CA2196079A1

CA2196079A1 - Benzoxazoles and pyridine derivatives useful in the treatment of the type ii diabetes

Info

Publication number: CA2196079A1
Application number: CA002196079A
Authority: CA
Inventors: David Haigh; Harshad Kantilal Rami
Original assignee: Individual
Current assignee: SmithKline Beecham Ltd
Priority date: 1994-07-29
Filing date: 1995-07-28
Publication date: 1996-02-15
Also published as: NO970373L; HUT76637A; IL114759A; MA23632A1; WO1996004260A1; BR9508468A; NO970373D0; OA10470A; DZ1916A1; PL318766A1; IL125525A0; NO307827B1; FI970357A; SK12297A3; AP776A; FI970357A0; MX9700763A; IL114759A0; EP0772605A1; AP9700918A0

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein Ro represents 2-benzoxazolyl or 2-pyridyl and R1 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

~ WO 9C1042C0 ~ 2 ! 9 ~ 0 7 ~ " ~n~n~8 BENZOXAZOLES AND PYRIDINE DERIVATIVES USEFUL IN THE TREATMENT OF THE TYPE II

This invenfion relates to certain novel c~ u ~ , to a process for preparing such .~ .u k to~ il ,.1 c ~ c containing such ~u~ u~ and to the use of such c~ u~ and '""'l" ~ in medicine.
r.. ,.. " , ;..., 1 Patent ~rrlir~rir,n Publication Number WO 94/01420 disclosesc (., . ~l~u~ ., ..k of formula (A):

A1-X-(CH2)n~-o-A2-A3-Y.R2 (A) or a I~ lly acceptable salt thereof, and/or a ~ " ;- _lly acceptable solvate thereof, wherein:
Al represents a substituted or ~".~ di aromatic h~,b,lu~_y~lyl group;
A2 represems a benzene ring having three optional, ~ ; n .. ~
15 A3 represents a moiety of formula -(CH2)m-CH(ORI )- wherein R1 represents substituted or ! -~ allcyl, aryl, arallcyl or al~yl~uLu-,yl and m represems an integer in the range of from 1 to 5, or A3 represents a moiety of formula -(CH2)mul-CH=C(OR1 )- wherein R1 and m' are as defined above;
R2 represents oR3 wherein R3 represents hydtogen, alkyl, aryl or arallcyl or R2 20 represents an aromatic h~,t~ ,y~,lyl group or -NR4R5 wherein R4 and R5 each ~ ~r I Iy represent hydrogen, alkyl or aL~yl~,albull~l or R4 and R5 together with the nitrogen atom to which they are attached form a L~,t~ , ring, providing that R2 represcnts an atomatic L~ u~,y~ lyl group only when Y' as defined below represents a bond;
25 X' represents NR' wh~erein R' represents a hydrogen atom, an aLlcyl group, an acyl group, an araLIcyl group wherein the aryl moiety may be substituted or, ' 1, or a substituted o m ~ ' aTyl group;
Y' represents C=O or C=S or a bond providing that Y' represents a bond only whenR2 represents the above mentioned aromatic h~ u~,y~,lyl group; and 30 n' represents an integer in the range of from 2 to 6.
These - - , ' are stated to have in~er alia good blood-glucose lowering activity and are therefore of potential use in the treatrnent and!or prophylaxis of hy~ ;ly~,~.,.ll;a and to be of particular use in the treatment of Type 1I diabetes.
It has now surprisingly been discovered that a particular group of .- ." ~
35 falling within the generic scope of the c~ ." ,1.~ ,.l~ of formula (A) have pani~.ulally good blood-glucose lowering activity combined with frcedom from adverse 1,- ... ~~.1,.~,;. _1 and cardiac effccts. These c..".l,.,",..l~ are therefore considered to hold potential to be of particular use in the treatrnent andlor ~JIU~)IlyldH:l of Ly~ ly~,a~ id and to be of particular use in the treatment of Type 11 diabetes.

I

vvo 96r04260 ' ~ ~ z f 9 ~ o 7 9 r~

These c~ vl.~ are also indicated to be of potential use for the treatment and/or prophylaxis of other diseases including l,yy~ iAr ~ and hyy~ si They are also indicated to be of use in the treatment andro} ~lulJhylA~is of udld;vv~,ulAu disease, especially dLh.,.v~cl.,.v~;s. In addition these ~.,..l,v~ are 5 considered to be useful for treating certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating, such as anorexia nervosa, and disorders associated with over-eating, such as obesisy and anorexia bulimia.
These c. ~ v~ are also indicated to be of of potential use in the treatment 10 and~ror ~lv~hyldA.; . of renal disease, especially renal disease associated with the de~ ,yll..,.n of Type II diabetes including diabetic - . ' vy~dly, glvlll~" u~
glomerular sclerosis, nephrvtic syndrome, LYY~.lL~ n~.yluv~ ,.v~;~ and end stagerenal disease. The ylvyL.~l~u~, acrion of an insulin sensitiser upon r.~,yhlvyAdl.~ is also indicative that an insulin sensitising agent can be expected to prevent, reverse, 15 stabilise or retard the ~)IV~ ;VII of microAIh--min~TiA io Alh~min~ltiA This is because Iffi~ ;A is considered IO be a predictor of future U~ IIIVY-LIIY~
especially in patients with clinical evidence of pre-diabetic insulin resistancesyndrome, alt~,.,l_Li~ y referred to as Syndrome X.
Accordingly, the present invention provides a compound of formula a):
CH3 / ~CO2H
R~ N ~ ,~J H OCH2R

or a ~ y acceptable salt thereof~ and/or a ~ lly acceptable solvate thereof, wherein R~ represents 2-b I~ Iyl or 2-pyridyl and R1 representS25 CH2OCH3 or CF3.
Preferably, R~ represents 2-~ ,. .lyl.
Suitably, Rl represents CH2OCH3.
Preferably, Rl represents CF3.
As indicated above, a compound of formula (I), and the PI~ A11Y
30acceptable salts thereof, may exist in one of several tautomeric forms, all of which are y_~_A by the present invention as individual tautomeric forms or as mixtures thereof.
Suitable pi~ ly acceptable salts include salts of carboxy groups and acid addition salts.
35Suitable l~h A~111=r~.~;1 Ally acceptable salts of carboxy groups include metal salts, such as for example Ahlminillm, alkali metal salts such as lithium, sodium or potassium, aLcaline earth metal salts such as -calcium om~ and Annm~minm -- 2 -- . . ~

_ _ _,, _ .. .... ....... .. ... .... ... .... ... . . . ..

~ WO 96/a4260 ~ .2; l 9 6 0 7 9 r~.,~ IA~ ~8 or substituled A 1111111~ salls. for example Ihose wirh lower alkylarnines such as hi.,~hyl~~ " hydroxy alkylarnines such as 2-hy~w~y~,LllyLullill._, bis-(2-l.yd.u~y~..i.yl)amine or tri-(2-hydluA~ ~,.hyl)arnine, cycloalkylamines such as bi~y~,lOll~,~.ylal~ c, or with procaine, dil~ yl~ ;,lh.f, 5 N-benzyl-13-1,l,~,..~,l.~d~.l h.." d~,Ly~Lual);~yldlll~c~ N,N'-bisdehy.Lu~.l.;e.ykul,il....
glucamine, N-ll.cl. yl~;lu,,~llill., or bases of the pyridine t-ypc such as pyridine, collidine, quinine or quinoline.
Suitable acid addiion salts include 1~! - . ., C . . i. Ally acceptable inorganic salts such as the sulphatc, nitrau, phosphate, borate, hydrochloride and Ly~L ul~lu~ilc and, 10 where fcasible, l~h ",,,~ Ally acceptable organic acid addition salts such asacetale, tartrate, malcate, citrate, succinate, benzoau, ascorbate, m~rhqn~s~l~rhfmqt-c~-keto glutarate and iX-~IY~
Suitable ~ y acceptabie solvates include hydrates.
The salts and/or solvates of the ~ .uu",lc of formula (I) may be prcparcd 15 and isolatcd according lo Cull~ iu~ l procedures, for exarnple sodium salts may be preparcd by using sodium methoxide in methanol, ~
In a further aspecl the present invention also provides a process for the ;. . of a compound of formula a). or a l~h ". ~ ly accepuble salt thereof, andlor a l.h . . . = ~ 1 i A lly accepuble hydrau thereof, which process 20 comprises hy l~vly ;.h.g a compound of formula (II):

R~ N ~O

wherein R~ and Rl are as defined in relation to formula (I) and Ll represents a 25 hydrolysable group; and thereafter, if requircd, preparing a 1~ iy accepuble salt of the compound of formula (I) andlor a p 1 -, . . ~ ~ " ;. Aliy accepuble solvate thereof.
A suitable hydluly~llJlc group Ll is a group of formula (a) or an epimer t_ereof:
1~
'-, Ph N ~OH
= ~i (a) A suiuble hydrolysable group Ll is an Evans chrral auxillary, for example a group of formula (b) or an epimer Ihereof:

2 ' ~; !i '2;1 '9 6 0 7 9 F~ '030~8 N C

CH2Ph (b) A suitable hydlvly~ablc group Ll is a C1 6 allcoxy group.
The hydrolysis of the compound of fommula (II) is carried out using conditions ayl~v~l;a~ for hydrolysing the particular group Ll chosen, for example when Ll is a group of formula (a) or a C1 6 alkoxy group, the hydrolysis is suitably carried out under acwdic conditions, for example using dilute sulphuric acid, cv~ ,.lLly in a diu~àll mixture, for example a 1:1 mixture, at any t ~ which provides a suitable rate of formation of the required product, generally at an elevated r ' '1" ~ ', . . r, such as in the range of from 50~C to 120~C, for example 90~C; or when Ll is a group of formula (b) the hydrolysis is generally carried out using lithium Lydlv~JwuAidc in an aqueous solvent, such as aqueous tetrahydrofuran, at any which provides a suitable ratc of formation of the required product, generally at a reduced tCl~ L~ such as in the range of from -10~C to 0~C, for example 0~C Altematively, when Ll is a group of formula (b) the hydrolysis may be effected under basic conditions, using for example aqueous sodium hydroxide, in an a~lVJ~ , solvent such as aqueous t~ yd~ ~ usually at ambient ~---r _ .
A compound of formula (II), wherein Ll is a moiety of the above defined formula (a) or (b), may be prepated from a compound of formula (III):

R~ N--O~/~coL2 wherein R~ and R l are as defined in relation to fommula (I) and L2 represents aleaving group; (i) for c~ 'l v~ lc of formula (II) wherein Ll is a moiety of the above defined formula (a), by reacnon with (S)-phenylglycinol; or (ii) for .. ,. ,l.o~ k of formula (II) wherein Ll is a moiety of the above defined fommula (b), by reaction with (S)-4-benzylu~àLulidi---2-one, preferably an activated 30 form thereof; and thereafter separating the required isomer from the mixture of diai~L~lcu;sul~ produced.
A suitable leaving group L2 is a halogen atom, for example a chlorine atom.

~ WO 96/04260 2 1 9 6 0 7 9 F~ n~8 i S
The reaction between the . I~ u -I'k of formula (III) and (S)-phenylglycinol may be carried OUt under l,UII ~ ~.vl.al amidation conditions, for cxample in an inert solventsuchasrlirhl..,..,.,. ;I.r,.r ataL,.,~ rwhichprovidesasuitablerateof formation of the required product, suitably at ambient LUllly~,l c Lul r and preferably in S the presence of a base such as n i.,.hylcul.;.ic.
A suitable activated form of (S)~L-benzyloxazolidin-2-one is a salted form, for example an alkali metal salted form, preferably a lithium salt.
The activatcd form of (S) 3~L-iJ~,~IL.y' ' ' -2-one may be prepared by any appropiate ~ v.,~l iu~al mcthod. Thus when the activated form is a lithium salt, it 10 may be prepared by treating (S) 4-b~ Lylu~c Luli li..-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 ..,~r.y.l.ofu cu" usually at a low [~.lly.,lO.LUlC, for example in the range of from -78~ to 0~C.
The reaction between the compound of formula (III) and the activated form of 15 (SJ 1-b.,r.Lyl~ -2-one may be carried out in an aprotic solvent, such as tetrahydlurul,~,., at a La~ "a~uu~ which provides a suitable rate of formation of the required product, cu~ Lly by allowing the reaction mixture to slowly warm from -78~ to 0~C
Preferably, the activatcd form of (S)4-l~llAylu~clLoliLu-2-one is prepared 20 and then reacted in-siru with the compound of formula (III).
A compound of formula (III) may be prepared by hydrolysing the carboxylic ester COOR2 of a compound of formula (IV):

- CH3 ~,Co.oR2 R~ N J~ OCH2R' (IV) wherein R~ and R l are as defined in relation to forrnula (I) and R2 represents an aLlcyl group, and thereafter converting the carboxylic acid group so formed into a moiely Co-L2~

A suitable alkyl group R2 is a C1 6 alkyl group, especially a methyl group.
The hydrolysis of the carboxylic ester may be effected by use of any ~,UII~ du~cl hydrolysing agent, such as an alkaline metal hydroxide, for examplesodium hydroxide.
The hydrolysis of the compound of forrnula (IV) may be carried out in any suitable solvent such as a methanol/water mixture, UU~ l8,udy a 1:1 mixture, at a L.~llly~ UI~ which provides a suitable rate of formation of the required product, suitably at an elevated t~ -y~ Lule and conveniently at the reflux L~llly-,lclLulc of the solvent.

Wo 96/04260 ~ S r~~ 8 ~
~1 9~,~79 The conversion of the carboxylic acid group into the moiety CO.L2 may be carried oul using any appropiate conventional procedure, depending upon the particular nature of the group L2 chosen, thus when L2 is a halogen a suitable procedure involves treatment of the carboxylic acid with an oxalyl halide, for 5 example oxalyl chloride when L2 is chlorine.
The reaction conditions for the conversion of the carboxylic acid group into the moiety CO.L2 will be dictated by the particular nature of L2 and the source of L2 chosen, for example when L2 is halogen and the source of L2 is oxalyl chloride then the reaction may be carried out in an inert solvent such as di~,Llu~u~ , or 10 benzene at a ti~Lu~ uuC which provides a suitable rate of formation of the required product, suitably at ambient r. ., 1~ . c. or at an elevated Li,~ Ji"~llillC such as the reflux t, ..,~ I,..,e of the solvent.
It will be appreciated that the ~c~ Liuu and separaion of a compound of formula ~II) wherein Ll is an epimer of the above defined moiety (a) or (b) and its 15 subsequent hydrolysis to afford a compound of formula (I) can be achieved by employing analogous methods to those described above for the 1~ c ~
separation and hydrolysis of a compound of formula (II) wherein Ll represents the above defined moiety (a) or (b).
A compound of formula ~II) wherein Ll is a moiety of formula (b) may also 20 be prepared by dchyiLur.yklLiull of a compound of formula (V):
QH o fH3 ,~J ~ lX
R~ N o OCHzR1 ~ V) wherein R~ and Rl are as defined in relatiûn to formula (I) and X is a moiety of the 25 above defined formula ,'b).
The d~ hydlu~yl~Liull of the compound of formula (V) is conveniently catTied out by treatment with a trialkylsilane, for example triethylsilane, preferably in the presence of uilluulua~ , acid and Cu~ -,ly using uinuulu~i, iu acid as solvent, at any t~ mlG providing a suitable rate of r...,.. ~ of the product, for 30 example at a ~cllly~ Lu~c in the range from 0~C to room L~ aiulc.
It will be appreciated that a compound of formula (Il) wherein L I is a moiety of formula (b) would also be obtained by dcLyil~ u~yl~fiuu of a compound of formula ~V) in which the hydroxy bearing ati-.ao~ .nlc is erim~rici~A
A compound of formula (V) may be prepared by reacting a compound of 35 formula (VIA):

~ WO 96/(14260 , ~ .. .2 1 9 6 ~ 7 9 rc"~

~' I H, ~C~O (VIA) wherein R~ is as defined in relation to formula (I), with a compound of formula (VIB):
O O

R'CH20 1"'' Ph (VIB) wherein Rl is as defined in relation to formula (I); and thereafter separating the 10 required isomer from the mixture of diaat~.lcuisu~ a 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 of formula (VIB) with an aLlcylboron triflate, for example dibutylboron triflate, preferably in the presence of an amine base such as ui~.J~yl~lf.,~e.
lS The activated form of thc compound of formula (VIB) may be prepared by the ay~)lU~ , CUII ~ iUll~d method depending upon the specific nature of the activated form chosen, for example the compound of formula (VIB) is reacted with ylbulull triflate and Lfi~,Lllykull..~., in an inert solvent such as dichlulu~ .Lllallc at a t~ .laullc in the range of from -78~ to 0~C
The reaction between the f , ' of formulae (VL~) and (VIB) may be carried out in an in an inert solvem such as dichlulu~ llallc. at a t' ~ "I'' ~ Alll r: which provides a suiuble rate of formation of the required product, cull~,.li.,l..ly by allowing the reaction mixture to slowly warm from -78~ to 0~C
Preferably, the activa~ed form of the compound of formula (VIB) is prepared 25 and then reacted in-situ with the compound of formula (VIA).
For ~ v ~-7~ of formula a) wherein R~ represents 2-b., ,- ~ yl, a suiuble compound of formula (VL~) is 4-[2-[N-(2-1..,,. ,. ,. " ,1yl)-N-illo]~Lllu~y]l~llL~ ly~le~
A suitable means for separating any required single isomer from a mixmre of 30 .11~ u,.. :, is clll ulllaLu~la~hy~ such as preparanve high pressure liquid cl~ y or silica gel column ~ y.

wo 96/04260 ' 21 q607q ~
One convenient method for preparing a compound of formula (II) wherein Ll is a C1 6 alkoxy group is the basic alcoholysis of a compound of formula (II~ wherein L1 is a moiety of formula (b).
A suitable base is an alkali metal alkoxide, for example when Ll is methoxy 5 the compound of formula (II) wherein Ll is moiety (b) is treated with sodium methoxide in methanol.
A compound of formula (I) may also be prepared by resolving a racemic compound of formula (VII):

CH3 1~ CO2H

R~ N J~ OCH2R' (VII) wherein R~ and Rl are as defined in relation to fommula (I); and thereafter, if required, preparing a ~ Ally acceptable salt of the compound of formula (I) and/or a l~ y acceptable solvate thereof.
The resolution of a compound of formula (VII) may be carried out using 15 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 ~ r ~ C~ R I salts which may then be separated by fractional crystallisation and thereafter the compound of formula (I) may be ~c~ cd from the separated ~'' CU;;rUIII~,l salt by cu--~.,--Lional means, such as hydrolysis.
It will be _~I lc.,;_Lcd that the .~ of formula (VII) comprise the ~"..,l.u k of formula (I) admixed with other optical isomers. A compound of formula (Vll) or a ~ . " ;. Ally acceptable salt thereof and/or a pl ~ A " " ~., ~ ;. Ally acceptable solvate thereof, forms a further aspect of the present invention. Theseparated isomers of the ~" .,l .,u ~ of formula (Vll), in addition to the ~ "l u of formula (l), or a l,l .A, - " ~ y acceptable salt thereof andlor a ~ ly acceptable solvate thereof, also comprise the present invention.
Suitable acids or bases for resolving the . . " "l,u ,.i~ of formula (VII) are as described in F,. - .. ;.,.. , Racemates and R-sol~tinn J Jaques et al, 1981, Wiley T, ~ especially at pages 255 and 256. Suitable methods for effecting the 30 resolution are also disclosed by Jaques et al.
The c~ ,l,u .l.1~ of formula (Il) and (III) form a further aspect of the present invention.
The c~ .. . ,l,uu.lli~ of formula (IV) and (VIA), for example 4-[2-[N-(2-b- .~ l)-N-methylamino]ethoxy]benzaldehyde~ are known c"" ~I~UU ..1~ or they 35 may be prepared using methods analogous to those used to prepare known I.u~ , for example those disclosed in Tnr~tnAfit~n:ll patent Application~
Publicarion Number WO94/01420.

~ WO 9C/04260 fr ~ 6 ~ 7 9 r~ r~8 Tbe ~ J"'~ of formula (VIB) are known cu~u~uu~d~ or they may be preparcd using methods analogous to those used to prepare known c~ .u ~ for example those disclosed in Organic Synthesis Vol. 68. p83, 1990 Ed. J.D. White or methodsanalogousthereto,in...~,,,l,;,,AI;ouwith.u..~ Liu~.dl~ l.ofl~kl~;yforthe 5 l~lCy~LLdLiUII of acid chlorides.
It will be a~lc ' that in any of the abu~ reactions any reactive group in the substrate molecule may be protected, according to cv,.~,,,Lio.~l chemical practdce. Suitab!e protecting groups in any of the abu.~ -1 reacions are those uscd cu,.~. '1y in the art. The methods of formaion and removal of such 10 prvtecting groups arc those coll~,.lLivndl methods ay~lu~ c to the molecule being protected.
,t will be aprreri~trd that the above mentione~ ,pf IdLiwl of the . ~ ., . .l,v k of formula a?, or a pl ,A . ", - c ~ y acceptable salt thereof andlor a ~ lly acceptable solvate thereof, is a ~c cos~lc~livc procedure and that the compound of 15 formula (I) is a single ~ Gf . ~- ., The present invenion also includes a compound of fvrmula (I) when present in admixture with less than 50% w/w of its racemic isomer, that is when it is greater than 50r~c opically pure, suitably 80-100% and prefcrably 90~100% pure, such as 90-95~o, mostpreferably 95-100%, forexample 9~%. 9697c, 97%, 98%, 99ric or 99.9% optically pure.
In one preferred aspect there is provided a compound of formula (I) or a ly acceptable salt thereof and/or a l'~ - . " . -- ~ . ,1 i. Ally acceptable solvate thereof, in optically pure form.
The absolute, ~ co I ~ ~ Y of ~.v~ u ,.k may be ~l~t~nin~ d using cvllY~llLiulldl methods, such as X-ray .,.y~Lallo~ .L,}.y.
As menioncd above the ru .. l.v .. 1~ of the invention are indicated as having useful therapcuic properies: l he present invenion a.,. u~ gly provides a compound of formula a)~ or a ~ A ~ ly acceptable salt thercof andlor a l~h~ -lly acceptable solvate thereof, for use as an active therapeutic substance.
Thus the present invenion provides a compound of formula (I), or a l ' 'Iy acceptable 5alt thereof and/or a ~ y acceptable solvate tbereof, for use in the treatment of and/or ~!~u~h,~ IdA is of hy~,l~l.yL,~
In a further aspect the present invention also provides a compound of formula a), or a ~ - c ~ Ally accep~able salt thereof and/or a p~ y acceptable solvate thereof, for use in the Ireatment and/or ~lul~h.yld~Lis of hyp. .1;l~
As indica~ed h~ch~b'_l'u~c the prcsent invention also provides a compound of formula (I) or a r~ l Ally acceptable salt thereof andlor a ~ il Ally acceptable solvate thereof for use in the trcatment of l~y~ ;un. uclLliuv~.ul disease, certain eating disorders and/or the trearment and/or ~u~hyldAis of renal disease.
g ..

WO 96104260 ~ . J~ q 6 ~ 7 9 P~ /Q3n~8 In addition, ~he present inven~ion also provides a compound of formula (I) or apl - "~ lly acceptable saltthereofand/ora ph~rm~relltir~lly acceptable solvate thereof, for use in the prevention, reversal, 5tAhili~Atit~n or retardation of the ~IV~ aiull of micrnAlh..mim.TiA to Alhumin~riA
S Cardiovascular disease includes in patticular ~Lh~,~u~ usis.
Certain eating disorders include in particular the regulation of appeùte and food intake in subjects suffering frvm disorders associated with under-eating ,such as anorexia nervosa, and disorders associated with over-eating, such as obesity andanorexia bulimia.
Renal disease includes renal disease associated with the du~.,lv~lll.,u~ of TypeIl diabetes including diabetic n~ V~LhY~ ~:IUIII~ glomerular sclerosis, nephroic syndrome, Ly~ L~.u~;ve U~.~JIIIU~UI~dU~;~ and end stage renal disease.
A compound of formula (I), or a r' ~ y acceptable salt thereof and/or a p~ . " ;. A11Y acceptable solvate thereof, may be a.llu;.,i~u. ~d pç~ se O}, preferably,asa~ c~ o~ alsocomprisingap~AulllA~ ly acceptable carrier.
Accordingly, the present invention also provides a PhA~ l ;r Al comprising a compound of the general formula (I), or a PhA~ 11y acceptable salt thereof, ora l~h ", ~ .";. ~lly acceptable solvate thereof, and a ~ ;. Ally acceptable callier therefor As used herein the term l~lhA~ _lly acceptable' embraces .~ 'U ~
c~ r~ and ingredients for both human and veterinary use: for example the term ~ ,./1;. Aily acceptable salt' embraces a veterinatily acceptable salt.
The Cv~ u~ihivll may, if desired, be in the form of a pack ~ . ' J by 25 written or printed hl~hul,hvll~ for use.
Usually the 1~ ,,d. Al ~ of the present invention will be adapted for oral A~ although .. ~ lV~ for adulill;~u~uiull by other routes, such as by injection and ~,luuL~ulCvu~ absorption are also envisaged.
PAu huulAuly suitable e- - ~ ;r..~ for oral Al h . l; l l; '~ are unit dosage forms such as tablets and capsules. Other fixcd unit dosage forms, such as powders presented in sachets, may also be used.
In ArcrTrlAnre with conventional l~h~ ;I A1 practice the catTier may comprise a diluent, filler, I1;~ wetting agent, lubricant, colourant, flavourantor other uu~ lduual adjuvant.
Typical carTiers include, for example, lu;wuuly~Ldlline cellulose, starch, sodium starch glycollate, polyvinyl~y.lulidunc, polyvi.,yll,oly~,ylluli.lu..e, IIIAL~II. - 1~1 stearate or sodium lauryl sulphate - lû -~ WO96/04260 ~ 1 21~9~ 60 ~C~ 7C)~n~

~ ost suitably the - - ", ~ ,,; l ;un will be formulated in unit dose fotm. Such unit dose will normally conrain an. amount of the active ing~dient in the ran~e of from 0.1 to 1000 mg, more usually 0.1 lo 500 mg, and more especially 0.1 lo 250 mg.
The presenl invention further provides a method for the treatmenl and/or S IJ~u~hyl~i~ of ily~ ;lyl.~ ;a in a human or non-human mammal which comprises e an effectiYe, non-loxic, amounl of a compound of the general formula a), or a r~ - . . . - ~ ... ;. Ally acceprable sall thereof and/or a ~ lly acceptable solvale thereof to a hy~ Iyu~ llic human or non-human mammal in need thereof.
- The present invention further provides a method for the treatment of10 Ly~ hyp.,l;c,nsiun, ~d;VV~UI-AU disease, certain eating disorders, the ~eatment andlor ~lupllyl~i~ of renal disease and/or the prevention, reversal, ct~hili~tinn or retardation of the ~-U~ iUII of microAihllminmi A to Ail . . 1 , ; A in a human or non-human mammal, which comprises a.i...;.,;~.. . ;,le an effective, non-loxic, amount of a compound of formula (1), or a l/l IA I . n ~ ~ ., . ;. nl ly acceptable 15 salt thereof and/or a 11~ ., .- ~ ;, Ally acceptable solvale thereof, lo a human or non-human mammal in need thereof.
Cv~v.,l~ dy, the active ingredienl may be A.l....;~ cd as a 1~l - ... - c..1;. ,.1 c~ n .... 1.. ~ ,. r, .. ~ defined, and this forms a particular aspect of the presem invenion.
In the treatment and/or IJIUI!hYI~;S of hY~ ;IY~ ;C humans, andlor the trearment and/or ~u~hyl~i~ of l-y~- 1;1-;-1- ...:- human, the compound of the general formula a). or a l~h - ... - ;. AIly acceptable salt thereof andlor a 1.l - ", ~ Ally acceptable solvate thereof, may be taken in doses, such as those described above, one to six imes a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about I to 1500 mg.
In the treatment andlor l~lu~Lyl~is of L~ ;ly~ uc nv.. ~lm~n mammals, especially dogs, the acive ingredient may be a L~ ,l~ 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,30 for example 0.1 mglkg to 20 mg/kg. Similar dosage regimens are suitable for the treatment and/or ~lu~h,~l~is of hy~ ., ,A in non-human mammal5.
The dosaees rcgimens for the rreatment of LJP~I tUII~ II, u~udiuv~uular disease and eating disorders hy~,l L~ ivll, u~ud;v v~ .uLu disease, certain eating disorders, the ~reatment and!or ~lu~Jhykud~ of renal disease andlor the prevention, 35 reversal, 5ts~ n or retardaion of the L~lu~ a~;ull of lldul..All ., ... ,; . " ;A to l.. u .;.. ;A will generally be those mentioned above in relation to Ly~ ;ly~ lia In a further aspect the presem invention provides the use of a compound of formula (l), or a ~ AIly acceptable salt thcreof andlor a l.~ c~ ly WO 96104260 ~ r / ~

acceptable solvate ehereof, for the .,ld,,ur;~u. ~ of a ~ , .1 for the rreatment and/orl~lV~ yl~ isoflly~ ly~,a~ ;d.
The present invention also provides the use of a compound of formula (1), or a ;. lly acceptable salt thereof, and/or a pk~, " - ~ ., ;. ~lly acceptable solvate S thereof, for the lllal~.LI,~ulc of a ~ for the treatment and/or lJIu~ullyld~ of y~ , lly~ iull~ cardiovascular disease or certain eating disorders and/or the l)-viuhylo~is of renal disease and/or in the prevention, reversal, 5t~hilic~it)n or retardation of the ~IU~ ;vn of micrn~lhumirnt i~ to ~llhlln~inllti ~
No 1. ,,; ~k~ effects have been established for a compound of formula (I) 10 or a l~l - n~ lly acceptable salt thereof and/or a P~ y acceptable solvate thereof, in the àln~ ~ . .. I l. . . I ;~1~1. A dosage ranges.
The following Procedures and Examples illustrate the invention but do not limit it in any way.
-~ W096/04260 ~ ' ~ ' 2'1 96Q79 r~ l cr~8 Example 1 (S)-3-[4-[2-[N-(2 Bc.. ~v~ N ' y' -]ethoxy]phenyl]-2-(2-methoxy-ethoxy),u. ~, acid ~CH3 ~CO2H

1~ \~N o O--OCH3 A solution of [2S, N(l S)]-3-[4-[2-[N-(2-b~ u~c~ulyl)-N-~ lylall~ o]ethoxy]-phenyl]-2-(2-1..~,.hu,~ hw~y)-N-(2-hydroxy-1-phenylethyl)l . u~/dll~llilC ( 1.846 g) in a mixture of IM sulphuric acid (45 mL) and dioxan/water ( 1:1, 150 mL) was heated at 90~C for 56 hours and then the pH of the mixture was adjusted to pH 3 by addltion of aqueous sodium hydrogen carbonate. The mixture was extractcd with ethyl acetate and the organic extracts washed with water, brine, dried (MgSO4) and evaporated to give an oil. ru~;r~ca~iull by ~,hlulllaLu~;~c~;ly on silica gel using a gradient of 1-5~o methanol in dichl.J.u...~iLdllc as eluent gave a foam of 88(~o e.e. (by HPLC). The 15 product was reacted with (S)-o-methylbenzylamine in acetone, and the resulting salt recrystallised several times from ethyl ac~.La~e-h~,,.cllc before being dissolved rn water, acidified with dilute hy~u~,lllvlic acid and extracted with ethyl acetate which was dried witn MgSO4. Eva~ulaLiull of the ethyl acetate solution afforded 1.... ;- Ally enriched title compound; [o]D25 -28~ (c=0.625, CHcl3); e.e 94%
(byHPLC); [FoundM+414.1791. C22H26N206requiresM+ 4141791]; IHNMR
spectrum identical with that describcd in Example 5.

Example 2 (S)-3-[4-[i-[N-(2-1~ -]ethoxy]phenyl]-2-(2,2,2-l~ y),u. 3,. ' - acid by hydrolysis of amide CH3 ~CO2H

~CO>-- oJ~ OCH2CF3 [2S, N(IS)]-3-[4-[2-[N-(2-13. ~ yl)-N-~.,.hyldl~ o]ethoxy]phenyl]-2-(2,2,2-Lill~u~u~"hu~.y)-N-(2-hydroxy- I-phenylethyl)~.u,ud,lO.llide (from Procedure 3) was hydrolysed by an analogous procedure to that described in Example 1 ru~ir~cdlio~by .,1"l ~, , ' y on silica gel using a radient of 0-5% methanol in L~,Llululll~L~lle as eluent gave the title compound, mp 116-7~C, after trituration with diethyl ether-hexane; [o~]D25 -24 6~ (c--0.24, CHcl3); e e 95% (by HPLC) [Found C, 57.9; H, 4 7; N, 6 8%; M+ 438 1403 C21H21F3N2Os requires C, 575; H, 1~ .

:

W096/04260 ~ J? .~1 96079 P~ ~ml8 4.8; N, 6.4%; M+ 438.1403]; ~iH (DMSO-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).

5 Example 3 (5)-3-[4-[2-[N-(2-B~..Lu,~Lul,~l)-N-methylamino]ethoxy]phenyl-2-(2,2,2-Acid, by Direct Hydrolysis of the Imide ~ N\~ ~ J ~COzH

10 Aqueous sodium hydroxide solution (2.5M, 65 mL, 0.163 mol, 2.3 eq) was added to a stirred solution of r3(2S), 45~J-3-[3-[4-[2-[N-(2-1~ ,lyl)-N-yl~ ]ethoxy]phenyl]-2-(2~2~2-llinuulu~llu~y)propanoyl]-4-~llLy~ n-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 reacion was diluted with water (1 L) and extractcd with .1,. l,1.. ,~ (3 x 700 mL). These diul~lu~u~ , solutions were evaporated and the residue purificd by ~,IL~ o . ~ y on silica gel using 5% methanol in ~ .hlu~u~ nc as eluent to afford (5)-4-b.,~Lylu~ Lulhlill-2-one. The original aqueous solution was acidified to pH 3.5 with dilute h~u~,hlu ic acid and re-extracted with dh,lllulu~ ,dlalle (3 x 700 20 mL). The diulllululll~ , solutions from the acid extraction were dried (MgSO4) ard evaporated to give a solid. This was recrystallised from dichlulull.~,d.l.e-diethyl ether to afford ~he title compound, mp 119.5-120.5~C. [~]D25 = -31~ (c = 2.50, CHC13); e.e. 99.69ro (by HPLC); [Found C, 57.7; H, 4.7; N, 6.25%; M+ (EI) 438.1412. C21H21F3N205 requires C, 57.5; H, 4.8; N, 6.4%; M+ 438.1403]; ~H
(CDC13) 3.û5 (lH, dd), 3.13 (lH, dd), 3.31 (3H, s), 3.72 (lH, m), 3.89 (2H, m), 4.04-4.14 (3H, m), 4.21 (lH, dd), 6.78 (2H, d), 7.03-7.40 (6H, m) and 11.20 (lH, br, exchanges with D2O); OF (DMSO-d6) = -72.7 (3F, t, 3J~F 9.3 Hz, CF3).

Example 4~0 (S)-3-[4-[2-[N-(2-F..- -~ rl)-N ' .' - -]ethoxy]phenyl-2-(2,2,2-tri-Acid by Hydrolysis of Methyl Ester ~ N CHJ ~

A mixture of (S)-methyl 3-[4-[2-[N-(2-l~ u~ ulyl)-N-1ll~,.L~Lul.;-.o]ethoxy]phenyl]-2-(2,2,2-~inuu.u,,lllo~y)l~-upa--o~;~ (1.256 g, 2.8 x 10-3 ~ Wo 96/042C0 '~ 6 0 7 9 - mol), aqueous hydrochloric acid (2.0M, 50 mL) and dioxan (50 mL) was heated at reflux for 7 hours, cooled and c~- ' in vacuo. The residue was suspended inbrine (200 mL) and extracted with ethyl acetate (3 x 300 mL). The combined ethylacetate solutions were dried (MgSO4) and evaporated to afford a waxy solid. This5 solid was triturated ~ith hexane, filtered and dried under vacuum at 65~C to afford the desired product, mp 113-5~C [a]D25 = -32~ (c = 1.02, CHU3); e.e. 99.4% (by ~'LC); [Found C, 57.25; H, 4.8; N, 6.3~o. C~IH2lF3N~Os requires C, 51.5; H, 4.8;N, 6.4%]. The IH NMR spectrum of this material was idenical to that produced in Example 3.
' -Example S
(5)-3-[4-[2-[N-(2~ ' ' ]ethoxy]phenyl-2-(2-Acid ~CN\>_, ~ ,~OCOH2CH,OM-(S)-Methyl 3-[4-[2-[N-(2-b ~ yl)-N-~.,.hyl~llf~o]ethoxy]phenyl]-2-(2-.Lhu~ llu~y)~lu~lO..;~, was hydrolysed in a manner analogous to that described for Example 4. The crude reaction mixture was ~,L-, ,, , ' - ' on silica gel using 5% methanol in L~,hlu~u~ c as eluent to afford the title compound, a gum.
[a]D25 = -27~ (c = 0.73, CHC13); e.e. 99.8% (by HPLC); [Found M+ (EI) 414.1779.
C22H26N206 requires M+ 414.1791]; ~H (CDCl3) 2.90 (lH, dd), 3.15 (lH, dd), 3.33 (3H, s), 3.37 (3H, s), 3.40-3.70 (4H, m), 3.93 (2H, t), 4.05 (IH, dd), 4.21 (2H, t), 6.81 (2H, d) and 6.95-7.40 (6H,m).

.; ~ . - .
~ . i, w096/04260 ~ 2'~ 9 6379 Procedure 1 (i)-3-[4-[2-[N-(2~ N-~ y' -]ethoxy]phenyl]-2-(2-S ' .~. ' y]propanoic acid CH3 /~'/--CO2H

oJ~ --OCH3 A mixture of mcdhyl 3-[4-[2-[N-(2-l.~ yl)-N~ lykullillo~edluAy]~ yl]-2-10 (2-lll~.dlUA~LhUAy)~ (1.08 g, Int. Patenr Appl., P~blicarion No. WO
9401420) and sodium hydroxide (253 mg) in methanol:water (1:1, 10 mL) was heatedunder reflux for 2 hours. After cv ~u. ~ILiUII of the resultant mixture in vac~o, the residue was diluted with water, acidified to pH 5 with 2M hydrochloric acid and dhen extracted with ethyl acetate. Washing of the ethyl acetate extracts with water and 15 drying (MgS04) and cv~ul~Lliun gave the tide compound as an oil which crystallised on trituration with diethyl ~Lh~ n~A~IC [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]; ~H
(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).
Procedure 2 (i)-3-[4-[2-[N-(2-B. .-~ --t~l)-lY ' .~' ~ ~]ethoxy]phenyl]-2-(2-~. ' y)propanoyl chloride @~CN~_ / J~CoCI

Oxalyl chloride (92 mg) was added to (+)-3-[4-[2-[N-(2-1; ,,.~ yl)-N-methyl-amino]~,l,uAy],ull~,,.yl]-2-(2-lll~llloA~lluAy)propanoic acid (100 mg) in di~,hlulu~ lc (2 mL). The mixture was stirred at room L~ Lul~ for 16 hours 30 and evaporated to dryness to give the tide compound as a gum which was used without further ~ 11; . - ~ ;. ..

wo 96/04260 ~ . 3' 'q?n ~
~ ~ - G~ 9 6 a 7 q Procedure 3 [2S, N~lS)]-3-[4-[i-[N-(2-R~ N-mell~ ~ ' - ]ethoxy]phenyl]-2-(2-N-(2-hydrOxy-l r ~1.11. ~I)YI ~

~CH3 ~ H OH

(i)-3-[4-[2-[N-(2-Bci~Lw~lyl)-N~ .llykull;llo]ethoxy]phenyl]-2-(2-methoxy-ethoxy)propanoyl chloride was dissolved in di._hlvlu~ ., (2 rnL) and a mixture of (S)-2-yh~,llyl~,ly~.illol (33 mg) and dry L~i..l~yk~ lc (37 mg) in flirhl~.,l." ~ l, -- .
10 (I mL) added. After stirring for 5 minutes water was added and the mixture extracted with di.,hlv.ui..~,.l.~.c The organic extracts were washed with water, brine, dried (MgSO4) and evaporated. The residue was clu~ y} ~ on silica gel using a gradient of 10-50~o acetone in hexane as eluent to afford firstly [2R, N(lS)]-3-[4-[2-IN-(2-1~ yl)-N-lu~ ulil~o]~ u~y]y~ lyl]-2-(2-~ Lllu~ lv~y)-N-(2 15 hydroxy-l-~ lul~yl)yluyoll~llidc followed by the desired [2S, N(lS)]-l"v~.-.. - ....1r tide compound as a foarn. [Ct]DZ5 -33~ (c=l.l, CHC13); 92.6% d.e. (by HPLC); p:ound M+ 533.2526. C30H3sN3Os requires M+ 533.2526]; ~E~ (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 C2H,m), 3.71 (IH,dd), 3.82 (lH,dd), 3.94 (lH,dd), 3.93 (2H,t), 4.22 (3H t), 5.05(IH,dt), 6.75-7.35 (1 ~Ti"-rlmpl~Y), 7.54 (lH,br, exchanges with D20).

Procedure 4 ~ 3-[4-t2-[N-(2-EI~ l)-N '1.~' ~ s]ethoxy]phenyl]-2-(2,2,2-h ~ , ~ acid ~C~ N--~ J~oc C2OC2H3 Medhyl 3-[4-~2-[N-(2-1~ Y~ Iyl)-N-~ ,dlyLllll;llo]~,lllv~y]yS,~,llyl]-2-(2,2,2-UVlV~,dlUAy)yl~ . ' (Int. Patent Appl., P~blicanon No. WO 9401420) was 30 hydrolysed by an analogous procedure to that described in Procedure I IO give the title compound as a solid, mp 116-117~C; [Found C, 57.4; H, 4.9; N, 6.4%.
C21H21F3N2Os requires C, 57.5; H, 4.8; N, 6.4~]; ~H (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) and 6.74-7.40 (8H m) w096/04260 ~ P~l/r,.~ n~8 ' ' ' 2 ~ ~6079 Procedure ~
(_)-3-[4-[2-[N-(2-F~ N-methylamino]ethoxy]phenyl]-2-(2,2,2-YJIJ~ I chlorjde ~N~ H2CF3 Oxalyl chloride (1.1 mL) was added to a solutioD of (+)-3-t~[2-[N-(2-1,~ .. ,..~ ,. ~lyl)-N-~ yl~Lullu]~lluAy]~ lyl]-2-(2~2~2-~inuulu~luAy)propanoic acid (1.72 g) in 10 dry 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 1~,; r;. -I ;. ,, Procedure 6 lS [2S, N(lS)]-3-[4-[2-[N-(2-~ JIyl) l'~ '' y]phenyl]-2-(2,2,2-'' y)-N-(2-hydroxy-1-phenylethyl).~

~CH3 /~ ~ --I~N~OH

~N o O'CH2CF3 ( )-3-[4-[2-[N-(2-B~lLUA~UIyl)-N~ ly;~ lillu]cill~ y]~ lyl]-2-(2~2~2-uiLluulu~,lloAy)propanoyl chloride was reactcd with (S)-2-phenylglycinol by an analogous procedure to that described in Procedure 3. CL..~ ,y on silica gel using a gradient of 10-70~o ethyl acetate in hexane as eluent afforded firstly [2R, N(lS)]-3-[4-[2-[N-(2-b~,.lLuAaLulyl)-N-lll~,.llykull;.lu]ethoxy]phenyl]-2-(2,2,2-2S ~illuulu~LlluAy)-N-(2-hydroxy-l-phenylethyl)~ luy~n~ullidc followed by the desired [2S, N(lS)]-I,lu~ul ll;de title compound as a foam; ~c~]D25 +14~ (c~0.5. MeOH);
99% d.e. (by HPLC); [Found M+ 557.2136. C2gH30F3N3Os requires M+ 557.2138~;
~ (CDC13) 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 (1 1 T~,rr,mpl,.y)~

~ W096/04260 , ';~ t ~! ~6079 .~

Procedure 7 ~2,2,2-TI '' , ' y~ethanoyl Chloride fCOCI
~ ,: 1 3CH2CF3 ~ .
A soluion of oxalyl chloride (20 mL, 0.23 mol, 1.15 eq) in dry dichlvl v.. ~,.hA ~.. , (50 mL) was added dropwise at room ~c~ a~u~c, with sirring, to a solution of (2,2,2-Llilluulv.,lllv~.y' ' ~ acid (Int. PatentAppl., Publication No. WO 87/07270, 31.6 g, 0.2 mol) and N,N~ Ir " II-AII l;rir (5 drops) in dry dichlolvl~ dlalle (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 rcmoved by distillation (bp 40-45~V760 mm Hg).
The residue was transferrcd to a Claisen distillation flask and the remaining solvent and oxalyl chloride removed by distillation (bp 45-60~V760 mm Hg). Vacuum distillaion of the residue then afforded the product, bp 50-55~/25-32 mm Hg.
~iH (CDC13) 4.00 (2H, q, 3J~F 8.3) and 4.57 (2H, s).
Procedure 8 (4S) q P yl-3-[2-(2,2,2-1. ' ~ ~)ethsnoyl' ~ 2-one ~ N ~(o ~o ,.1_/
CF3 ih (4S)-4-Be,l~ -2-one (5.21 g, 0.029 mol) was dissolved in dry THF
(60 mL) and cooled to -70~C under argon. n-Butyllithium (18.4 mL, 1.6 M solutionin hexane, 1.1 eq) was added over 10 minutes and the resulting mixture stirred at -70~
Cfor20minutes. Asolutionof(2,2,2-1linuulv~ilv~-y)ethanoylchloride(5.19g,1 eq) in dry 1~ (60 mL) was added over 10 minutes, the mixture stirred at -70~C for a further 30 minutes then allowed to warm to room t~ awl~i ovemight. The reactdon was quenched by addition of brine (20 mL) and . "~r~ n vacuo. The residue was diluted with brine (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were dried (MgSO4), evaporated and the residue ~ 1 on silica gel with diulllvlulll~ ., as eluent to give the product as an oil. [C~]D25 = ~48~ (c = 2.55, CHC13); e.e. 100'~ (by HPLC); [Found (CI, Ammonia) MH+ 318.0934. Cl4HI4NO4F3 requires MH+ 318.0953]; o~
(CDC13) 2.82 (lH, dd), 3.34 (IH, dd), 4.02 (2H, q, 3J~ 8.6), 4.30 (2H, m), 4.69 (lH, m), 4.84 (2H, s) and 7.15-7.40 (SH, m); ~F (CDC13) = -74.8 (3F, t,3JHF 8.6, CF3).

w0 96/04260 ' 2 1 q ~ ~ 7 q 1 ~1,~ . ~

Procedure 9 [3(2S, 3R), 4S]-3-[3-[4-[2-[N-(2~ yl)-N ' ~ ]ethoxy]phenyl]-3-hydroxy-2-(2,2,2-t- '' c Y)IJ~ I]-4-~ i n-2-olle \~N ~ J O
CF, Ph (4S)~Benzyl-3-[2-(2,2,2-L inuulu~d~uAy)ethanoyl]oxazolidin-2-one (31.7 g, 0.1 mol) was dissolved in dry dichlvlu~ "c (300 mL) under argon and cooled to -78~C (internal ~CIII~ U~C of solution), using liquid nitrogen/acetone as the cooling medium~ Tl;wll.ylal~ullc (16~72 mL, R2 eq) was added, followed by the slow addition, over ~ 'y 10 minutes, of di-n-butylboron triflate (Aldrich Chemical Company, l OM solution in dichlu.u...~ u.c, 110 mL, 1 1 eq) such that the reaction t~ Lu-c was maintained below -70~C The mixture was stirred at -78~C
for 50 minutes, then the cooling bath was replaced with an ice bath and the mixture stirred at 0~C for an additional 50 minutes before being recooled to -78~C A solution of 4-[2-rN-t2-1.~ yl)-N-.I..,~ Lu..;l,o]ethoxy]l,~,l..cldcll~.le (29.6 g, 1.0 eq) in dry Lchlu~ul~l~,dl~ult (220 mL), precooled to -50~C, was added over ca M2 minutes, such that the reaction ~.~ Lulc was maintained below -70~C. The resulting mixmre was stirred at -78~C for 30 minutes, then walmed from -78~C to 0~C over 60 minutes along a linear gradient (waTming rate ~ I .3~C.min-l) and stirred at 0~C for a further 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, the layers were separated and the aqueous layer was extracted with dichlululll~,.Laac (3 x I L). The diullluluul~ ulG soluions were l~;CulllbillCd with the original ulll~,iLIult layer from the reaction mixture and this organic solution was then washed with water (2 L) and brine (2 L), dried (MgS04) and evaporated to afford a foam. IH NMR of this crude reaction mixture suggested a mixture of the desired aldol product (3 ~ .c~ , comprising 95~o major di~ClCU;~UIll~) and starting materials. The crude mixture was .,LI~ J on silica gel using a gradient elution comprising 15% ethyl acetate in d;cLlulull~ .le initially (until the desired product began to elute) and rising to 50% ethyl acetate in dichlu~ulll~ lle to complete the elution of Lhe desired product. Unreacted imide and aldehyde were recovered from the early fracnons, followed by a quantity of impure product and then dhe tide compound (comprising 2 diastereoisomers, ratio 97.8:2.2 by NMR). La]D25 ~ W096l04260 2 i ~6 0 79 ~ 31-~8 - +45~ (c = 2.82, CHC13). ~Found (EI) M+ 613 2v42. C31H30F3N30, requires M+
613.2036]; ~H(CDC13. only maiordia;~a,.~,vi.v~ isrecorded~ 2.75 (IH, dd), 2.90 (lH, d, e~xchangcs wlth D2O), 3.25 (lH, dd), 3.34 (3H, s), 3.80-4.00 (5H, m), 4.07 (IH, dd), 4.24 (2H, t), 4.45 (lH, m), 4.99 (IH, apparent t), 5.48 (IH, d), 6.85 (2H, d) S and 6.95-7.40 (I lH, m); ~F (CDC13) = -74.7 (3F, t, 3JHF 8.5, CF3). Thc minorvia~lcu;~uln~l in the purified product was idennfied as the [3(2S, 3S), 4S]-diastereo-isomer.

Procedure 10 F~ .. dt;u~ of[3(2S), 4S]-3-[3-[4-[2-[N-(2-B~ I)-N-~; 7l ~ y]~ 1]-2-(2~2~2-l~inuu~ 1]-4-~'( "" 2-onebyDek~.l,u~

~N CH ~ ~lo CFa Ph Tli~,l.ylsilalle (120 mL, 0.75 mol) was added over 5 minutes to a stirred, ice cooled solution of [3(2S, 3R), 45~-3-[3-[4-~2-[N-(2-b.,, ,~ yl)-N-IU~ ' ~]~ uAy]~ ,yl]-3-hydroxy-2-(2,2,2-l-;n~ y)propanoyl]-4-in-2-one (46.23 g, 7.5 x 10-2 mol) in u;nuv.uac~,iic acid (650 mL).
Tbe mixture was stirred at 0~C for I hour, then at room tcu~ a~ G for a furlher 60 hours. The buLlc of the solvent and residual viethylsilane was removed by rotarye~ al~UIaUUll, firstly al 40 mm Hg and finally at ~5 mm Hg. The residue was dissolved in di-,hlulul~l~,llallc (800 mL) and water (800 mL), then stirrcd vigorously during the cautious addition of solid sodium i I (~29 g) (frothing !) until the pH of the aqueous layer was pH 7. The layers were separatcd and the aqueous layer was exttacted wilh dichlwulll~.lllallc (800 mL). The combincd dicllluu laycrs were washed with water (600 mL), dried (MgSO4) and evaporated. Thc tesidue was triturated with hot hexane and the resulting solid collecled by filtt~tion.
Rccrystallisation ft~m diethyl ether-hexane afforded the title compound, mp 107-109~G a single dia~ cu; ~ull.~,A by IH NMR ~ ,Uu~,u~y. [Ol]D25 = +38~
(c = 1.51, CHC13); [Found C, 62.1; H, 4.9; N, 7.2%; M+ (EI) 597.2089.
C3lH30N3O6F3 rcquires C, 62.3; H, 5.1; N, 7.0%; M+ 597.2087]; ~H (CDC13) 2.82 (lH, dd), 2.96 (lH, dd), 3.C4 (lH, dd), 3.32 (lH, dd), 3.34 (3H, s), 3.70 (IH, m), - 3.88 (lH, m), 3.94 (2H, t), 4.12 (lH, m), 4.18 (lH, m), 4.25 (2H, t), 4.57 (lH, m), 5 34 (lH, dd), 6.82 (2H, d) and 7.00-7.35 (1 IH, m); ~F (CDC13) = -74.8 (3F, t. 3JHF
8.6, CF3).

"

WO 96/04260 ' '~ i . ! 1 , ~ P~

Procedure 11 P.~ " of [3(2S~, 4S]-3-[3-[4-[2-[N-(2-~P. ,~ 1) N ...,II,.~ -]
ethoxy]phenyl]-2-(2,2,2-l~ r ~I]-4-b~..L~' ~ " 2-one by Di.. ~ Separation N 1 ,J o CF, Ph (S)-4-Be~ 2-one (0.291 g, 1.64 x 10~3 mol) was dissolved in dry Ts~F
(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 -70~C for 10 minutes prior to the addition of a solution of (+)-3-[4-[2-[N-(2-I~IlLu~.~ Lul~l)-N-~ ullillo]ethoxy]phenyl]-2-(2~2~2-llinuulu~ u~)propan chloride (prepared from 0.36 g of the acid by Procedure 5, above) in dry TE~
(15 mL). The reaction was stirred and allowed to warm to room Lc~ ulc overnight before being diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined ethyl acetate layers were washed with water (200 mL) and brine (200 mL), dried (MgSO4) and evaporated to give a brown gum. This was .,1.., _ . ' ' on silica gel using a gradient of 35~o to 509'o ethyl acetate in hexane as eluent to afford fiIstly the (R, S)-.1~ .co:~.... . followed by the title compound, a foam. This material was ~ Iu:.~,u~i~lly identical with that prepared by the aldol 20 route (Procedure 10).

Procedure 12 (S)-Methyl 3-[4-[2-[N-(2-1~ ul~l)-N ~ - y~ 1]-2-(2,2,2-tl ~ ~3 jl~ ~ r ~N~ / 3 ~H2~c2F3e A solution of sodium methoxide [prepared from sodium hydride (609to dispersion in mineral oil, 138 mg, 3.41 x 10 3 mol) dissolved in dry methanol (3.5 mL)] was added to an ice cooled and stirred suspension of [3(25), 4S]-3-[3-[4-[2-[N-(2-1~ yl)-N-~ u]ethoxy]phcnyl]-2-(2~2~2-L~inuu~u~ u~y)propanoyl]

4-~"L~ _,..l;riin-2-one (1.879 g, 3.1 x 10-3 mol) in dry methanol (100 mL). The mixture was stirred at 0~C for a total of 20 minutes, then the reaction was quenched by the addition of dilute aqueous L ydluuLlu~ ic acid (2.0M, 1.75 mL) and ~ . n, ~ -d in v~c~o. The residue was suspended in water (100 mL), extracted with ethyl acetate WOgC/0t260 i ' f ~ f qf~0Z~

f~3 x 200 rnfL) and the combined ethyl acetate solutions washed with brine (500 mL), -dned f~MgS04) and evaporated. The resulting gum was .,1.. - ~ ~ r~ on silicagel using 4% ethyl acetate in dichlu~u~ "hollc as eluent to afford the producl as a clear gum. [fX]D25 = -17~ (G = 1.24, CHC13); [Found ~EI) M+ 452.1561.
C2~H23N2O5F3 requires M+ 452.1559]; e.e. 100% (by HPLC); ~H (CDC13) 3.02 (2H, m), 3.34 f3H, s), 3.65 (lH, m), 3.72 (3H, s), 3.94 (2H, t), 4.00 (lH, m), 4.13 (lH, dd), 4.24 (2H, t), 6.80 ;2H, d) and 6.96-7.40 (6H, m).

Procedure 13 ~45) q ~ ,~rl-3-[2-(2- !r~ r)ethanoyl] ~- -- 2-one ~ O

f Nfvo ~0 ~.

MeO

The title compound was prepared from 2-(2-~ ,J~vAy..l~uAy)ethanoyl chloride by amethod analogous to that described in Procedure 8. CLI~ ~, . ~ y on silica gel 15 using a gradient of 70-80% diethyl ether in hexane as eluent afforded the product as a gum. [a]D25 = +54~ (c = 2.70, CHCI3); IFound ~EI) M+ 293.1263. ClsHIgNOs requires M+ 293.1264]; ~H (CDC13) 2.81 (lH, dd), 3.33 (lH, dd), 3.41 (3H, s), 3.63 t2H, t), 3.78 f'2H, t), 4.25 (2H, m), 4.70 (lH, m), 4.74 (lH, d), 4.76 (lH, d) and 7.10-7.40 (5H, m)-Procedure 14 [3(2S, 3R), 4S]-3-[3-[4-[2-[N-(2-1! ' fr1)-N J -~ 'r' J1]-3-hydroxy-2-(2- !r- ~ . \'rl] q ~- 4r '- '- 2-one >-- --oJ~ ~' MitO
The title compound was prepared from (4S)-4-benzyl-3-L2-(2-r~ LuA!r...huAy)ethanoyl]oxazolidin-2-one by a method analogous to that described in P~ocedure 9. The crude reaction mixture was cll~u~ u~la~l~cd on silica gel using a gradient of 15-40'Yo ethyl acetate in dichlu.u.l.~,.ll,u~c to afford the product as a gum ( ~ ,g 2 J~ , ratio >99:1 by IH NMR). ~a]D25 = +49~ (c = 1.14, CHC~13). [Found (FAB, NOBAlNa) MH+ 590.2472. C3~H3sN3Og requires MH+

wo 96/04260 ~ 6 0 7 9 59Q2502]; ~H (CDC13. oniy majo mI;4~LCICC.;~VIII~,I is recorded) 2.71 (lH, dd), 3.25 (lH, dd), 3.31 (3H, s), 3.35 (3H, s), 3.56 (2H, m), 3.72 (2H, m), 3.78 (lH, d, exchanges with D2O), 3.85-4.00 (4H, m), 4.22 (2H, t), 4.31 (lH, m), 4.89 (lH, dd), 5.42 (lH, d), 6.83 (2H, d) and 6.95-7.40 (1 lH, m); The minor dhL~ Gu;;~u~ in the 5 purified product was idenified as the [3(25, 3S), 4S]-di~ v;su Procedure 15 [3(2S), 4S]-3-[3-[4-[2-[N-(2-BL.. 4UA.~,ul~ N ~ ~' ~ ]- ' y]~ I]-2-(2-~ ~r)Y~r Jl] ~ 2-one \~N~O~,.~_/

MeO

[3(2S, 3R), 4S]-3-[3-[4-[2-[N-(2-l~ul~Lulyl)-N-l~ LyLullillo]~Lllu~y]~ lrl]-3-hydroxy-2-(2-,,.~,.1,u,~,.l,uAy)propanoyl]-4-benzylnY~nliriin-2-one (0.561g) wasreacted with triethylsilane for 6.25 hrs in a manner similar to that described for Procedure 10. The reaction mixture was diluted with water (200 mL) and d;~,hlvIu~ h~ , (200 mL) and solid sodium i .;. 1,. ,, ~r Ir was added cautiously until the aqueous layer showed pH 6.5. The layers were sepatated, the aqueûus layer was extt~Lcted with di~,lIlulu~ , (2 x 30u mL) and the combined dichlu.u.I.~ lc solutions were washed with brine (400 mL), dried (MgSO4) and evc~, ~ The 20 residue was ' ~ . ' ' on silica gel using 35% ethyl acetate in rl~ ..r as eluent to afford the tide compound, a gum, as a single by IH NMR. [V~]D25 = +45~ (c = 1.39, CHC13); [Found M+ (EI) 573.2473. C32H35N3O, requires M+ 573.2475]; ~H (CDC13) 2.76 (IH, 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 ~lH, dd), 4.12 (lH, dd), 4.22 (2H, t), 4.52 (lH, m), 5.31 (lH, dd), 6.79 (2H, d) and 6.90-7.40 (l lH, m).

Procedure 16 (S)-Methyl 3-[4-[2-[N-(2-Be.. ~.vA.~4ul~1)-N .~ ]ethoxy]phenyl]-2-(2-' ~

¢~c N~ CO2Me ~ Wo 96104260 ~ 2 '1 1~6 ~ 7 9 [3(2S), 4SJ-3-[3-r4-[2-[N-(2-lh,~lLuA~ILulyl)-N-~ llyld~ o]~ ul~y]~ lyl]-2-(2- -~ ,LLu~ ,L~ y)propanoyl]-4-b~ ylu~dLulidin-2-one was reacted with sodium methoxide in a manner analogous to that described in Procedure 12. The crude reacrion mixture was ~,1.1, ~ ' ' on silica gel using 20% isohexane in diethyl S ether as eluent to af~ord the title compound, a gum. [a]D25 = -12~ (c = 1.26, CHC13);
LFound (El) M* 428.1974. C~3H2~N~06 requires M+ 428.1948]; e.e. >99.8% (by HPLC); ~H (CDC13) 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 (lH, dd), 4.23 (2H, t) and 6.75-7.40 (8H, m).

~ . ~ .1 .. . . . . .. . .

W0 96/04260 ;~ Z-l q-~ ~ 7 ~

DEMONSTRATION OF EFFICACY OF COMPOUNDS

Obese Mice, Oral Glucose Tolerance Test.

5 C57bll/6 obcse (ob/ob) mice were fed on powdered oxoid diet. After at least one week, the mice conrinued on a powdered oxoid diet or were fed powered oxoid dietcontaining the test compound. After 8 days on the ~ ;I diet all of the mice wcre fastcd for 5 hours prior to receiving an oral load of glucose (3g/kg). Blood samples for glucose anaiysis were taken 0, 45, 90 and 135 minutes after glucose 10 ~ and the results appear below as the percentage reduction in area under the blooti glucose curve where test compound trcated groups are compared with the control group. 8 mice were used for each treatment.

Table % Reduction in Level in diet area under blood Example (~Lmol. kg-l of diet) glucose curve 0.3 24 2 0.3 24 Effects on packed red cell volume and heart weight:

These were ~l~te~Tnin~d aftcr repeat oral ~ l, ,;,; ~",, ir~ of compound (once daily at a 20 dose of 3 ~LmoVkg body wt for 14 days, by gavage) to female Sprague- Da,wley rats for 14 days. Changes shown are percentage changes from control. Sutisrical r~ were made by Student t test for non-paircd data; *pcO.05, ***pcO.OOI
vcrsus controls. No effect no significant difference from control group. Results were obtained from 8 rats per treatment group.

Heart weight Packed cell voiume Example (% increase) (% reduction) No effect No effect 2 No effect Noeffect

Claims

Claims:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein R0 represents 2-benzoxazolyl or 2-pytidyl and R1 represents CH2OCH3 or CF3.

2. A compound according to claim 1, wherein R0 represents 2-benzoxazolyl.

3. A compound according to claim 1 or claim 2, wherein R1 represents CF3.

4. A compound according to claim 1 being:

(S)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2-methoxy-ethoxy)propanoic acid;or (S)-3-[4-[2-[N-(2-bezoxazolyl)-N-methylamino]ethoxy]phenyl-2-(2,2,2-trifluoroethoxy)propanoic acid; or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof.

5. A compound according to any one of claims 1 to 4, when present in admixture with less than 50% w/w of its racemic isomer.

6. A compound according to any one of claims 1 to 5, when 90-100% optically pure.

7. A compound according to any one of claims 1 to 6, in optically pure form.

8. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable hydrate thereof, which process comprises:

(a) hydrolysing a compound of formula (II):

wherein R0 and R1 are as defined in relation to formula (I) and L1 represents a hydrolysable group; or (b) resolving a racemic compound of formula (VII):

wherein R0 and R1 are as defined in relation to formula (I); and thereafter, if required, preparing a pharmaceutically acceptable salt of the compound of formula (I) and/or a pharmaceutically acceptable solvate thereof.

9. A pharmaceutically composition comprising a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.

10. 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 (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, to a hyperglycaemic human or non-human mammal in need thereof.

11. A method for the treatment of hyperlipidaemia, hypertension, cardiovascular disease, certain eating disorders, the treatment and/or prophylaxis of renal disease, 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(I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.

12. A compound of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.

13. A compound of formula (I), or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of hyperglycaemia, 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.

14. The use of a compound of formula (I), 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, the prophylaxis of renal disease and/or the prevention, reversal, stabilisation or retardation of the progression of microalbuminuria to albuminuria.

15. An intermediate compound of formula (II) or (III).