethane as eluent gave a foam of 88% e.e. (by HPLC). The 15 product was reacted with (5)-a-methylbenzylamine in acetone, and the resulting saitrecrystallised several times from ethyl acetate-hexane before being dissolved in water,acidified with dilute hydrochloric acid and extracted with ethyl acetate which wasdried with MgSC>4. Evaporation of the ethyl acetate solution afforded enantiomerically enriched title compound; [(¾25 -28° (c=0.625, CHCI3); e.e 94% 20 (byHPLC); [Found M+414.1791. C22H26N2O6 requires M+ 414.1791]; ^NMRspectrum idendcal with that described in Example 5.

Example 2 (S)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2J.2-25 trifluoroethoxy)propanoic acid by hydrolysis of amide

N θ'

co2h och2cf3 [2S, N(lS)]-3-[4-[2-[N-(2-Benzoxazolvl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-30 trifluoroethoxy)-N-(2-hydroxy-l-phenylethyl)propanamide (from Procedure 3) washydrolysed by an analogous procedure to that described in Example 1. Purification by chromatography on silica gel using a gradient of 0-5% methanol indichloromethane as eluent gave the title compound, mp 116-7°C, after triturationwith diethyl ether-hexane; [a]^25 -24.6° (c=0.24, CHCI3); e.e. 95% (by HPLC). 35 [Found C, 57.9; H, 4.7: N, 6.8%: M+ 438.1403. C21H21F3N2O5 requires C, 57.5; H, 4.8; N, 6.4%; M+ 438.1403]; δΗ (DMS0-d6) 2.96 (2H,m), 3.22 (3H,s), 3.88 (2H.m), 3.95-4.18 (2H,m), 4.27 (3H,m), 6.8-7.37 (8H,m) and 12.9 (lH,br s, exchanges with D20). - 14 - 5 Example 3 (5)-3-[4-[2-[N-(2-Benzoxazolyl)-.\'-Tnethylamino]ethoxy]phenyi-2-(2,2,2-trifluoroethoxy)propanoic Acid, by Direct Hydrolysis of the Imide ÇH, o-V HOCVF> 10 Aqueous sodium hydroxide solution (2.5M, 65 mL, 0.163 mol, 2.3 eq) was added to asürred solution of [3(25), 45]-3-[3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino] ethoxy ] pheny 1] -2- (2,2,2-trifluoroethoxy)propanoyl] -4-benzyloxazolidin-2-one (from Procedure 10)(42.5 g, 0.071 mol) in THF (500 mL)and water (125 mL). The mixture was stirred for 20 minutes, the reaction was diluted 15 with water (1 L) and extracted with dichloromethane (3 x 700 mL). Thesedichloromethane solutions were evaporated and the residue purifïed bychromatography on silica gel using 5% methanol in dichloromethane as eluent toafford (5)-4-benzyloxazolidin-2-one. The original aqueous solution was acidifîed topH 3.5 with dilute hydrochloric acid and re-extracted with dichloromethane (3 x 700 20 mL). The dichloromethane solutions from the acid extraction were dried (MgSC>4)and evaporated to give a solid. This was recrystallised from dichloromethane-diethylether to afford the title compound, mp 119.5-120.55C. [α]ρ25 = -31° (c = 2.50,CHC13); e.e. 99.6% (by HPLC); [Found C, 57.7; H, 4.7; N, 6.25%; M+ (El) 438.1412. C2iH21F3N2O5 requires C, 57.5; H, 4.8; N, 6.4%; M+ 438.1403]; Ôh 25 (CDCI3) 3.05 (1H, dd), 3.13 (1H, dd), 3.31 (3H, s), 3.72 (1H, m), 3.89 (2H, m), 4.04-4.14 (3H, m), 4.21 (1H, dd), 6.78 (2H, d), 7.03-7.40 (6H, m) and 11.20 (1H, br,exchanges with D2O); δρ (DMSO-dg) = -72.7 (3F, t, 9.3 Hz, CF3).

Example 4 30 (5)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl-2-(2r2,2-tri-fluoroethoxy)propanoic Acid by Hydrolysis of Methyl Ester

H OCH2CF3 A mixture of (5)-methyl 3-[4-[2-[N-(2-benzoxazolyl)-N- 35 methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoate (1.256 g, 2.8 x 10'3 V'G Ον - -15 - mol), aqueous hydrochloric acid (2.0M, 50 mL) and dioxan (50 mL) was heated atreflux for 7 hours, cooled and concentrated in vacuo. The residue was suspended inbrine (200 mL) and extracted with ethyl acetate (3 x 300 mL). The combined ethylacetate solutions were dried (MgSC^) and evaporated to afford a waxy solid. This 5 solid was triturated with hexane, filtered and dried under vacuum at 65°C to affordthe desired product, mp 113-5°C. (a]cr5 = -32° (c = 1.02, CHC13); e.e. 99.4% (byHPLC); [Found C, 57.25; H, 4.8; N, 6.3%. C21H21F3N2O5 requires C, 57.5; H, 4.8;N, 6.4%]. The JH NMR spectrum of this material was identical to that produced inExample 3. 10

Exampie 5 (S)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyI-2-(2-methoxyethoxy)propanoic Acid •J ch, λ V- N. s) H OCH-CH.OMe

J O 15 (S)-Methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)propanoate was hydrolysed in a manner analogous to that describedfor Example 4. The crude reaction mixture was chromatographed on silica gel using5% methanol in dichloromethane as eluent to afford the title compound, a gum. 20 [afo25 = -27° (c = 0.73, CHC13); e.e. 99.8% (by HPLC); [Found M+ (El) 414.1779.C22h26n2°6 requires 414.1791]; (CDC13) 2.90 (1H, dd), 3.15 (1H, dd), 3.33 (3H, s), 3.37 (3H, s), 3.40-3.70 (4H, m), 3.93 (2H, t), 4.05 (1H, dd), 4.21 (2H, t),6.81 (2H, d) and 6.95-7.40 (6H,m).

25 - 16 -

Procedure 1 (±)-3-[4-[2-[N-(2-Ben2oxazoIyI)-N-methylamino]ethoxy]phenyI]-2-(2-5 methoxyethoxy]propanoic acid

A mixture of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-

10 (2-methoxyethoxy)propanoate (1.08 g, Int. Patent Appl., Publication No. WO 9401420) and sodium hydroxide (253 mg) in methanokwater (1:1, 10 mL) was heatedunder reflux for 2 hours. After évaporation of the résultant mixture in vacuo, theresidue was diluted with water, acidified to pH 5 with 2M hydrochloric acid and thenextracted with ethyl acetate. Washing of the ethyl acetate extracts with water and 15 drying (MgSÛ4) évaporation gave the title compound as an oil which crystallisedon trituration with diethyl ether/hexane. [Found C, 63.8; H, 6.5; N, 7.0%; M+414.1791. C22H26N2O6 requires C, 63.8; H, 6.3; N, 6.8%; M+ 414.1791); Ôh(CDC13) 2.91 (lH,dd), 3.15 (lH,dd), 3.34 (3H,s), 3.38 (3H,s), 3.41-3.69 (4H,m), 3.93(2H,t), 4.05 (lH,dd), 4.21 (2H,t), 6.80 (2H,d) and 6.83-7.38 (6H m). 20

Procedure 2 (±)-3-[4-[2-[N-(2-BenzoxazoIyI)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)propanoyl chloride 25

Oxalyl chloride (92 mg) was added to (±)-3-[4-[2-[N-(2-benzoxazolyl)-N-methyl-amino]ethoxy]phenyl]-2-(2-methoxvethoxy)propanoic acid (100 mg) in -dichloromethane (2 mL). The mixture was stiired at room température for 16 hours 30 and evaporated to dryness to give the title compound as a gum which was usedwithout further purification. - Y? - d , -, 010470

Procedure 3 [25, N(15)]-3-[4-[2-[N-(2-Benzoxazoiyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)-N-(2-hydroxy-l-phenylethyI)propanamide

(±)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxy-ethoxy)propanoyl chloride was dissolved in dichloromethane (2 mL) and a mixture of(5)-2-phenylglycinol (33 mg) and dry triethylamine (37 mg) in dichloromethane 10 (1 mL) added. After stirring for 5 minutes water was added and the mixture extracted with dichloromethane. The organic extracts were washed with water, brine, dried(MgSO4) and evaporated. The residue was chromatographed on silica gel using agradient of 10-50% acetone in hexane as eluent to afford firstly [2/?, N(15)]-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)-N-(2- 15 hydroxy-l-phenylethyl)propanamide followed by the desired [25, N(15)]- propanaraide title compound as a foam. [α]θ25 -33° (c=l. 1, CHCI3); 92.6% d.e. (byHPLC); [Found M+ 533.2526. C30H35N3O5 requires M+ 533.2526]; (CDC13) 2.81 (lH,dd), 3.07 (lH,dd), 3.35 (3H,s), 3.36 (3H,s), 3.48-3.58 (2H,m), 3.52-3.62(2H,m), 3.71 (lH,dd), 3.82 (lH,dd), 3.94 (lH,dd), 3.93 (2H,t), 4.22 (3H,t), 5.05 20 (lH,dt), 6.75-7.35 (13H,complex), 7.54 (lH,br, exchanges with D2O).

Procedure 4 (±)-3-[4-[2-[N-(2-BenzoxazolyI)-N-methylamino]ethoxy]phenyl]-2-(2,2,2·trifluoroethoxy)propanoic acid 25

.CO?H r och2cf3

Methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoate (Int. Patent Appl., Publication No. WO 9401420) was 30 hydrolysed by an analogous procedure to thaï described in Procedure 1 to give thetitle compound as a solid, mp 116-117°C; [Found C, 57.4; H, 4.9; N, 6.4%.C21H21F3N2°5 requires C, 57.5; H, 4.8; N, 6.4%]; ÔH (CDC13) 3.03-3.17 (2H,m),3.29. (3H,s), 3.73-3.83 (lH,m), 3.85 (2H,m), 4.02 (2H,m), 4.04-4.30 (2H,m) and6.74-7.40 (8H m). - 18 -

Procedure 5 (±)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyI]-2-(2^,2- trifluoroethoxy)propanoyl chloride ίο 10 15 15 20 20 25 25 30 30 010470

COCI

Oxalyl chloride (1.1 mL) was added to a solution of (±)-3-[4-[2-[N-(2-benzoxazolyl)N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid (1.72 g) indry benzene (30 mL). The mixture was heated at reflux for 2 hours, cooled andevaporated to dryness to give the title compound as a gum which was used withoutfurther purification.

Procedure 6 [2S, N(lS)]-3-[4-[2-[N-(2-BenzoxazolyI)-N-methylamino]ethoxy]phenyl]-2-(2,2,2trifluoroethoxy)-N-(2-hydroxy-l-phenylethyI)propanamide (±)-3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoyl chloride was reacted with (5)-2-phenylglycinol by ananalogous procedure to that described in Procedure 3. Chromatography on silica gelusing a gradient of 10-70% ethyl acetate in hexane as eluent afforded firstly [2Æ,N(15)]-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)-N-(2-hydroxy-l-phenylethyl)propanamide followed by the desired[25, N(15)]-propanamide title compound as a foam; [a]D25 +14° (c=0.5, MeOH);99% d.e. (by HPLC); [Found M+557.2136. C29H3QF3N3O5 requires M+557.2138];Ôh (CDCI3) 2.35 (lH,br, exchanges with D2O), 2.91 (lH,dd), 3.13 (lH,dd), 3.36(3H,s), 3.70-3.87 (2H,m), 3.84 (2H,d), 3.95 (2H,t), 4.12 (lH,dd),4.22 (2H,t), 5.01(lH,m), 6.75 (2H,d), 6.97 (lH,br s, exchanges with D2O) and 7.01-7.36(llH,complex). - 19 -

Procedure 7 0 ί 0 4 7 0 (2,2,2-Trifluoroethoxy)ethanoyl Chloride

f/COCI och2cf3 5 A solution of oxalyl chloride (20 mL, 0.23 mol, 1.15 eq) in dry dichloromethane (50mL) was added dropwise at room température, with stirring, to a solution of (2,2,2-trifluoroethoxy)ethanoic acid (fnt, Paient Appl., Publication No. WO 87/07270, 31.6g, 0.2 mol) and N,N-dimethylformamide (5 drops) in dry dichloromethane (400 mL).The mixture was stirred for an additional hour, then heated under reflux for 2 hours, 10 cooled and the bulk of the solvent removed by distillation (bp 40-45°C/760 mm Hg).The residue was transferred to a Claisen distillation flask and the remaining solventand oxalyl chloride removed by distillation (bp 45-60°C/760 mm Hg). Vacuumdistillation of the residue then afforded the product, bp 50-55725-32 mm Hg.δπ (CDC13) 4.00 (2H, q, 8.3) and 4.57 (2H, s). 15

Procedure 8 (4S)-4-Benzyl-3-[2-(2,2,2-trifluoroethoxy)ethanoyl]oxazolidin-2-one

20 (4S)-4-Benzyloxazolidine-2-one (5.21 g, 0.029 mol) was dissolved in dry THF (60 mL) and cooled to -70°C under argon. zz-Butyllithium (18.4 mL, 1.6 M solutionin hexane, 1.1 eq) was added over 10 minutes and the resulting mixture stirred at -70°C for 20 minutes. A solution of (2,2,2-trifluoroethoxy)ethanoyl chloride (5.19 g, 1eq) in dry THF (60 mL) was added over 10 minutes, the mixture stirred at -70°C for a 25 further 30 minutes then allowed to warm to room température ovemight. The reaction was quenched by addition of brine (20 mL) and concentrated in vacuo. Theresidue was diluted with brine (300 mL) and extracted with ethyl acetate (3 x 300mL). The combined organic extracts were dried (MgSC^), evaporated and theresidue chromatographed on silica gel with dichloromethane as eluent to give the 30 product as an oil. [ct]D25 = +48° (c = 2.55, CHC13); e.e. 100% (by HPLC); [Found(CI, Ammonia) MH+ 318.0934. C14Hi4NO4F3 requires MH+ 318.0953]; δ^ (CP.C13) 2.82 (1H, dd), 3.34 (1H, dd), 4.02 (2H, q, A/^ 8.6), 4.30 (2H, m), 4.69 (1H,m), 4.84 (2H, s) and 7.15-7.40 (5H, m); δρ (CDC13) = -74.8 (3F, t, 8.6, CF3). - 20 - vc 0 1 0 4 7 0

Procedure 9 [3(2S, 37?), 4S]-3-[3-[4-[2-[N-(2-BenzoxazoIyl)-N-methylamino]ethoxy]phenvl]-3-hydroxy-2-(2,2,2-trifluoroethoxy)propanoyl]-4-benzyloxazolidin-2-one

(4S)-4-Benzyl-3-[2-(2,2,2-trifluoroethoxy)ethanoyl]oxazolidin-2-one (31.7 g, 0.1mol) was dissolved in dry dichloromethane (300 mL) under argon and cooled to -78°C (internai température of solution), using liquid nitrogen/acetone as the cooling 10 medium. Triethylamine (16.72 mL, 1.2 eq) was added, followed by the slowaddition, over approximately 10 minutes, of di-/z-butylboron triflate (AldrichChemical Company, 1.0M solution in dichloromethane, 110 mL, 1.1 eq) such that thereaction température was maintained below -70°C. The mixture was stirred at -78°Cfor 50 minutes, then the cooling bath was replaced with an ice bath and the mixture 15 stirred at 0°C for an additional 50 minutes before being recooled to -78°C. A solutionof 4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]benzaldehyde (29.6 g, 1.0 eq) indry dichloromethane (220 mL), precooled to -50°C, was added over ca. 12 minutes,such that the reaction température was maintained below -70°C. The resultingmixture was stirred at -78°C for 30 minutes, then warmed ffom -78°C to 0°C over 60 20 minutes along a linear gradient (warming rate - 1.3°C.min·1) and stirred at 0°C for afurther 75 minutes. The reaction mixture was poured into a quenching solution ofmethanol (500 mL), pH 7 phosphate buffer (250 mL) and hydrogen peroxide (27.5%w/v, 110 mL) and stirred vigourously for 30 minutes. Water (4 L) was added, thelayers were separated and the aqueous layer was extracted with dichloromethane 25 (3x1 L). The dichloromethane solutions were recombined with the original dichloromethane layer ffom the reaction mixture and this organic solution was thenwashed with water (2 L) and brine (2 L), dried (MgSOa) and evaporated to afford afoam. !Η NMR of this crude reaction mixture suggested a mixture of the desiredaldol product (3 diastereoisomers, comprising 95% major diastereoisomer) and 30 starting materials. The crude mixture was chromatographed on silica gel using agradient elution comprising 15% ethyl âcetate in dichloromethane initially (until thedesired product began to elute) and rising to 50% ethyl acetate in dichloromethane tocomplété the elution bf the desired product. Unreacted imide and aldéhyde wererecovered from the earlv fractions, followed by a quantity of impure product and then 35 the title compound (comprising 2 diastereoisomers, ratio 97.8:2.2 by NMR). [aj^25 - 21 010470 =+45° (c = 2.82, CHC13). [Found (El) M+ 613.2042. C31H30F3N3O7 requires M+613.2036]; (CDC13, onlv major diasiereoisomer is recorded) 2.75 (1H, dd), 2.90 (1H, d, exchanges with D2O), 3.25 (1H, dd), 3.34 (3H, s), 3.80-4.00 (5H, m), 4.07(1H, dd), 4.24 (2H, t), 4.45 (1H, m), 4.99 (1H, apparent t), 5.48 (1H, d), 6.85 (2H, d) 5 and 6.95-7.40 (11H, m); δρ (CDC13) = -74.7 (3F, t, 8.5, CF3). The minor diasiereoisomer in the purified product was identified as the [3(25, 35), 45]-diastereo-isomer.

Procedure 10 10 Préparation of [3(25), 45]-3-[3-[4-[2-[N-(2-Benzoxazolyl)-N- methyIamino]ethoxy]phenyI]-2-(2,2,2-trifluoroethoxy)propanoyl]-4-benzyloxazoiidin-2-one by Dehydroxylation

15 Triethylsilane (120 mL, 0.75 mol) was added over 5 minutes to a stirred, ice cooledsolution of [3(25, 37?), 45]-3-[3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-3-hydroxy-2-(2,2,2-trifluoroethoxy)propanoyl]-4-benzyloxazolidin-2-one (46.23 g, 7.5 x 10'2 mol) in trifluoroacetic acid (650 mL).The mixture was stirred at 0°C for 1 hour, then at room température for a further 60 20 hours. The bulk of the solvent and residual triethylsilane was removed by rotaryévaporation, firstly at 40 mm Hg and finally at -5 mm Hg. The residue wasdissolved in dichloromethane (800 mL) and water (800 mL), then stirred vigorouslyduring the cautious addition of solid sodium bicarbonate (-29 g) (frothing !) until thepH of the aqueous layer was pH 7. The layers were separated and the aqueous laver 25 was extracted with dichloromethane (800 mL). The combined dichloromethanelayers were washed with water (600 mL), dried (MgSO4) and evaporated. Theresidue was triturated with hot hexane and the resulting solid collected by filtration.Recrystallisation from diethyl ether-hexane afforded the title compound,mp 107-109°C, a single diastereoisomer by NMR spectroscopy. [a]p,25 = +38° 30 (c= 1.51, CHCI3); [Found C, 62.1; H, 4.9; N, 7.2%; M+ (El) 597.2089. c3lH30N3O6F3 requires C, 62.3; H, 5.1; N, 7.0%; M+ 597.2087]; δΗ (CDCI3) 2.82(1H, dd), 2.96 (1H, dd), 3.04 (1H, dd), 3.32 (1H. dd), 3.34 (3H, s), 3.70 (1H, m), 3.88 (1H, m), 3.94 (2H, t), 4.12 (1H, m), 4.18 (1H, m), 4.25 (2H, t), 4.57 (1H, m),5.34 (1H, dd), 6.82 (2H, d) and 7.00-7.35 (11H, m); δρ (CDCI3) = -74.8 (3F, t, 3/^ 35 8.6,. CF3). W'j ·, «· 22 ·" 011)470

Procedure 11

Préparation of [3(25), 45]-3-[3-[4-[2-[N-(2-Benzoxazolvl)-N-methylamino]-ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoyI]-4-benzyloxazoIidin-2-one byDiastereoisomer Séparation

(5)-4-Benzyloxazolidin-2-one (0.291 g, 1.64 x 10'3 mol) was dissolved in dry THF(10 mL) and the resulting solution cooled to -70°C under argon. n-Butyl lithium(1.6M in hexane, 1.03 mL, 1.64 x 10'3 mol) was added and the mixture was stirred at 10 -70°C for 10 minutes prior to the addition of a solution of (±)-3-[4-[2-[N-(2- benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoylchloride (prepared ffom 0.36 g of the acid by Procedure 5, above) in dry THF(15 mL). The reaction was stirred and allowed to warm to room températureovemight before being diluted with water (200 mL) and extracted with ethyl acetate 15 (2 x 200 mL). The combined ethyl acetate layers were washed with water (200 mL) and brine (200 mL), dried (MgSC>4) and evaporated to give a brown gum. This waschromatographed on silica gel using a gradient of 35% to 50% ethyl acetate in hexaneas eluent to afford firstly the (R, 5)-diastereoisomer, followed by the title compound,a foam. This material was spectroscopically identical with that prepared by the aldol 20 route (Procedure 10).

Procedure 12 (5)-MethyI 3-[4-[2-[N-(2-Benzoxazolyl)-N-methyiamino]ethoxy]phenyl]-2-(2T2,2-trifluoroethoxy)propanoate 25

.CO.Me

T och2cf3 A solution of sodium methoxide [prepared from sodium hydride (60% dispersion inminerai oil, 138 mg, 3.41 x 10’3 mol) dissolved in dry methanol (3.5 mL)] was addedto an ice cooled and stirred suspension of [3(25), 45]-3-[3-[4-[2-[N-(2- 30 benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoyl]’ 4-benzyloxazolidin-2-one (1.879 g, 3.1 x 10’3 moi) in dry methanol (100 mL). Themixture was stirred at 0°C for a total of 20 minutes, then the reaction was quenchedby the addition of dilute aqueous hydrochloric acid (2.0M, 1.75 mL) and concentratedin vacuo. The residue was suspended in water (100 mL), extracted with ethyl acetate - 23 - ü10470 (3 x 200 mL) and the combined ethvl acetate solutions washed with brine (500 mL),dried (MgSCL) and evaporated. The resulting gum was chromatographed on silicagel using 4% ethyl acetate in dichloromethane as eluent to afford the product as aclear gum. [a]D25 = -17° (c = 1.24, CHC13); [Found (El) M+ 452.1561. 5 C22H23N2°5F3 requires M+ 452.1559]; e.e. 100% (by HPLC); δΗ (CDC13) 3.02 (2H, m), 3.34 (3H, s), 3.65 (1H, m), 3.72 (3H, s), 3.94 (2H, t), 4.00 (1H, m), 4.13 (1H,dd), 4.24 (2H, t), 6.80 (2H, d) and 6.96-7.40 (6H, m).

Procedure 13 10 (45)-4-Benzyl-3-[2-(2-melhoxyethoxy)ethanoyI]oxazolidin-2-one

The title compound was prepared from 2-(2-methoxyethoxy)ethanoyl chloride by amethod analogous to that described in Procedure 8. Chromatography on silica gel 15 using a gradient of 70-80% diethyl ether in hexane as eluent afforded the product as agum. [ct]D25 = +54° (c = 2.70, CHC13); [Found (El) M+ 293.1263. C15H19NO5rcquires M+ 293.1264]; (CDC13) 2.81 (1H, dd), 3.33 (1H, dd), 3.41 (3H, s), 3.63 (2H, t), 3.78 (2H, t), 4.25 (2H, m), 4.70 (1H, m), 4.74 (1H, d), 4.76 (1H, d) and 7.10-7.40 (5H, m). 20

Procedure 14 [3(2S, 3R), 4S]-3-[3-[4-[2-[N-(2-BenzoxazolyI)-N-methylamino]eihoxy]phenyI]-3-hydroxy-2-(2-methoxyethoxy)propanoyi]-4-benzyloxazoIidin-2-one

25

The title compound was prepared from (45)-4-benzyl-3-[2-(2- methoxyethoxy)ethanoyl]oxazolidin-2-one by a method analogous to that described inProcedure 9. The crude reaction mixture was chromatographed on silica gel using agradient of 15-40% ethyl acetate in dichloromethane to afford the product as a gum(comprising 2 diastereoisomers, ratio >99:1 by NMR). [a] 925 = +49° (c = 1.14,CHC13). [Found (FAB, NOBA/Na) MH+ 590.2472. C32H35N3O8 requîtes MH+ 30 wo % - 24 - ü ï 0 4 7 0 590.2502]; Ôpj (CDC13, onlv major diastereoisomer is recorded) 2.71 (1H. dd), 3.25(1H, dd), 3.31 (3H, s), 3.35 (3H, s), 3.56 (2H, m), 3.72 (2H, m), 3.78 (1H, d,exchanges with D2O), 3.85-4.00 (4H, m), 4.22 (2H, t), 4.31 (1H, m), 4.89 (1H, dd), 5.42 (1H, d), 6.83 (2H, d) and 6.95-7.40 (11H, m); The minor diastereoisomer in the 5 purified product was identified as the [3(25, 35), 45]-diastereoisomer.

Procedure 15 [3(25), 45]-3-[3-[4-[2-[N-(2-BenzoxazoIyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)propanoyI]-4-benzyloxazoIidin-2-one 10

[3(25, 37?), 45]-3-[3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-3-hydroxy-2-(2-methoxyethoxy)propanoyl]-4-benzyloxazolidin-2-one (0.561 g) wasreacted with triethylsilané for 6.25 hrs in a manner similar to that described for 15 Procedure 10. The reaction mixture was diluted with water (200 mL) and dichloromethane (200 mL) and solid sodium bicarbonate was added cautiously untilthe aqueous layer showed pH 6.5. The layers were separated, the aqueous layer wasextracted with dichloromethane (2 x 300 mL) and the combined dichloromethanesolutions were washed with brine (400 mL), dried (MgSO4) and evaporated. The 20 residue was chromatographed on silica gel using 35%'ethyl acetate in dichloromethane as eluent to afford the title compound, a gum, as a singlediastereoisomer by NMR. [α]^25 = +45° (c = 1.39, CHCI3); [Found M+ (El)573.2473. C32H35N3O7 requires M+ 573.2475]; Ôh (CDCI3) 2.76 (1H, dd), 2.94(2H, m), 3.30 (3H, s), 3.33 (4H, m), 3.40-3.70 (4H, m), 3.93 (2H, t), 4.00 "(ÎH, dd), 25 4.12 (1H, dd), 4.22 (2H, t), 4.52 (1H, m), 5.31 (1H. dd), 6.79 (2H, d) and 6.90-7.40 (11H, m).

Procedure 16 (S)-Methyl 3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyI]-2-(2- 30 methoxyethoxy)propanoate

OCH2CHjOMe CO2Me

WO 1J - 25 - 010470 [3(25), 45]-3-[3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxyethoxy)propanoyl]-4-benzvloxazolidin-2-one was reacted with sodiummethoxide in a manner analogous to that described in Procedure 12. The crudereaction mixture was chromatographed on silica gel using 20% isohexane in diethyl 5 ether as eluent to afford the title compound, a gum. [a]D25 = -12° (c = 1.26, CHCI3);[Found (El) M+ 428.1974. C23H28N2O6 requires M+428.1948]; e.e. >99.8% (byHPLC); Ôh (CDCI3) 2.95 (2H, m), 3.29 (3H, s), 3.34 (3H, s), 3.35 (3H, m), 3.69 (4H,m), 3.93 (2H, t), 4.05 (1H, dd), 4.23 (2H, t) and 6.75-7.40 (8H, m). 10 - 26 Y 7 \ .4

DEMONSTRATION OF EFFICACY OF COMPOUNDS 010470

Obese Mice, Oral Glucose Tolérance Test. 5 C57bll/6 obese (ob/ob) mice were fed on powdered oxoid diet. After at least oneweek, the mice conrinued on a powdered oxoid diet or were fed powered oxoid dietcontaining the test compound. After 8 days on the supplemented diet ail of the micewere fasted for 5 hours prior to receiving an oral load of glucose (3g/kg). Bloodsamples for glucose analysis were taken 0, 45, 90 and 135 minutes after glucose 10 administration and the results appear below as the percentage réduction in area underthe blood glucose curve where test compound treated groups are compared with thecontrol group. 8 mice were used for each treatment.

Table 15

Example

Level in diet(μπιοί. kg** of diet) % Réduction inarea under bloodglucose curve 1 0.3 24 2 0.3 24

Effects on packed red cell volume and heart weight:

These were determined after repeat oral administration of compound (once daily at a20 dose of 3 pmol/kg body wt for 14 days, by gavage) to female Sprague- Dawley rats for 14 days. Changes shown are percentage changes from control. Stadsticalcomparisons were made by Student t test for non-paired data; *p<0.05, ***p<0.001versus Controls. No effect no significant différence from control group. Results wereobtained from 8 rats per treatment group. 25

Compound

Heart weight Packed cell volume

Example (% increase) (% réduction)

No effectNo effect

Claims

- Z? - 'S Daims: ü i 0 4 7 0

or a pharmaceutically acceptable sait thereof, and/or a pharmaceutically acceptablesolvaté thereof, wherein R° represents 2-benzoxazolyl or 2-pyridyl and R^ representsCH2OCH3 or CF3. 10
2. A compound according to claim 1, wherein R° represents 2-benzoxazolyl.
3. A compound according to claim 1 or claim 2, wherein R^ represents CF3. 15 4. A compound according to claim 1 being: (5)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxy-ethoxy)propanoic acid;or 20 (S)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyI]-2-(2,2,2- trifluoroethoxy)propanoic acid; or a pharmaceutically acceptable sait thereof, and/ora pharmaceutically acceptable solvaté ±ereof.
5. A compound according to any one of daims 1 to 4, when présent in admixture25 with less than 50% w/w of its racemic isomer.
6. A compound according to any one of daims 1 to 5, when 90-100% opticallypure. 30 7. A compound according to any one of daims 1 to 6, in optically pure form.
8. A process for the préparation of a compound of formula (I), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutically acceptablehydrate thereof, which process comprises; (a) ·- hydrolysing a compound of formula (II): 35 28 (II) UI Ο4 70 ο R-N Cl

O wherein R° and R1 are as defined in relation to formula (I) and L1 represents ahydrolysable group; or 5 (b) resolving a racemic compound of formula (VII): OCHjR’ (VII) wherein R° and R1 are as defined in relation to formula (I); and thereafter, ifrequired, preparing a pharmaceutically acceptable sait of the compound of formula (I) and/or a pharmaceutically acceptable solvaté thereof.
9. A pharmaceutical composition comprising a compound of formula (I)according to claim 1, or a pharmaceutically acceptable sait thereof, or apharmaceutically acceptable solvaté thereof, and a pharmaceutically acceptablecarrier therefor. 15 W. A compound of formula (I), or a pharmaceutically acceptable sait thereofand/or a pharmaceutically acceptable solvaté thereof, for use as an activetherapeutic substance.
11. A compound of formula (I), or a pharmaceutically acceptable sait thereofand/or a pharmaceutically acceptable solvaté thereof, for use in the treatment of 20 and/or prophylaxis of hyperglycaemia, hyperlipidaemia, hypertension, cardiovasculardisease, certain eating disorders, the treatment and/or prophylaxis of rénal diseaseand/or the prévention, reversai, stabilisation or retardation of the progression ofmicroalbuminuria to albuminuria. 29 010470
12. The use of a compound of formula (I), or a pharmaceutically acceptable saitthereof, and/or a pharmaceutically acceptable solvaté thereof, for the manufacture ofa médicament for the treatment and/or prophylaxis of hyperlipidaemia, hypertension,cardiovascular disease or certain eating disorders, the prophylaxis of rénal disease 5 and/or the prévention, reversai, stabilisation or retardation of the progression ofmicroalbuminuria to albuminuria.
13. An intermediate compound of formula (II) or (III).