AU1006199A - Benzoxazoles and pyridine derivatives useful in the treatment of the Type II diabetes - Google Patents

Description

-r

'I

W'

I

AUSTRALIA

PATIENTS ACT 1990 C .OMPLET&

SPECIFICATION

FOR A STANDARD

PATENT

(6RIGINAb) *2Name. of Applicant: SmithKline Beechamiplc Actual Inventors: HAIGH, David. AND RAMI, Harshad.

Address for Service: Invention Title: DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000 Benzoxazles and pyridine derivatives useful in the treatment of the Type It diabetes r.

The following statement is a fulfl description Of this invention, including the best method of performing it known to-us: ~1 RENZGXAZOLES M D PYRIDINE DERIVATIVES 'JSEFUL IN -THE TREATN4ENT, OF YHE TYPE II This application is a divisionuI applicatibn derived froim Australian Patent Application No.

3382Q 2 the entire contents of which are incorpowaed herein by reference.

This invention relates to certai novel compounds, to a process for preparing such rompounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.

International Patent Application. Publication Number WAD 94/01420 discloses comupounids of formula Ai '(CH 2 )n'-O-A 2

'-A

3

-_Y.R

2

(A)

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

A

1 represents a substituted or unsubstituted. arormatic heterocyclyl group;

A

2 represents a benzene ring having three optional substituents; 15 A 3 T represents a moiety of formula -(CH 2 )m-CH(QR' wherein R 1 represents substituted or unsubstirur.d alkyl, aryl, aralkyl or alkylcarbonyl and rm represents an integer in the range of rom 1 to 5. or A 3 represents a moiety of formula I CH--C(ORI')- wherein RI'and m' are as defined above; 11 represents OR 3 wherein reprcsents hydrogen, alkyl, aryl or aralkyl or RT represents an aromatic heterocyclyl group or -NR 4

'R

5 'wherein R 4 and R 5 each independently represent hydrogen. alkyl or alkylcarbonyl or R 4 and RS'together with the nitrogen atom to which they are attached form a heterocyclic ring, providing that

R

2 represents an aromatic: heterocyclyl group only when Y' as defined below represents a -bond; 23 Xrepresents NR' wherein R' represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group wherein the aryl moiety may be substituted or urisubstituted, or a substituted or unsubstituted aryl group; 2 Y, represents C-O or C=S or a t-ond providing that Y.Tepresents a bond only when R2represents the above mentioned aromatic heterocyclyl. group; and n' represents an integer in the range of from 2 to 6.

These compounds are stated to have ihier alia good blood-glucose lowering activity and are therefore of potential use in the u=euncnt and/or prophylaxs of hyperglycaemia and to be of particular use in the treatment of Type II diabetes.

It has now suxrprisingly been discovered that a particular group of compounds falling Within the generic scope of the compounds of formula have parxicusary *good blood-glucose lowering activity combined with freedomn froiti adverse haematlogical and cardiac effects Thes compounds art therefore, considered to hold potentWa to be of particular use in the treatmnent and/or prophylaxis of hyperglycaeiia and to be of piticular use in the u=eaneit of Type It diabetes.

T" cm'ad reas ict-,d- to be of potential use for- the rCeamw~nt and/or prophylaxis of orher dismaes-cluiiflg hyperlipidaemia and hypcrtcnszofl.

11hey are also indicated to be of use in Ihe tatment a .nd/or prt-phylaxs of curdovascuiar disr-ase, especiallyathersclero*iS. In addon thesc compounds art ccnsidered to be useful for treating certain eating disorders. in particular the regulation of appetite and fo~od initake in subjects ,,ffening from disorders associated with under-eating, such as anorexia nervosa, anui casorders associat-W with overeating such as obesity and arexia btilimia.

These compounds are also indicated to be of of potential use in the treatment and/or prophylaxis of renal disease, especally renal disease acssociated with the development of Type 11 diabetes including diabetic nephroparhly. glomerulonephritis, glomenilar sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal disease. Thr prophylactic action of an insulin sensitiser upon nephropathy is also inadicative that an insulin sensidsing agent can be expected tL7 Prevent, revems, stabibise or retard the progressorY of rnicraalburninuria to alburnuria. This is becawme inicroalbuminiaja is considered to be a predictor of future nephropathy, especially in patients with clinical' evidence of pre-diabetic insulin resistance syndrome, alreniatively refcn'ed to as Syndrome X.

Accordingly. the pc-nt invention provides a compound of formula

C,

R I

OCH

2

R'

or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof. wherein RO represents 2-benzoxazlyl or 2-pyridyl and R 1 rpresents CH7OCH3 or CF 3 Preferably. RO represents 2-benzoxazolyl.

Suitably. RI represents CH 2

OCH

3 Preferably, R I represents CF 3 As indicated above, a compound of formula and the pharmaceutically soceptable salts thereof, may exist in one of several mtauoteric formi, all of which are encoumssed by the present invention as individual tautomeric forms or as mixtures throf.

Suitible pharTnacutically acceptable'salts include salts of carboxy groups and acdd addition salts.

3$ Suitable pharmaceutically acceptable salts of carboxy groups includc metal salnts, such as for example aluminium, alklih metal salts such as lithium sodium (s potassium akaine earth metal salts such as calchiu or magnesium and ammon~ium or substituted ammoniLn satWfreape those wNith lowcr aikylarnines such as tr 'hyanec hvdroxy alky~amines such as 2-hydroxvtthylamine.

bis-(2-hydroxyethyl)amine or Eri-(2-hydroxyethyl)arttinc, cycloalkvLarnines such as bicyclohexylamine, or with procaine. dibenzylpipeiidine,__ N-benzyl--p heethylanine, dehydroabietylamine, N.N-bisdehydroabieEy=ar=in, glucamine. N-rnethylglucamine or bases of the pyridinc typv. such as pyrne,~ colhidunc, quirine or quinoine.

Suitable acid addition salts include pharmaceutically acceptable inurganic salts such as the sulphate, nitrate, phosphate. borate, hydrochloride and hydrabromide and, where feasible, pharmaceutically acceptable organic acid adidition salts such as actate, rtmte, majeare, itrate succinate, benzoate, ascorbate, methanesuiphonate, a-keto glurarae and Qi-glycerophosphate- Suitable pharmaceutically acceptable solvates include hydrates.

The salts and/or solvates of the compounds of formula 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 the present invention also provides a process for the -Preparation of a compound of formula or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable hydrate thereof, which process comprises hydrolysing a compound of formula (ULI): 0

-I

Nz LJJ~r

R

0 adR r sdfnd nrlto ofrua I n 'rpeet A4-i suiabl e sdro inedbin grlatisn ato ofomula (a raepet tiethereo

H-

A stutable hydrolysable group L 1 iV-,,-Evans chiral auxilary, for example a po~p of foirmula or an epiroer thereof: -3- 0 N 0 CHPhi (b) A suitable hydrolYsabie group Ll is a Cl..6 alkoxy group.

The hydrolysis of the compound of formula (HI) is carried out using conditions apprp r for hydrolysing the particular group Ll chosen, for example when L I is a group of formula or a C 1-6 alkoxy groupw the hydrolysis is suitably carried out under acidic conditions, for example using dilute sulphuric acid, conveniently in a watr/dioxan mixture, for example a 1;:1 mixture at any temperature which provides a suitable rate of formation of the required product, generally at an elevated temperture, such as in the range of from 50 0 C to 1200C, for example 90 0 C; or when

L

1 is a group of formula the hydrolysis is generally carried out using lithium hydroperoxide in an aqueous solvent, such as, aqueous tetrahydrofuran, at any temperatur which provides a suitable rate of formation of the required product.

15 generally at a reduced temperature. such as in the range of from -I10 0 C to 0 0 C, for example OOC Airernatvely, when L I is a group of formula the hydrolysis may be effected under basic conditions, using for ex-mpie aqueous sodium hydroxide, in an appropriate solvent such as aqueous teaaliydwfixu usually at ambient A compound of formula wherein LI is a moiety of the aborve defined formula or may be prepared from a compound of formula (IMl) CH3

O

wherin ROand R are asdefine in relation to formula (I)and L 2 represenlts a leaving group; for compounds of formula (11) wherein Ll is a moiety of the above defined formula by reacion with (S)-pheylglycinol., or for compounds of formula (11) wherein LI is a moiety of die above defined forrvula ty reactoo with (S>-4-benyloxaZOlidifl-2-ofe. preferably an activated form hmvof and thereafier separ&irg the required isomer from the mixt Of A suimble leaving grop L)i halen atom. for exampl a chlorine ax-m The reaction between the compounds of formula (l11) and (S)-phenylgly-cinol may be carried out under conventional ainida"Lion conditions. for example in an inert solvent such as dichioromechane at a temperature which provides a suitable rate of formation of the required product, suitably at ambient temperature and prtferably in the presence of a base such as triedliylamine.

A suitable activated form of (S)-4-benzvloxazolidin-2-onc is a salted form. for example an alkali metal salted form, preferably a lithium salt.

The activated form of (S)-4-benzyloxazolidin-2-one may be prepared by any appropJICr conventional method- T7hus when the activated form is a lithium salt, it may. be prepared by treating (S)-4-benzyioxazolidin-2-one with a source of lithium ions in the presence of a base, suitably provided by n-butyllithium, in an aprotic solvent such as tetrahydrofuran. usually at a low temperature. for example in the range of from -78" to 0 0

C

The reaction between the compound of formula (111) and the activated form of (SY4-benzyloxazolidin-2-one may be carried our in an aprotic solvent. such as tequired product, conveniently by allowing the reaction mixture to slowly warm from -78, toOC.

Preferably, the activated form of (S)-4-benxyloxazolidin-2-one is prepared and then reacted in-siwu with the compound of formula (ml).

A compound of formula (IM) may be prepared by hydrolYsing the carboxylic esrw COOR 2 of a compound of formula (TV): CH, CO.0R 2 OCH0 (IV) w~hein RO and RlIart asdefined in relatono formnula ()and R 2 repesents an aLkyl group, and thereafter converting the carboxylic acid group so formned, into a moiety co-I- 2 A suitable alkyl group R 2 is aC 1 _6 alkyl group, especially a methyl group.

The hydrolysis of the, carboxylic ester may be effected by use of any conventional hydrolysing agent. such as an alkmline metal hydroxide. for example sodium hydroxide.

Tot hydrolysis of the compound of fonmula (IV) may be carried out in any suble solvet suich as a methanol/wa=e mixture. conveniently a 1:1 mnix=,e it a MUMpraw which provides a suitable rate of formnation of the required product suitab~y at an elevated remperaor and conveniently at the ref lux temperatuzre of the The conversion of the carboxylic acid group into the moiety CO.1 2 L may be carried out using any appropiate conventional procedure- depending upon the particularnature of the group L 2 chosen, thus when L 2 is a haloge n a suitable proced=r involves treament of the carboxylic acid with an oxalyl halide, for example oxalyl chloride when L 2 is chlorine.

The reaction conditions for the conversion of the carboxylic acid group into the moiety CO.L 2 will be dictated by the particular nature of L 2 and the source of L 2 chosen. for example when L 2 is halogen and the source of L2 is oxalyl chloride then the reaction my be carried out in an inert solvent such as dichloromethane or benz=n at a teruperanire which provides a suitable rate of formation of the required product, suitably at ambient temperature or at an elevated temperatlre such is the reflux temperatre of the solvent- It will be appreciated that the preparation and separation of a compound of formula (II) wherin L I is an epitner of the above defined moiety or and its subsequent hydrolysis to afford a compound of formula can be Iachieved by employing analogous mthods to those described above for the preparation.

Vseparation and hydrolysis of a compound of formula (1)wherein L 1 represnts the above defined moiety or A compound of formula (11) wherein Ll is a moiety of formula mnay also :~20 be prepmredby dehydroxylaion of acompound of formula 0

CH

2 above defined formula.(b)- IThe debhytroxylation. of the compound of formula is conveniently carried .~.out by ueaunct with a tialkylsilale. for example trieshyLsilante. preferably 1in the ptesnce of rrifluoroacetic acid and conveniently usig trifluorowe :ic acid as olven.

amany temperature providing a suitable rate of formulation of the produ. for eapeat a temperature in the range firn 0*C to room temerarure.

It will be apprtciated thai a compound of formula (11) wberein Ll is a moiety of ftprmula would also be obtained by dehydroxylauion of a compound of formla ()in vhich fth hydroxy bearing stceocutre is epimeried.

A comnpound of formula MV may be prepared by reacting a compound of formaI (MI) -6-

CHH

W-N 0JzJ,(VIA) wherein RO is as defined in relation to formula with a compound of formula

(VIB):

0 0

R'CH

2 0 Ph ('IB) wherein R 1 is as defined in relation to formula and thereafter separating the required isomer from the mixture of diastecismr producedL Suitably in the above mentioned reaction. the compound of formula (VIB) is in an activated form, which is preferably provided by meating the compound formula (VIB) with an alkrylboron aiflate, for example dibutyiboron triflate.

preferably in the presence of an amine base such as triethylamine.

The activated form of the compound of formula NVIB) may be prepared by the appopraxeconventional method depending upon the specific nature of the activated form chosn, forexample the compound of formula (VIB) is reacted with dibutylboron trillaw and miethylamine in an inert solvent such as dichloromethzne at a atemperaturein the moge of frot-78' tOCe Ile reaction between the compounds of formulae (VIA) and (VIB) may be *carried out in an in an inert solvent such as dichlorottbafle, at a temperature which provides a suitable rawe of formation of the required product, convenienty by allowing the reaction mixture to slowly warm from -790 toV Preferably, the activated form of die compound of formula (VIB) is prepared aEd then reacted in-simu with t compound of formula 011A).

Fr cornpounds of iormulat wherein RO represents 2-benoxazolyl. a suitable compound of formula (VIA) is 4-[2-[N-(2-benzoazOdylNmmthyiaminojtho"yJbeflnehyde- A suitable means for separating'any required single isomer fr-om a mixture, of sc-hromarography, such as preparative hg rsuelqi chromatography or silica gel column chromnatography.

-7- One convenient method for preparinne a compound of for-mula ill) wherein L' is a C 1 6 alkoxy _=up is 'he basic alcoholysis of. a compound of formula (II) wherein L I is a mnoiety of formula Mb.

A suitable base is an alkali metal alkoxide, flor examiple L I is Methoxythe compound of formula (HI) wherein L I is moiety is treated with sodium methoxide in methanoL A compound of formula may also be prepared by resolving a racemic compound of formula (VII): R-N (-I wherein RO and R 1 are as defined in relation to formula and thiereafter, if required, preparing a pharmaceutically acceptable salt of the compound of formula (I) and/ar a pharmaceutically acceptable solvare thereof.

Thle resolution of a compound of formula (VII) may be carried out using 5 known resolution procedures. for example by reacting the compound of formula (VII) with a resolving agent, such as an optically active acid or base, to provide a mixture of diastereoisoweric salts which may then be separated by tractional aystallisation and thereafter the compound of formula may be regenerated from the separated salt by conventional means, such as hydrolyss.

It will be appreciated thai the compounds of formula (VII) compxise the compounds of formula admixed with other optical isomers. A compound of formula (VII) oir a pharmaceutically acceptable sat therof and/or a pharmaceutically acceptable solvate thereof, forms a further aspect of the present invenition- The separated isomers of the compouneds of formtula (VUI). in adition to the compounds of formula, or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, also compris t pmeent invention..

Suitable acids or bases for resolving the compounds of formula (VII) awe as described in Enanoarsm. Rwemwes and Resolutior,. I Jaques "u 198 1, Wiley Interscience, especially at pages 255 and 256- Suitable methods for effecting the resolution awe also disrlosed by Jaques s..

The compounds of foimla (U1) and (MI) form a fimnhcr aspect of trt crset urin- The compounds of formula (IV) and (VIA). for cxample biaz yl)-N-miethymioehoxylbztzalehyd ame known comnpounds or they -may be prepared usig metthods aaogous to those used to prtpare known compounds, for example those disclosed in Inernational Paret Applicarion Nubicamion Number W094A) 1420.

The compounds of formula (VIIB) ane known compounds or they mray b,: prepared using methods analogous to those used tprc known compomunds., for exaple those disclosed in Organic Synthesis Vol. 68. p83. 1990 Ed. JD. WItc methods analogous thereto. in combination with covetional methodology for the preparation of acid chloride&~ it winl be aprtreciared that in any of the abovezrentioned reactions any rec4i-ve growp in the substrate molecule may be Protected. according 1o c ovenuonal chemical practice. Sultable protecting gmops in any of dthe abovemntioned reactom r those used contventionally in the art-. Te methods -of farmaion and removal of !Wch proecting groups are those conventional methods; appropri=r to the mclecule being It will be appreciajed chat the above-mentioned preparion of the compounds of formula or a pharmceutically acceptable salt terof an6=o a pharmaceuticallY accptable solvate thereof, is a stereoselective procedure mid that the compound of formula is a single stereoisomr. Tepsnhneton also includes a compound of formula when present in adrnx~e with Ims than50% wfw of its naccumc ISOMr. that is when it is greater than 50% optically puff- suitably 80100% and prefrrbly 90-100% purr- such as 90-95%. aimt preferably 95-100%. for example 98%. 99% or 99.9% optically t In one preferred asetthere is provided a compound of foxiniula or a pbameucally acceptable, sal theimaf UrKI/or a phanflacCUUcally acceptable solvac thereof, in optically pine form.

Thm absolute steeochemnistry of compounds may be determined using conventiocal methods, such as X-ray crystallography.

As mentioned above the compouinds of the invention are indicaxed as having.

useful theaputcM Properties: The presenE inverv accodingly provide a conpound of foxmuha or a pharmacenticaly acceptable salt thereof andlor a pha~ceuxically acetbesolvare thereof. for~ Use as an active therapeutic substance, TIhus the present mvmrnon provideS a coinpowid of formula (1.or a pbaumaccutically acceptable salt xhauof and/or ILpharmm*-uticilly acceptable solvax dwwef~. for use in dhe nearmeri of and/or prophylaxis of hyperglycae=X.L in a furfther aspect the present invention also prtrridc i compowid of fornula.

aI). cr a pharmaceutically acceptable Wat theeof and/or a pharmaceuticay acceptable solare thereof, or use in te treatment and/or praphylaxis of hypedlipitiaeuia.

As indicad hereinbefote the present invendon also provides a comrpounid of ~formuala or a phvrmceutically acceptable Salt theeof Undor a Pharmaceutically acetal solvate diereo for isin the ttweaet of hypmimesion. cardiov=ascl disease, certain camig disordr wAndor the temient and/or prophylaxis of rena disease.

-9.

In addidon. the prestnt invelltion also prov ides a compound of formuia or a parmceticllyaceptahle, salt heof and/or a pharmceutically acceptable solvate themef. for use in the prevention, reversal. stabilisation or retardation of the progression of znicrua1bnnrtur.i to -albuminuria- Caxdiovasculai disease includes in particular aiheiosdlersis_ Certain eating disorders include in1 particular- the regulation of appetite and food intake in subjects suffering from disorersassociated %-th under-eating such as anorexi nervosa, and disorders associaitd with over-cating. such as obesity and aDmia bulimia- Renal disease includes renal disease ass.iawd with the develpment of Type- U diabetes including diabetic ncphrrpathy, glomnerulonephritis. glometular seeis, acphroic syndrome. nypertensxve nephrosrccwsis and end stage renal disease.

A compound of fonnula or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable salvate thereof. may be administered at o, 15 preferably, as a pharmnaceutical composition also comprising a phmaraeunically acceptabl carrier.

Accordingly, the preseat invention also provides a pharmaceutical composition comprising a compound of the general fontmla or a pharmceutically accepiable salt thereof, or a pharmaceuitically .acceptable solvaze thereof. and a pwaezaiy acceptable carrer therefor.

As used herein the term pharmacentically wcqpal*, embrame compounds.

compositons and ingredients for both human and vzuuY Use: for example t 'm pharmaceuically acceptable sWe embrects a vainauily acceptable SNL Thedmoiinia .i eie.b h form ofa akseen~d Cr= o die intuisforc e- i h omo ~kacmau USURY the pharmaceuical composiioisof tht presert ivnt will bt adapted for eral administrujon, although comosnotis for adiiudriliian by routes, such as by injuuou and percuraomw absmxpdam also enviasaged.

Particularly suitabe corqpositions for aral admintistrationi ane tit dosage form such- as tablers and apsuls. Othe fixed unit dosage forms, such as powders Presented in =ahem may also be used- In accordance with conventional pharmaceutical practice the carmer- may cnxsea diluent, filr. disinetegrant. wetting agent. hibriant, colcuxrat. flavourant or otba. convenntional, adjuvL Typical crrzers. include, for ex mpl.irocrystalin cellulose, strch.

sodum, swh glycolare polyvumylipyrrlidome polyvinypolypyl&3om magnesiurnman- oir sdium lanryl sulphr-.

r+(LYL~r-\LI-aii r .1 j r r rr r I i::i 1 o Most suitably the composition will be formulated in unit dose form. Such unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more especially 0.1 to 250 mg.

The present invention further provides a method for the treatment and/or 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 or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof to a hyperglycaemic human or non-human mammal in need thereof.

The present invention further provides a method for the treatment of hyperlipidaemia, hypertension, cardiovascular disease, certain eating disorders, the treatment and/or prophylaxis of renal disease and/or the prevention, reversal, stabilisation or retardation of the progression of microalbuminuria to albuminuria in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula or a pharmaceutically acceptable 15 salt thereof and/or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.

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

In the treatment and/or prophylaxis of hyperglycaemic humans, and/or the treatment and/or prophylaxis of hyperlipidaemic human, the compound of the general formula 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 25 generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg.

In the treatment and/or prophylaxis of hyperglycaemic non-human mammals, especially dogs, the active ingredient may be adminstered by mouth, usually once or twice a day and in an amount in the range of from about 0.025 mg/kg to 25 mg/kg, for example 01 mg/kg to 20 mg/kg. Similar dosage regimens are suitable for the treament and/or prophylaxis of hyperlipidaemia in non-human mammals.

The dosages regimens for the treatment of hypertension, cardiovascular disease and eating disorders hypertension, cardiovascular disease, certain eating disorders the treatment and/or prophylaxis of renal disease and/or the prevention, revrsal. stabilisation or retardation of the progression of microalbuminuria to alkiminuria 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 or a pharmaceuticaly acceptable salt thereof and/or a pharmaceutically -ll- "i i I I i 1 r a

I

I

acceptable solvate thereof. for the manufacture of a medicament for the treatment and/or prophylaxis of hyperglycaemia.

The present invention also provides the use of a compound of formula 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 and/or the prophylaxis of renal disease and/or in the prevention, reversal, stabilisation or retardation of the progression of microalbuminuria to albuminuria.

No toxicological effects have been established for a compound of formula (I) or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable S solvate thereof, in the abovementioned dosage ranges.

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

A

e .12- J f £r t S, y Example 1 3 4 [2-[N(2Benzoxazol)Nmethyamino~ethoxylphenyl]2(2 me hox ethoxy)propanoic acid

CH

3 C 2 ~yN/ 0OCH 3 A solution of [2S, N(J S)1F 3 44-[ 2 .[N-(2.benzoxazoylNimtylaruno~ethoxyIphenyll]2-(2-rnethoxyetoxy)-N(2-hydrxy-.l-phenylethyl)propanarnide (1.846 g) in a mixture of I M sulphuric acid (45 niL and dioxan/water 1, 150 niL was heated at 90*C for 56 hours and then the pH of the mixture was adjusted to pH 3 by addition of aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the organic extracts washed with water, brine, dried (MgSO 4 and evaporated to give an oil. Purification by chromatography on silica gel using a gradient of methnol n dihioomethane as eluent gave a foamn of 88% e.e.(yPL)Th 15 pouct was reacted with (S)-cz-methylbenzylarnine in acetone, and the resulting salt recrystallised sevarul dine from ethyl acetate-hvmae before beung dissolved in water, acidified with dilute hydrochloric acid and exrcted with ethyl acetate which was dried with MgSO 4 Evaporation of the ethyl acetate solution afforded enantiosnerically enriched title compound. [aID 25 -2V~ (czO.625, CHCI 3 e.e 94% 20 (by HPLC); [Found M+ 414.179 1 C22H 2 6 (requires M+ 414.1791]; IH NMR spectrum identical with that described in Ex "Inpe Example 2 3 4 42[N(2BenzxazoIl)N-mehJylahdno~etioxyphenyl( 2 ,,2 25 trilluorciehoxy)propanoic adid by hydrolysis of amide

CH

3 COH

"'OCH

2

CF

3 trifluoroethoxy)-N(2.hydroxy. I-phenylethyl)propanarnide (from Procedure 3) was hydrolysed by an analogous Procedure to that described in Example 1. Tfcsa by chromatograpy on silica gel using a gradiet of 0-5% methanol in dichlorometbane as eluent gave the title compound, mp 11 6P7C, after trituado :with &e&hy ether-hexac

[CEID

2 24.

CC

3 X; e.e. 95% (by IIpWC.

[Founid C59;Hi 4.7; N M* 438.1403. C-, 1

H

21

F

3

N

2

O

5 requires C.-57.5; HL 13~- PCUEMMP513038 4.8; N, M+ 438.1403]; 8H (DMSO-d 6 2.96 3.22 (31l~s), 3.88 (2H.rn), 3.95-4.18 2Hm), 4.27 (31Lm). 6.8-7.37 (8H.m) and 12.9 (1H,br s, exchanges with

D

2 0).

Example 3 (S)-3-4-[2-[N-(Z-Benzoxazolyl).N.methlainlethoxy]pheflyl- 2 2 ,2 2 tnifluoroethoxy)propanoic Acid, by Direct Hydrolysis of the Imide CO H

HCH.CF,

Aqueous sodium hydroxide solution (2.5M, 65 ml., 0. 163 mtol, 2.3 eq) was added to a stirred solution of 4S]-3-[3-[4-[24N.(2-benzoxazolyl)-Nincthylaininolethoxylphenyll-2-(2,2-trifuorothoxy)popafloyl]- 4 benzyloxazolidin-2-one (ftrm Procedure 10)(42.5 g, 0.071 mol) in THF (500 ml.) and wate (12 The mixture was stirred for 20 minutes, the reaction was diluted 15 with water (I L) and extracted with dichloromethane (3 x700 These dichloromethane solutions were evaporated and dhe residue Vivified by chromatography on silica gel using 5% metanol in dichloromethan as eluent to afford (S)-4-benzyioxazolidin-2-one. The original aqueous solution was acidified to pH 3.5 with dilute hydrochloric acid and re-extracted with dichloromethane (3 x 700 20 tin.). The dichioroiethane solutions from the acid extrction were dried (MgSO 4 and evaporated to give a solid. This was recrystallised. from dichioromethane diethyl etezafford the title compound, mp 119.5-120.59C [hx]D5 -31*(c=2.50.

ala 3 e.e. 99.6% (by HPLC); [Found C 57.7; H. 4.7; N, 6.25%; M 4 (Ml) 4 438.1412Z C 21

H

21

FJN

2 0 5 requires C 57-5; H1, 4.8; N, M+ 438.1403]; 8

H

(CDCI

3 3.05 (1H, did, 3.13 (IH. dd). 3.31 (3IL 3.72 (1K1 3.89 (211, mn), 4.04- 4.14 (3K, 4.21 (1H. dd). 6.78 (2H, 7.03-7,40 (61L, m) and 11.20 (1H, br, exchanges with D 2 SF (DMSO-V~ =-72.7 (3F, t, 3 JjHj 9.3 Hz, CF 3 Exmple 4 (S)424N.2.BezoxaBzoxly)-N.ethylavnoletoxylphelyl-2-(2,22-tri- Whorethoxy)propanoic Acid by Hydrolysis of Methyl Ester A ixueo(S-mnethyl 3-[4-[2-fN-(2-benzoxazolyl)-N- ,hryaioethxybhenyl]-2-(2,22-tifluroehoxy)pxopanoar (1-256 g, 2.8 x 100 moi), aqueous hydrochloric acid (2.QM, 50 rroL) and dioxan (50 ML.) was heated at reflux for 7 hours, cooled and concentrated in vacua. The residue was suspended in brine (200 niL) and extracted with ethyl acetate (3 x 300 The combined ethyl accuit solutions were dried (MgSQ 4 and evaporated wo afford a waxy solid. This solid was triturated with. hexane, filtered and dried under vacuum at 651C to afford the desired product, nip 1 13-51C [ID25 320 (c 1-02, CHC1 3 Ce- 99.4% (by HPLC); [round C, 57.25; H, 4.8; N, C 21

H

21

F

3

N

2 0 5 Yequire-s C, 57.5; H, 4..8; N, The IH NMR spectrum of this material was identical to that produced in Example 3.

Example 5 (S).3.[4[12[N.(2-Benzoxazoyi)-N-methylan1iflo~ethoxyIphny- 2 2 methoxyethoxy)proplflic Acid

COIH

N cki- N c 4CH 1 Om (S)-Methyl 3.[4-[2-[N-(2-beflzoxazolyl)-N-flethylaminfolethOXyIphenyI- 2 2 methoxyethoy)propaloate was hydrolysed in a manner analogous to tza described fbr Example 4. The crude reaction mixture was chromatognaphed on silica gel using methanol in dichioromethane as eluent to afford the tidle compound, a gurn- [cx]D 25 -270 (c 0.73, CHCl 3 e-e. 99.8% (by HPLC); (Found M* (El) 414.1779.

C22H 2 O 6 requires M+ 414. 17911; 8Hj (CDC1 3 2.90 (IH, dd). 3.15 (1K Ldcl), 3.33 (3K 3.37 (311, 3.40-3.70 (411 mn), 3.93 (2K 4.05 (IH, dd), 4.21 (2H. t), 6.81 (211 d) and 6.95-7.40 (6H=m).

Procedureli 3 -[4-[2.[iN42-Benzoxazoy)=N.methvlaminolethoxyjphenylyA.-(2.

inethoxyethoxyjpropanoic acid

CH

3 C 2 A mixture of' methyl 3-[4-(2-[N-(2-benzoxazoly)-N-ehyaminojethoxyjp. ieyl-2- 2 mzoythoxy)propanoate (1.08 g, Int. Parent App!.. Publicaion No. WO 9401420) and sodium hydroxide (253 mg) in methanoi:wat.er 1, 10 mL.) was heated under ref lux for 2 hours. After evaporation of the reulan io -,acuo, the residue was diluted with water, acidified to PH 5 with 2M hydrochloric acid and then extracted with ethyl acetate. Washing of the ethyl acetate extracts with water and 15 drying (MgSO 4 and evapoation gave the tide compound as an oil which crystallised on trituration with diethyl etheTAhexanc. [Found C. 63.8; H. 6.5; N. M+ *414.1791. C22H N 2

O

6 requires C 63.8; H, 6-3; N, 414.1791]; SH.

(CDQ1 3 2.91 (ilidd), 3-15 (1H,dd), 3.34 3,38 3.41-3.69 4 1-1m), 3.93 (2Ht). 4.05 (1H-Ldd), 4.21 (2H,t).-6.80 (2Hd,) and 6-83-7.38 (6H mn).

Procedure 2 methoxyethozy)propanoyl clrd CH3

O~

OXAlyl chloride (92 mg) was added to 3 -[42-[N-(2-benzoxazoyl)-Nmety.

Uflinolethoxylphenyll-2-(2-methoxythoxy)propanoic acid (100 mg) in diebormnedmae (2 The mixture was stirred at room temperature for 16 hours and evaporated to dryness to give the title compound as a gum which was used Without further purificadon.

V-k Procedure 3 [2S, N(IS)l.

3 44 -t 2 .fN.(2.Benzo ~I.methiaminoetoy]pheyl2( vmehoxyethoxy)-N(2-hydroxy-lphenylethyI)propanamid 0 H Ph CH3 H3 ethoxy)propaloyl chloride was dissolved in dichlorometblfle (2 mL) and a mixture of (S)-2-phenlgl8ycifol (33 mg) and dry triethylamil (37 mg) in dichloromethafle (1 ml-) added. After stirring for 5 minutes water was added and the mixture extracted with dichiotomethafle. The organic extracts were washed with water, brine, dried (MgSO 4 and evaporated. The residue was chromatographed on silica gel using a gradient of 10-50% acetone in hexane as eluent to afford firstly [2R, 2 benzoxazoy)-Netyla o)thoxypheny2(2etoxycty)--2 hydmxy-1-phCalelthyl)prepananiide followed by the desired [2S, N(IS)Ipropanamide title compound as a foam. [cL]je -33* (c71.1, CHCl 3 ,92.6% de. (by HPLC);, [Found M+ 533.2526. C3OH 35

N

3 O5 requires M+ 533.2526); 6H (CDC1 3 *2.81 (1Hdd), 3.07 (lH~dd). 3.35 3.36 (3Hs). 3.48-3.58 3.52-3.62 (MHm). 3.71 (IH~dd), 3.82 (1Hdd), 3.94 (lH~dd), 3.93 4.22 OWLt) 5.05 (IH~dt). 6.75-7.35 (13HconpK), 7.54 (IH br, exchanges with D 2 0).

Procedure 4 triflueroethoxy)propaloic acid CH~

C

2

H

N H2 F OCHC 3 Methyl 3 4 24 N-(2bnzoXyI)-N-methylamnOithoxy1ph~yll 2 tujIiuoroxyK)proPnoate (mI. Parcni Appi., Puhlicoaan No. WO 9401420) was hydMyd by an analogous pocedure to that described in Procedure I to give the tite cxoaldas a solid. nip 116-117"C; [Found C. 57.4; H. N. 6.4%.

C

2

AH

2

F

3

N

2 5 mquiim C 57.5; K 4.8; N. 6.4%1; 8H (CDCI 3 3.03-3.17 (2Km), 3.29 (311s) 3.73-3.83 (111m). 3.95 (2H~rn). 4.02 (2Km). 4.04-4-30 (2Km) amd 6.74-7.40 (8Hi i).

-17- Procedure (±,I-2[.2Bno~y)Nmtvaioehx~hnl--222 trifluoroethoxy)propanoyl chloride CH~,

COD~

Oxalyl chloride I nL) was added to a solution of (±)-3-[4-[2-IN-(2-belz~xazolyl)- N-methylatinoehoxy~peryl.2-CZZ2.Uf1uorhoxy)p1E)panoic acid (1.72 g) in dry benzene (30 mL). The mixture was heated at reihix for 2 hours, cooled and evaporated to dryness to give the title compound as a gutm which was used without further purification.

Procedure 6 [2S, N(lS)1-3(44-2-[N(2-Benzox1Oyl)-N-m~lioetbYISlItOXyJphenfl]l2-R22 trifluoroetboxy).N(2hydroxy--phelethyt)propaflSalfde -4[-N(-emaoy)Nmetyviocmlhnl--22) trifluaroethoxy~prpanoyl chloride waRs reatd. with (S)-2-phenylgiycirml by an analogous piucedure to that described in Proordttue 3. Qur~matography on silica gel using Ia graient of 10-70% ethyl acetate in hexan as eluan affortded firstly (2R.

N(S]3[-2[-2b~aoy)N-zvuioewypey]2(,2 trifluoetx~y)-N-(2-hydmxy-l-pylthy)Opanifde followed by the desired [2S. N(ISfl-propanaxnidc title compound as a foam [zLID 2 5 1 4 MeOH); 99% d. (by HPLC); [Found, 557.2136..C29H13F 3

N

3 0 5 requires M* 5571 13tybf(CI)Cl 3 2.35 (1H.bf, exchanges with PP2). 2.91 (1 HAd). 3.13 (IHAMd. 3.36 (3Hs). 3.70-3.87 (211,m). 3.84(2KdL) 3.95 (UKi). 4.12 (1 HAd),4.22 5.01 30 (1Km). 6.75 (2114). 6.97. (lbr s. exchages with D70) aMi 7.01-7.36 IMCOirilex).

01 19, Procedure 7 (2,2,2-Trifluoroetboxy)ethanoyl Chloride cool OCH2CF 3 A solution of oxalyl chloride (20 mL, 0-23 mol. 1.15 eq) in dry dichloromethane mL) was added dropwise at room tcemperawre. with stirring, to a solution of (2.2.2trifloroethoxy)efthaic acid (Int. Pawmn App!.. PubLicarion No- WO 87A)770. 31.6 g, 0-2 rnol) and NY-dimccehyiformamide (5 drops) in dry dichloronwthane (400 roL).

The mixture was stirred for an additional hour. then heated under reflux for 2 hours, cooled and the bulk of the solvent removed by distillation (bp 40-45 0 CI76 mm Hg).

The residue was transferred to a Claisen distillation flask and the remaining solvent and oxalyl chloride removed by distillation (bp 45-60'C/760 mm Vacuum distillation of the residue dien afforded the product, bp 50.55*0/25-32 mm Hg_ SH (CDC1 3 4.00 (2H, q. 3 Jtr, 83) and 4-57 (2H. s).

Procedure 8 0 0

:CF

3 Ph~ 20 (45}.4.Bcnzyloxazolidin-2-oflc (5.21 S, 0.029 mnol) was dissoved in dry THF.

:nL) and cooled to -70TC under argon-, n.Bityllitiutn (19.4 niL., 1.6 M solution in bexane. 1 aq) was added over 10 minutes and the resulting mixture stirred at C for 20 mninutes A solution of (2.2,2-trifluoroethoxy)ethaflcyl chloride (5.19 g, eq) in dry THF (60 mL) was added over 10 minutes. the mixurre stirred at -101C for a, fudthe 30 minutes then allowed to warm to rm ternperture Overnight. The reauowa was quenched by addition of brine (20 mL) and concentaved. in vacuo. Toe residue was diluted. with h~int (300 niL) and extracted with ethyl acetate (3 x 300 niL). The combined organic exvacts were dried (MgSO) evaparated and the, aiedoecri Wgnphtd on silica elwith Mone as eluent to give the p'od6c &s an Oil- [at> 5 +480 (c =2-55. OCC3) 00% (by HPLC); (Found Ammnimia) MH- 318M0934. C 14 Hl*NO 4

F

3 requkvs MHW 318.09531; bH

(CDC

3 12 (111 dd). 334 UKH dd), 4.02 (2K q; 3jF 8.6) 4.30JR1. .4.6 (111.

in), 4894 (2Hf s) and 7.'15-7.40(511.mt);AF$OCCI -74.80 (3F. g qF 3 -19- Procedure 9 3R), 4S--31-2[-2Rnoaovl,-mty~ioehxjbni-i oH P0o CF, ph (4 Bzl31-'-,-~ootoyeu y~xz~i--n (31-7 g, 0.1I wIno) was dissolved in dry dichiorornethane (300 rnL) under argon and cooled to 78'C (itna mrtnperar of solution), using liquid nitrogen/acezone as the cooling medium-. Trierhylamine, (16.72 niL. 1.2 eq) was addcd, followed by the slow.

addition. over approxcimvb.t 10 minutes, of di-n-burylboron Eriflate (Aldrich Chemical Company. 1-1).OM Ution in dichloromethane, 110 mL. 1.1 eq) such thatth reaction temperature was nwntained below -70C The niixtur was stirred at -78*C for 50 minutes, then the itnoling bath was replaced with an ice bath and thet mixture stirred at 0 0 C for an additi~ni1 50 minutes befr'e being recooled to -78*C. A solution of 4-j2-N- (2-beozo yI)-N-mthyhanoethoxylbenzaldehde (29.6 g. 1.0 e)in dry dichlorornerhae precooled to was added over ca. 12 minutes.

swh that the reaction z Mra~Wr was maintained below -70r-C The resulting mixre W- S~tre at -WC. fr 30 minutes, then~ waned from -79C to O ovar minutes along a linear gradient (wv.rsrate I. ii- and stirred at w'C. for a further 75 autmiits The reaction rrixture wats pored into a quenching Woution of methanol (5W0 nL). pH 7 ph%,,ph4te buffer 250 mE) and hydrogen peroxide- (27.5% wtv, 10 mLl and strd v igourusly fo 30!1flutes Water (4 I was added, the' layers wer scoaed mid the aqueous layer was exxttd with dichkomtdane (3 x 1 L' I.7hdichlovtrthanC solutions were mvvkbined with the original dichlvramdtine layer from the reaction miture xid this argun= solution was then washed with water (2 L) and brine (2L. z& and evaporated to afford a fom 114 NUR of this crude reactioa Mi4r' tsu a Mixture of the desired &Wk~ prd (3 cornFWLjor dia olirie4m i ad startng rnameials. 11be crude mixtiure w~ ~otograpbed on silica gel using a gradiet. clion cau:06iSig ISM rthyl INT4'11 in dichlcxvxrthane initially (until the desired product began to elute)- Acetatgt 5~ety wue in did loreumedtmha to.

comp2 the cluin -of die desire product Unreacted wrride anid aldhyde were rwwnvred from he arly frtions fo)Hwed by a quatity of iMpre Moid=c and dhe the tide comptpcud (coWitrsing 21 diseoson zatio 97.82, by NMR). Ea), (c 2.82. CHC13). [Found ZED) W 613.2042.: C 3 -FNO etires M 4 613.2036]; 8Hj (CI)C1 3 cIv major diasteroisoiner is rec'orded) 2.75 dd). 2.90 (1K d, exchanges with D, 3.25 (11L. dd). 3.34 (3H, 3,80-4.00 (5H1. in) 4.07 OKii dd), 4-24 (21L 4-45 (IH. rn), 4.99 (lH. apparent 5.48 (IH. d) and &.95-7.40. (1111. rn); 8F (CDC13) =-74.7 (3F, t, 3 JjJF 8-5, The minor diastceoisorner in the purified product was identified as rte 13(-S, MS 4S]-diastereoismer.

Procedurt Preparcion of 4S].34[344-[2-(N-(2-Benzoxaznlyl)-N.

nietbylmiojeboxylpheylj-2-(Z2.2trifluoroethoxy)propanoylj-4bauyloxazolidin-2-one by Dehydroxylation 0 0

*CHI

*CF, Ott Triethylsilane (120 ml, 0.75 mol) was added over 5 minutes to a stiffed. ice cooled solutioa of [3(2S, 3R), 4S]-3-[3-[4-[2-[N-(2-benzoxazolyl)-Nmethylaminolezhoxylphenyll-3-hydroxy-2.(2,2.2-irifluoroethoxy)propaoyl-4benzyloxazolidin-2-ace (46.23 g. 7.5 x 10-2 nol) in trifluoweacetic acid (650 niL).

The ruixture was stirred at (PC for 1 hour, then at roon tempture~ for a furwh= lioi The bWk of the solvent and residual trietyisilane was removed by rw evaporation, firstly at 40 nm Hg an ially t Sm h eiu a pH of th ~uwu ayer and fin a. -5e lamr we S, sarTe thsde wa~slae diseoraved i h diclaroetehane (800 L).wt Th00 cmbi.ne tirreviorou sl y during the cautious addition of solid sodium bicarbonate (-29 S) (frothing) until the layers were washed with wairr (600 niL, dried (MgSO 4 and evaporated. The residue was trturated with hot hexane and dhe resulting solid -collected by flutado.

Recystllsauonfrom diethyl ether-hexarie afforded the title compound, imtp 107-IO9C a single datrosrr by 'H NMR spectoscopy. (aID 25 +38* (c 131. CHCI 3 [Found (A 62.1; H. 4.9; N. M+ 597.2039.

C

3 1 H~i$ 3

O

6

F

3 requires C, 62-3;. l,5A N. M+ 597.2087;: St, (CI1C1 3 2.82 (1H. dd). 2.96 dd), 3.04(1K dd). 3.32 (lII. dd). 3-34 (3K 3.70 mn), *3.88 (OIL ra), 3.94(2K .4.12 (11L rn), 4.18 4.25 (2H, 4-57 (1K.m), 5.34 (1K dd). 6-82(2K d) and. 7-735 1K fi (CDCt 3 =-74-8 (3F. t.3M 86cF 3 Procedure 11 Preparation of 4SI-3- [3-(4-[2-(N42-Benzoxazolyl)-N-methylaminolethoxylphenylj-2-(2,2,2-trifluoroethoxy)propanoyl]-4-benzyloxazolidin-2-one by Diastereoisomer Separation 0 0 (S)-4-Beszzyloxazolidin-2- one (0-291 g, 1.64 x 10-3 moi) was dissolved in dry THF mL) and the resulting solution cooled to -70'C under argon- n-Butyl lithium (1.6M in hexane. 1.03 nIL. 1.64 x 10-3 tol) was added and die mixtur was stirred at -1O'C for 10 miinutes prior to the addtion of a soludio of bezxamlyl)-N-mehyanino~eihoxyjph= yl]-2.-f2,2,2zTiiflucroezoxy)proparYI chloride (prepared from 0.36 g of the acid by Procedure 5S5 above) in dry THF niL). Thse reaction was stirred and allowed to warm to room tcvmute oventight before being diluted with Water (20 n-L) and extr-acted with ethyl acetate (2 x-200 niL). The cobndethyl acetate layers vme washed with water (200 niL) and hime (200 niL). dried (MgSO4) and evaporated to grve a biWn gum This sws clu xnazogaphed on silica get using a gradient of 35% to 50% ethyl acetate in hexant as etumr to afford firstly t SY-diaszueolzmzr. followed by the title comnpound.

a foam. This materia was spcocpciyidentical with that prepared by the 9&.1l ME LOUt (Procedure Procedure 12 ($).MeftyI 3-14-2-IN-(2-flady)N-mnhva~hiojezbxphnvll2-22,2-

T

Y

CORW

OZCF3 'A zolamo of sodium nieroxide [jparu fro= sodii hydride (6%dispeuin in mI uaal oil, 138 mig. 3.1 xi 10-3 mol) dissobred in dry ranhanol (335 nL)] was added to, an ice cooled and stirred suspenso of 4S1-3-{3-[4-42-(N.{2 aewlyU-N-methylaminojethoypby]-2 ZZ- vr~~ypopstoyl].

4.1 yloxabqHn-2-w (1.379g. 3.1 x i0~nwi) in dry methano (100 mQL. The by -the siio'n o(f t NjuOWk hydrochiwaie acdd (2.OM. 1.75 mnL) and cuonmaed in vmw. The residue was suspended in m (0014" eaweu with ethyl -22-.

(3 x 200 mL.) and the combined ethyli acerate solutions washed with brine (500 mu).

dried (MgSQ 4 and evaporated. The resulting gurn was chrornarop-aphed on silica gel using 4% ethyl acetate in dichloromedhan as clvent to afford the product as a cleargum.. ID2A= -17' (c=124, CHCI 3 fj-ound (El) M-452A561.

C22H23N 5

F

3 requires MI 452-1559]; e-e. 100% (by !PLC): 8H (CDCI 3 3-02 (2K1 tm), 3-34(3OR 3-65 (111, 3.72 3.94 (2H, 4.00 (1 H, in' 4.13 (1H., dd), 4-24 (21L, 0, 6.80 (2H, d) and 6-96-7-40 (6H. mn).

Proctduj 13 (4S)-4-BeayI.34[2-(2-methoxyethoxy)ethanyI~oxaniidin-2-ae 00 The title compound was prepared from 2-(2-methU ioytzy -chloide by a imthod analogous to that described in Procedaum S. Cbnxnuiogmphy on silica gel 1i, using a gradient of 70-40% diethyl ether in hexane as elitnt afforded the product as a Sum- (C1D~ 25 54w(c 2-70, CHC1) [Found (El) M+ 293.1263. CtSH 19

NO

requibs M* 293-12641: &H (=DC 3 2.81 (11L. 4d), 3.33 U1K dd). 3.41 O3H. 3.63 (2K 3.78 (21M 4-25(21 R in), 4-70 (UL mn), 4.74 (1H. 4.76 (UL1 d) and 7. Newue 14 [3(2S, 31t), 4S-42N23m dya~~u ijpbmyI.3- 0 0 I0 The title compound was prepared fitit (4S)-4-benzyl-3-2mtboxyhoy)ehanylowolidin-2-.on by a nuxod anuiqm o dwha descibed in PIOWW Me cudereatm omeW&Si n Sil=c &I Using a puh.E of 15-401 ethyl =CUM MS tohao.ha affmd the product as a gmn (ciaIiisig2 Iosox raio>993 byIHNN fcz1 0 2 .49Q(e= 1.14., aCH,. (ound (FAB NOBAJNa) MW 590.2472 CuH"NA ruuirs MW -23- 590-25021, 8H (CDC1 3 On'lyrnajor diastee s reoded) 2371 (IH. dd)4 3-25 (111 dcl). 3.31 (3H, s),l 3.35 (311. 3-56 (211 in) 3--r (211. 3-78 (IH. d.

exchanges with D1)0) 3-85-4-00 (4H. 4-2- (2H, 4-31 (IH. 4.89 (111. di).

5-42 (11, 6.83 (2H1. d) and 6-95-7.40 (1 IH. inn) The minor diaStereOisCxnIII thet purified prod=c was identified as the [3(25,3S), 4S1-diastereocis-NIer- Procedure 0 00 [3(2S, 3R). 4S.-3 4 [2[N(2bnoxlyl)-N-e-hym1lcthOX,pIcfl- 3 K;:::hyxy2(2methoxyeoxy)opnoy belZ1Oflibdif- 2 -Ie (0-561ig) was matd with tfichyWLsan for 6-25 hrs in a Inwznmrsimila to that described for Procedure 10- The reactos mixture was dil ut d with wwa (200 niL) and (200 il) and solid sodium bicabonaze was. added cautiously uintil the .pius layer showed pH 6-5- The layers were siau.the aquies layer was exmatd with dichkireth*~e (2 x 300 ruL and the combined fd innoroth slutiors we= wase anh hine (40 viL). dried a&d eaporated. The 20 resduewas ctuumow= We on silica gel uising 35%.tahyl acetat in as=umwafedh iecxpoun&a g=m as a sIngle diuio~ by IHNMR- tgI 0 2=+45(c 139.*Cl 3 );[oud M*(E 573.2473- C3243SN 3 O requires 4 57271 CMC13) 2,76 (1li. dd), 2.9 (2K1 wn). 3-30(OK 3-33(4K 3-40-3.70 (4K i) 1.93 (M11 t) 4.0011K dci) 4.12 (11. dd), 4.22 (2H1.t), 4-52 (lH. mn), 5.31 (IH dd). 619(2K 4) WWd 690-740 pr.dre A4 i~tOyPUUOt 4SI-3-[3-[4-[2-[N-(2-benzoxazoly1)-N-merhylaminolethox-y)phenylj-2-(2- me~thoxycthoxy)propanovl]-4-benzyloxazolidin-2-one was reacted with sodiurn methoxide in a manner analogous to that described in Frocedure-12. The crudepr reaction mixture was chromatographed on silica gel using2% isohemae in diethyl ether as eluent to afford the title compound, a gum. [(x]1D2 1l2' (c 1.26, CHCI 3 (Pound (ED) M+ 428.1974. C 2 8 12N 2 0 6 requires M+ -428.194981; e.e. >99.8% (by HPLC); 8 H (CDC1 3 2.95 (2H. mn), 3.29 O3H, 01- 3.34 3.35 (311, in), 3.69 (411 mn), 3.93 (2H, 4.05 (1 H, dd), 4.23 I and 6.75-7.40 (8H, mn).

A J 7A w- DEMONSTRATION OF EFFICACY OF COMPOUNDS Obese Mice, Oral Glucose Tolerance Test.

C57bll16 obese (ob/ob) mice were fed on powdered oxoid diet. After at least one week, the mice continued on a powdered oxoid diet or were fed powered oxoid diet containing the test compound. After 8 days on dhe supplemented diet afl of the mice wat fasted for 5 hours prior to receiving an oral load of glucose (3glkg). 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 ame under the blood glucose curve where test compound treated groups are compared with the control group. 8 mice. were used for each teatment-

-A

Table Example Level in diet (gimol. kg1 of diet) 0.3 0.3 Reduction in area under blood glucose curve 24 24 S. SS.4 Effects on packed red cell volume and, heart weight: These were determined after repeat oral administration, of compound (once daily at a dose of3 junol/kg body wtfor 14 days, by gavage)to female Sprague- Dawley ram for 14 days. Changes shown ame parcerna changes hm control Staitcal co6adrsons wern made by Studet t test for non-paired damna *p<0t.05, **p<.0D1 versus, conmols. No effect no significan differene from control group. Results were oboaned from 8 rats per treannent group.

Compound H1408t weigt Packed cell volume reduction) SEx-ampk e

I

2 No effct No effect No effect 1.: -26A Throughiout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comnprises" and "comprisi'3g", will be understood to imply the inclusion of a stated integer or step or group of integers Or steps but not the exclusion of any other integer or step or group Of integer Or steps.

.4

Claims (5)

1. 2-beinzoxazoIyI or 2-pyridyl and R 1 represents CH20CH3or CF 3 2. A compound according to claim 1, whertin R 0 represents 2-benzoxazolYl.
2. 3. A c Iompound according to claim I or claim 2, wherein R 1 represents CF 3 15 4. A compound according to claim 1 being: ethoky)propanoic acid;or u1ifluoroethoxy)propaloic acid-, or a pharmaceutically acceptable salt thereof. andlar a pharmaceuticallY acceptable solvatc thereof. A compound according to any one of claims 1 to 4, whnpeetin admixtur less than 50% Wwo encronz A compond according to any one of claims I to 5. when 90- 100% optically pure.
3. 7. A copund according to any one of claimsI1 to 6. in optically pure form.
4. 8- A procesSfor tin~ preparation of a, compound of formula or a pharmaceuticallY acceptable salt thereof, and/or a pharmaceutically acceptable hydmae thereof, which procss cotprises: V.3, 4w hydroysifig a compound of formula
5. 627- 0 CH 2 H NOCH' 2 R where Iin RO and R 1 are as defined in relation to formula JI) and L 1 represents a hydrolysable group; or resolving a raceinic compound Or formula (VII): 1 C01H OCH 2 R whemnR and RI areas5 defined in relatioInt bml(1;adi required, preparing a pharmactutica'llY acceptable ato h opudo oml I 10 and/Ior a pharmfaceutically acceptable solvate thereof. 9. Aphariaclinal cmp~itio copriing a compound of formula (1) acconding to claimIoap5IcCfCY Ptbeal erfoa phurmaceutically accpmtl solvate thexef. and a phETDa~tliCUlY accptable therefor. 1. A method for the utumft and/ar prophlaxis ot hyprgyvaC3Xfl& in a human or non-human maIMmal which corises amittn nefc'.nntxc amount of a compound of the geeifrua(),o hmcuiclYacpal WE therof AlWdr AphaDaeucllYcepale sovathcf. .ahprlcei human or now-huWmf mamimal innedteof 1. A method for the vunnet of hyperlipidaeufla, hypertension. cardiovSCUI2Y diSease certasi ng ditdes 6Ci UtMmet and/or prophylami of renal discase the prevention. =vetSaL, stabilisazion, orretardati of the progressoflof niau~bW~ii~i~o abumifluria in. a human Or non-human marmaL which comprimesadministering an efective, non-toxic, amount of a compound of formula ()or a pharmaceutically acceptable salt. thcreof andor. a PharinaceuticllY acceptable Solvate thereof, toa human or non-huUm an amal in need thereof. 12. ~onpaid f fmiua-(),r jphM c ally adc tabe Wal theeof' wd~ora phiiti~e~i ailY a eptbesolvate thereof, for useas an Active therapeutic sibsWL 29- 13. A compound of formula or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable Solvat~e thereof, for use in the treatment of and/or prophylaxis of hyperglycaemia. hyperlipidaernia, hypertension, cardiovascular disease, certain eating disorders, the treatment and/or prophylaxis of renal disease and/or the prevention, reversal, stabilisation or retardation of the progression of microalbumnifuria. to albuminuria. 14. The use of a compound of formula or a pharmaceutically acceptable salt thereof,- and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a muedicament for the treatment andor prophylaxis of hyperlipidaemia, hypertension, cardiovascular disease or certain eating disorders, the prophylaxis of renal disease and/or the prevention, reversal, stabilisation or retardation of the progression of microalbuminitria to albuminuria. 15. An intermediate compound of formula (11) or (11l). DATED this. eighth day of January 1999 SinithKlin Beecham p~lc. By its Patent Attorneys DAVIES COLLISON CAVE