CA2225627A1 - Azetidinone derivatives for the treatment of atherosclerosis - Google Patents

Abstract

Azetidinone compounds of formule (I) in which: R1 and R2, which may be the same or different, is each selected from hydrogen, halogen or C(1-8)alkyl; R4 and R5 which may be the same or different is each selected from hydrogen, C(1 6)alkyl, C(2-6)alkenyl, aryl, aryl(C1-4)alkyl and heteroaryl(C1-4)alkyl each of which may be optionally substituted or R4 and R5 may be linked together to form the remainder of a (C3-7)cycloalkyl ring; X is a linker group; Y is an optionally substituted aryl group; Z is oxygen and R3 is C(1-8)alkyl, C(3 8)cycloalkyl, C(3-8)cycloalkylC(1-6)alkyl, heteroaryl, heteroaryl(C1-4)alkyl, aryl, or aryl(C1-4)alkyl, each of which may be optionally substituted or Z is S(O)n in which n is 0, 1 or 2 and R3 is C(1-8)alkyl, C(3-8)cycloalkyl, C(3 8)cycloalkylC(1-6)alkyl, aryl, aryl(C1-4)alkyl, heteroaryl, or heteroaryl(C1 4)alkyl, each of which may be optionally substituted are inhibitors of the enzyme Lp PLA2 and are of use in therapy, in particular treating atherosclerosis.

Description

W O 97/02242 PCT~EP96/02765 AZETIDINONE DERIVATIVES FOR THE TREATMENT OF ATHEROSCLEROSIS

The present invention relates to certain novel monocyclic ~-lactam compounds, processes for their preparation, intprmçdi~tps useful in their p~ ;rtn, 5 ph~rm~çt:l.l;ç~l compositions co~ h~ g them and their use in therapy, in particular in the tre~tment of atherosclerosis.
Lipoprotein Associated Phospholir~sP A2 (Lp-PLA2). The sequence of the enzyme, the i.col~tion and purifi~tit)n thereof, i~ol~t~d nucleic acids çnroriing the enzyme, recombin~nt host cells transformed with DNA enro i;"g the enzyme are IlPsrrihed in patent ~pplir~ti,.n WO 95/00649 (.~mithRlinP P~eerh~m plc). Sug~Pst~d thr. t~pc~"l ;~ uses for inhibitors of the enzyme inrllldPd atherosclelosis, ~ etPs~
rhrllm~toi~l arthritis, stroke, myocardial infarction"c;pelfu~ion injury and acute and chronic infl~mm~tion A later patent applir~tion (WO 9S/09921, Icos Corporation) and a related publication in Nature (TjoeL~er et al, vol 374, 6 April l99S, 549) desa-ibe lS the same enzyme, ~lsholloh calling it by the name 'Platelet Activating Factor Acetyl Hydrolase' (PAF acetyl hydrolase) and suggest that it may have potential as a therapuetic protein for regulating pathological infl~mm~tnry events.
Lp-PLA2 is responsible for the conv~l~ion of phosph~titlyl~holinP to lysophosphatidylcholinP during the conversion of low density lipoploleJ,~ (LDL) to its oxidised form. The enzyme is known to hydrolyse the sn-2 ester of oxi-iioed phosph~ti~ylcholine to give lysophosph~ti~iylcholine and an oxidatively morlifiPd fatty acid. Both products of Lp-PLA2 action are biologically active with lysophosph~ti~lylcholine, a component of oxidised LDL, known to be a potent rhrmo~ttT~rt~nt for circ~ ting monocytes. As such, lysophosph~tiflylcholine is thought play a signifir~nt role in atherosclerosis by being responsible for the ~cc~lmnl~tion of cells loaded with rholPst~rol ester in the arteries. Inhibition of the Lp-PLA2 enzyme would the.ef~-~ be expected to stop the build up of these macrophageçnrirhçd lesions (by inhibition of the form~tion of lysophosrh~ti-lylrholinP- and oxi~;~Pd free fatty acids) and so be useful in the tre~tmpnt of atherosclerosis.
The increased lysoph~-.crh~tirlylçhQlinP content of oxidatively modified LDL is also thought to be responsible for the endothP~ dy~ nrtion observed in patients with atherosclerosis. Tnhibitors of Lp-PLA2 could therefore prove bpnpfiri~l in the tre~tmçnt of this phenomenon. A Lp-PLA2 inhibitor could also find utility in other disease states that exhibit endothelial dysfunction inç~ ing diabetes, h~liel sion, angina pectoris and after i.sch~Pmi~ and reperfucion Lp-PLA2 inhibitors may also have a general application in any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA~. Examples of such disorders include psoriasis.

W 0 97/02242 PCTtEP96tO2765 Lp-PLA2 inhihitors may also have a general applir~tif)n in any disorder that involves lipid pero~i-htinn in co~ ;on with Lp-PLA2 activity to produce the two injurious products, lysophosphi~t1'lylch~ np and o~cidatively modified fatty acids. Such conflition~~ include the aforPmPntinn~d con~ition~A ath~l~oscl~.usis, diabetes, rhPIIm~~~~id S arthritis, stroke, infl~~mm~tnry con~iticm.~ of the brain such as ~l7hPin~Pr's Disease, Illyoc~dial infarction, ~ r .~ injury, sepsis and acute and chronic inflA.. z~lion Further such con~litinn~~ include various llt;ulop~yclliatric disorders such as schizophrenia (see Psychorhi rn~.~ro1ogy Bulletin, 31, 159 165, 1995).
We have now it1entifiPd a series of compounds which have been found to act 10 as inhibitors of Lp-PLA2.
Accordingly, the present invention provides a compound of fo~n R' o~N~cR4Rs_X--Y (I) in which:
15 R1 and R2, which may be the same or different, is each ~lPcted from hydrogen, halogenorC(1 g)a1kyl;
R4 and R5 which may be the same or dirre~ is each ~l~cte~l from hydrogen, C(l 6)alkyl, C(2 6)alkenyl, aryl, aryl(Cl 4)alkyl and heteroaryl(C 1 4)alkyl each of which may be optionally ~..b~ d or R4 and R5 may be linked together to form the 20 rçm~in-ler of a (C3 7)cycloalkyl ring;
X is a linker group;
Y is an optionally sllhstitl-t~ aryl group;
Z is oxygen and R3 is C(1 g)a]kyl, C(3 g)cycloaLkyl, C(3 g)cycloaL~cylC(l 6)alkyl, heteroaryl, heteroaryl(C 1 ~)alkyl, aryl, or aryl(C 1 4)aLkyl, each of which may be optionally substituted or Z is S(~)n in which n is 0, 1 or 2 and R3 is C(1 g)aLkyl, C(3 g)cycloaL~yl, C(3 g)cycloaLkylC(l 6)allyl, aryl, aryl(Cl 4)aLkyl, he~lualyl, or heteroaryl(Cl 4)aLkyl, each of which may be optionally substi~llt~-d and .oy~lnAing compounds in which:
X is a direct bond; a group Xl(CH2)m in which xl is CO, CONR6, COO, CONR6CO, or CONR6O in which R6 and m are as hereinbefore (1~fin~tl or a C
12)alkylene chain optionally in~lu~Jtcd by Xl;
Z is S(~)n in which n is 0, 1 or 2 and R3 is C(1 g)aLkyl, C(3 g)cycloalkyl, C(3 g)cycloaLkylC(l 6)alkyl, aryl, or aryl(C 1 4)alkyl, each of which may be optionally sllbstihlt~d; and R4 and RS is each hydrogen.

W O 97/02242 PCT~EP96/0276'i Suitably, X is a direct bond; a group X1(CH2)m in which xl is CO, CONR~j, COO, CONR6CO, or CONR60 in which R6 is hydrogen or C(1 6)alkyl and m is 0 or an integer from 1 to 12; a group (Xl)aX2 in which a is 0 or 1 and x2 is a C(l 12)aL~cylene chain illL~lu~L~d andtor tçrrnin~ted at the end ~ Pnt to Y by one or more groups X3 sçlPct~pd from O, S(O)x, NR6, alkene or aL~cyne, in which ~c is 0, 1 or 2; or a C(1 12)aL~cylene chain optionally ul~lup~d by Xl.
Suitable sub-sets of co l.p~u.lds within fom~ (I) include those in which:
(a) X is a direct bond; a group Xl(CH2)m as herçin~,fore ~efin~ a group (Xl)aX2 as hereinbefore ~lefinP~l or a C(1 12)alkylene cham optionally L~ u~Led by Xl;
Z is oxygen and R3 is C(1 g)alkyl, C(3 g)cycloaLkyl, C(3 g)cycloalkylC(l 6)alkyl, hetelual yl, heteroaryl(Cl ,I)aL~yl, aryl, or aryl(Cl 4)alkyl, each of which may be optionally substituted or Z is S(~)n in which n is 0, 1 or 2 and R3 is h~le...~l or heteroaryl(C l 4)aL~yl, each of which may be optionally s~,b~
R4 and R5 are as hereinbefore defin~; or 15 (b) X is a direct bond; a group Xl(CH2)m as hereinbefore dPfinPd a group (Xl)aX2 as her~inhPfore ~lefin~tl or a C(1 12)alkylene chain optionally il.L~.upLed by Xl;
Z is S(~)n in which n is 0, 1 or 2 and R3 is C(1 g)aLkyl, C(3 g)cycloaL~cyl, C(3g)cycloaLlcylC(l 6)alkyl, aryl or aryl(Cl 4)aL~cyl, each of which may be optionally ~u~l;l..l~d;
R4 and R5 which may be the same or dirr~ is each sPl~ct~d from hydrogen, C(l 6)aLkyl, C(2 6)aL~enyl, aryl, aryl(Cl 4)alkyl and heteroaryl(Cl 4)alkyl each of which may be optionally sub.stitllted or R4 and R~ may be linked together to form the rPm~in(lPr of a (C3 7)cycloalkyl ring, with the proviso that R4 and R5 are not both hydrogen; or (c) X is a group (Xl)aX2 as hereinbefore cl~fin.~d:
Z is S(~)n in which n is 0, 1 or 2 and R3 is C(1 g)alkyl, C(3 g)cycloaLkyl, C(3 g)cycloalkylC( 1 6)alkyl, aryl or aryl(C 1 4)aL~yl, each of which may be optionally substit~lt~d; and R4 and R5 is each hydrogen.
Compounds of formula (I) are inhibitors of Lp-PLA2 and as such are expecled to be of use in treating atherosclerosis and the other disease con~litionc noted above.
Representative eY~mples of R1 and R2 include hydrogen, bromo, methyl and ethyl. Suitably, Rl and R2 is each hydrogen or one of R1 and R2 is hydrogen and the other of R1 and R2 is methyl (to give a trans-methyl). Preferably, R1 and R2 is each 3~ hydrogen.
Reprçsent~tive values for when R3 is aryl(C 1 4)aL~yl include arylC(1 3)alkyl.
Within this, representative examples of the aryl group include phenyl and nap},Lhyl.
Suitable examples of R3 include benzyl, 2-phenylethyl and 3-phell~lplo~J~l in each of which the phenyl ring may be optionally substituted by up to three sub~ e~

W O 97/02242 PC~EP96/02765 Suitable ~ .e~ ; for a phenyl or nap}~ yl nng in R3 include halo, hy~uAy, C
6)aL~CYl~ C(l 6)alkoxy~ c(l-6)aL~l~Aycdlbonyl~ C(2 6)alkenyluAy~allJollyl~ Cal~Ay, carboxyC(1 6)aLI~yl and C(1 6)aL~uAy~u~ ylc(l-6)alkyl- More pl~r~-~ hly~ R3 is carboxybenzyl or a colle~onding C(1 6)alkyl or C(2 6)alkenyl ester thereof.
Repl~se~ ive eY~mrlPs of the aryl group for when R3 is aryl include phenyl and naphthyl. Preferably, the aryl group is optin~ y ~ I;l-.e-l phenyl. Suitable.sllbstitnent~ for a phenyl or naphthyl ring include halo, hy~llo~y, C(1 6)aLkyl, C(l 6)aLk~XY~ C(1-6)aLh~Y~UI~OnYL C(2 6)a1kenY1~AY~~ Y1~ AY~ C~I~AY~(1-6)aLkylandC(1 6)alh"~yc ~IYlc(l 6)aLkYL
ReprecPnt~tive eY~mplP-s for R3 when R3 is C(1 g)alkyl, C(3 g)cycloalkyl or C(3 g)cycloa~ylC(l 6)aL~cyl include methyl, n-butyl, t-butyl and n-hexyl, cyclohexyl and cyclohexyl methyl, suitably n-butyl, t-butyl or n-hexyl. .Suit~hlP subs~;l..el~ for the aLIcyl or cycloaLkyl group in R3 include halo, hydroxy, C(1 6)aLkyl, C(1 6)aL~o~cy, C(1 6)aLko~ycalbollyl, C(2 6)aL~enyloxycarbonyl, carboxy, carboxyC(1 6)aL~cyl and C(1 6)a~ yc~l,onylc(l 6)alkyl.
Further lc~plesen~tive values for R3 include helel~ ylC(l 3)aLkyl, plt;re,~.bly heteroarylmethyl. Representative PY~mrlps of the he~lo~ylaryl group for use in R3 include pyridyl, pyridyl N-oxide, furanyl, thienyl and thiazolyl. Suitable ~ubsl;~
for a heteroaryl ring in R3 include halo, hydroxy, C(1 6)aL~cyl, C(1 6)alkoxy, C6)alkoxycarbonyl, C(2 6)aL~enylo~y~l,onyl, c~l~ y, carboxyC(1 6)allyl and C
6)alk~ Y~ ol'ylc(1 6)aL~yl.
It will be appreciated that within R3, an optional ~,..'~,l;l..~..~ may be located in the aLkyl, cycloaLkyl, aryl and/or h~loalrl por~ion. Preferably, the ~.u~ e~tiS
carboxy or a C(1 6)alkyl or C(2 6)alkenylester thereof.
Preferably, R3 is arylC(1 3)alkyl or heteroarylC(l 3)alkyl, more preferably arylC(1 3)aLkyl, most preferably benzyl, whicn may be optionally ~ b~.l;lul~ in particular by a carboxy group or a C(1 6)aLkyl or C(2 6)aL~cenylester thereof.
Preferably, Z is S(O)n. Preferably, n is 1 or 2, more preferably 1.
Preferably, S(o)nR3 is opdonally sllbstihled ben~y~ rhinyl7 more preferably 4-carboxybenzylclllphinyl or a C(1 6)aL~cyl or C(2 6)aL~enylester thereof.
Repl~selltative ex~mpl~s of R4 and R5 when an alkyl group include methyl, ethyl and propyl. Representative P~mplps of a C(2 6)alkenyl group include allyl.Representadve e~c~mrlPs of a (C3 7)cycloalkyl ring include cyclopropyl.
Repres~nt~tive e~r~mplP~ of aryl(Cl 4)aL~yl and heteroaryl(Cl 4)a'~yl include benzyl and furylmethyl, respectively. Replt;se--L~Liv~ eY~mple-s of R4 and R5 when aryl or araLkyl include phenyl and benzyl. Suitably, R4 and R5 are both hydrogen or R4 is hydrogen and R5 methyl.
Representative eY~mplPs of X include CO(CH2)m, CONH(CH2)m, COO(CH2)m, CONHCO(CH2)m, CONHO(CH2)m and C(l 12)alkylene. Preferably, W O 97/02242 PCT~EP96/02765 x1 is CO or CONR6, more preferably CONH. Preferably, m is 1, 2, 5, 6, 7 or 9, prP.fP.r~bly 6.
Further ieplc;sel,L~tive ey~mplps of X include X4(CH2)pCH~H(CH2)q~
X4(CH2)pC_C(CH2)q or X4(CH2)p(0)r(CH2)q(0)S in which X4 is a direct bond or S CONR6, p is an integer from 1 to 12, q is 0 or an integer from 1 to 12 such that p+q 12, suitably < 6, r is 0 or 1 and s is 1 or r is 1 and s is 0, with the proviso that if r ancl s are both 1, then q 2 1. In preferred eY~mrlf~s in this subset of compounds, X isCONR6(CH2)4C=-C or (CH2)0(CH2)6-Preferred e-Y~mplPsc of X include CONH(CH2)6, CONR6(CH2)4C=C and (CH2)0(CH2)6 Suitably, Y is a benzene ring, optionally sub~ L~ d by up to three further substitll~f~-nt.c. Suitable substitllent.c include halo, hydroxy, C(1 g)aLkyl and C(1 g)aLkoxy. Preferably, Y is phenyl optionally s~bstit--tf~d by halo.
Useful combin~tiQnc of ~.ub~ e~ i for compounds of formula (I) which are f~Yemrlifif~.d herein are sllmm~r~ in the following table:

R3 R4 R~ X
1 carboxy- hydrogen methyl CONH(CH2)6 benzylsulfinyl 5-carboxyfuran-2-hydrogenhydrogenCONH(CH2)6 methylsulfinyl bel~ybulfinylhydrogenhydrogen(CH2)0(CH2)6 benzylsulfinylhydlugellhydlugellCONR6(CH2)4C=C

Compounds of formula (I) in which the group R3 incorporates a carboxy substitllent are generally found to have illlpl~lved activity against the target enzyme in 20 in vivo models, in particular, a superior ability to inhibit plaque ~c.c~i~te~l Lp PLA2.
In such studies, it is however found that such compounds have better pharmacokinP.ti~
plupelLies if initially ~min.ctered as an aLkyl or alkenyl ester 'pro-drug'. The ester grouping is then rapidly hydrolysed in the liver to release free carboxyl. Generally, compounds with an a -methyl sul,~ ent that is those in which one of R4/R5 is 25 methyl are more potent than the corresponding des-methyl compounds.
It will be readily appleciat~d by the skilled person that C-4 of the ~-lactam ring is a chiral centre which will give rise to the presence of stereoisomers. The present invention en~)mp~c.cP,s all such stereQi.comers. An ~dtliti()n~1 chiral centre will be introduced when R4 and R5 are not the same. This will give rise to the PYi.CtP.nf P of 30 extra stereoi.comf~.r.c. The present invention encr mp~cces all such stereoi.colnPr.c It will be further readily appreciated by the skilled person that, in compounds of formula (I) in which n is 1, that is sulphoxide compounds, the presence of the SO

W O 97/02242 PCT~EP96/02765 moiety will introduce an ~d~itinnAl chi~al centre into the molPclllp- and the.~Çore give rise to the eYi.ctPn~e of extra stereoicomPrC. The present invention ç~ p~c~rs aU
such stereoisomers.
In ~l~fell~d compounds of formula (1), the ~bsolllte configllr~tio~c at C-4 and S the SO moiety are R and S respectively. In pl~rell~d col-lpou-lds of formula (I) when R4=H, R5=Me, the absolute configuration at the cL-carbon ~to which R5 is ~tt~chPd) isS.
When used herein, the term '~kyl' and similar terms such as 'aL~oxy' i...'l..tlP~ all straight chain and brAn~hPd isomers. Re~ e--l~Liv~ PYr~ thereof include methyl, 10 ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and n-he~cyl.
Snit~lP~b~ e~ foranaLkylgroupin~ le,for~Y~mrl~ hAlogçn cyano, az~do, nitro, carboxy, (Cl 6)aLIcoxycarbonyl, carbamoyl, mono- or di-(Cl 6)aLkylcarbamoyl, sulpho, slllrhAmQyl, mono- or di-(Cl 6)a1~yl...~ lA...oyl, amino, mono- or di-(C l 6)aLkylamino, acylamino, ureido, (C l 6)aLhl~y~ l,o.ly~.ll"o, 15 2,2,2-trichloroetho~y~cubonylamino, aryl, heleio;yclyl, hydroxy, (Cl 6)aLt~oxy, acyloxy, oxo, acyl, 2-thienoyl, (Cl 6)aLkylthio, (Cl 6)aLkyl~ h;~yl, (C
6)aL~cyl~lllph-nyl, hyd~u~yi~ihlo, (Cl 6)aL~,Ayi...i~lo, hydrazino, 11Y~ JnQ~
b~.~ol.ydlu~ oyl, gu~ni~lin~ Amitlino and iminr)AlkylaIrlino.
When used herein, the term 'aryl' in~ Ps, unless otherwise defin~-l phenyl or naphthyl optionally ~lb~ d with up tO five, preferably up to three ~b~ ,~,.l~.
Suitable ~,bs~ ~ntc for an aryl group in~lllde~ for eYAmpl~, halogen, cyano, (C1-6)aLcyl, (C3-7)cycloaLkyl, (Cl-6)aLkoxy, halo(Cl-6)aLkyl, hydroxy, amino, mono-or di-(C1-6)aL~cylamino, acylamino, nitro, c~l~y, (Cl-6)aL~uAycd.l,onyl, (C 1 -6)aL~enylu~y~,~ l~nyl, (C 1 -6)aL~coxycarbonyl(C 1 -6)aLkyl, (C 1 -6)aL~ylc~,.ylo~cy, carboxy(C 1-6)aLkyloxy, (C 1 -6)aLkylcarbonyloxy, (C 1 -6)aLkylthio, (C 1 -6)aLkylclllrhinyl, (C1-6)aL~cylc~llphonyl, slllrh~moyl~ mono- and di-(Cl-6)-aL~cyl.slllrh~moyl, carbamoyl, mono- and di-(C 1-6)aLlcylcarbamoyl, and heterocyclyl.
When used herein, the term 'heteroaryl' includes single and fused rings, each ring suitably compncing up to four, preferably 1 or 2, he~.uato.ns each sel~ctecl from oxygen, nitrogen and sulphur. Each ring may have from 4 to 7, preferably 5 or 6, ring atoms. A fused heteroaryl ring may include carbocyclic rings and need include only one heteroaryl ring. Suitable fused ht:L~ ua,yl rings include bicyclic systems.
When used herein, the term 'heterocyclyl' inclll~es aromatic and non-aromatic single or fused Angs comprising up to four hetero-atoms in the ring ~l~ct~ from oxygen, nitrogen and sulphur and optionally substituted with up to three substihllontc Suitably the hc~-u-;yclic ring compri~Ps from 4 to 7, preferably 5 to 6, r ng atoms. A
fused heterocyclic ring system may include carbocyclic rings and need only include one h~u~yclic ring.

W O 97/02242 PCT~EP96/02765 fused heterocyclic ring system may include carbocyclic rings and need only include one hele~ ,lic ring.
When substitntP~ a heteroaryl or a heterocyclyl group may have up to thr~e substihlpntc Suitable such s~s~ ent~ include those previously mPntionP(l for an aryl 5 group as well as oxo.
When used herein, the terms 'halogen' and halo' include fl~lorinP., chlrJrinP.
bromine and iodine and fluoro, chloro, bromo and iodo, l~specLi~ely.
Preferred compounds of formula (I) inr~ e [6-(4-chl~ ph~..ylhexyl)]-2-[~benzyl.c~llrhinyl-2-oxo~7Ptirlin-l-yl]propion~mill~p~ in 10 particular diastereoisomers lb, 2a and 2b, çspeci~lly isomer 2b;
(a-5,4-R,SS)-N-[6-(4-Fluorophenyl)hexyl]-2-[4-carbo~yl,en~l.c~llrhinyl]-2-oxoazetidin-l-ylpropion~mide- and the corresponding allyl ester;
(+/-)-N-(6-[4-Chlorophenyl]hex-l-yl)-4-(3-furylmethyl.culrhinyl)-2-oxo~7P.ti-lin-l-yl~ret~mifle. (diastereomer 2);
(+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(5-metho~ycarbonyl-2-furylmethyl.clllrhinyl)-2-oxoazetidin-1-yl~r.et~mi-le (diastereomer 2);
N-[6-(4-Fluorophenyl)hex- 1 -yl]-~(5-allylo~y ,~1~onylfuran-2-methylthio)-2-oxo~7P.ti-iin-l-yl~ret~mi~le;
N-[6-(4-Fluorophenyl)hex- l-yl]-4-(5-carboAyrulal~-2-methylsulphinyl)-2-20 oxoazetidin-l-yl~ret~mi~le (Diastereomer 2) and the corresponding allyl and methy1 esters thereof;
N-(6-{4-Chlorophenyl}hexyl)-4-(S-carbo~yrul~l-2-methyl.clllrhinyl-2-oxo~7P.ti~lin-l-yl)~ret~mkhP. (Diastereomer 2) and the corresponding allyl and methyl esters thereof.
N-[6-(4-chlorophenyl)hexyl]-t4-(4-carboxymethylphP.noxy)-2-oxo-~7Pti~lin-l -yl]-25 ~cet~micle;
N-[6-(4 Chlorophenyl)hexyl]-[4-(2-fluorophenoxy 2-oxo ~7P.ti~lin-l yl) ~cet~mi~1e N-(6-(4-Chlorophenyl)hexyl)-(4-(4-allyl~y~,~ 1,onyl-methylphenoxy)-2-oxo~ 7.otiflin-l-yl)~ret~mitlp 1-(2-(6-(~Chlorophenyl)hexyloxy)ethyl)-4-benzyl.cnlrhinyl-2-oxoazetidine 30 (Diastereoisomer 2);
1 -(2-(6-(4-Fluorophenyl)hexyloxy)ethyl)~(4-ethoxycarbonylbenzylsulphinyl)-2-oxo~7Pti~linP (Diastereoisomer 2); and 1 -(2-(6-(4-Fluorophenyl)hexyloxy)ethyl)-4-henzyl.clllphinyl-2-oxoazetidine ~ (Diastereoisomer 2).
More plc~felled compounds include:
N-[6-(4-chlorophenylhexyl)]-2-[4-benzyl.cnll hinyl-2-oxo~7~.ti~in-l-yl]propior~mille, in particular diastereoisomers lb, 2a and 2b, especi~lly isomer 2b(1);
(~-5,4-R,SS)-N-[6-(4-~luorophenyl)hexyl]-2-[4-carboxybenzyl.c~llphinyl]-2-oxoazetidin-l-ylpropion~mi~le and the corresponding allyl ester;

W O 97/02242 PCT~EP96/02765 N-16-(4-Fluorophenyl)hex- l-yl]-4-(5-carbo~yru~-2-methyl.clllrhinyl)-2-o~n~7Pti~1in-l-ylAretAmirle (Diastereomer 2) and the c-,l,c;sp~,nding allyl and methyl esters thereof;
N-(6-{4-Chlorophenyl}hexyl) 4 (5-carbo~-yfulal~-2-methylclllrhinyl-2-o~n~7Ptitlin 5 Y1)A~'et~m;~lP (Diastereomer 2) and the cc,lresponding allyl and methyl esters thereof;
1 -(2-(6-(4-Fluorophenyl)hexyloxy)ethyl)~benzyl.c--lrhinyl-2-o~o~7P.titlin~, (Diastereoisomer 2);
1-(2-(6-(4-Fluorophenyl)hexyloxy)ethyl) 4 (4-eth~-ywl,ol~yll~l.~l.~..lrhinyl)-2-oYo~7Pti~iinp (Diastereoicom~r 2); and 10 1-(2-(6-(4-Chlorophenyl)hexyloxy)ethyl)-4-benzyl.clllrhinyl-2-~ xo~7Ptitlin~. (Diastereoisomer 2).
Since the compounds of the present invention, in particular compounds of formula (I), are intPn~ed for use in phArm~ Al compocitionc, it will be ~ Prst~od that they are each provided in sl~bst~ntiAlly pure form, for PYAmrlP at least 50% pure, 15 more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Irnpure l~lepA.,1l;onc of the compounds of formula (I) may be used for pl~,Odlillg the more pure forms used in the ph~rmAreuti~l CGIllpoS;lionc Althol-gh the purity of intermP~iAtP compounds of the present invention is less critical, it will be readily untl~prstood that the substAnti~lly pure form is preferred as for the COml)GUll~lC
20 of formula (I). Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
When some of the compounds of this invention are allowed to crystallise or are recrystAllic~-i from organic solvents, solvent of crystAllicAtion may be present in the crystalline product. This illvenLion inrluriPs within iB scope such solvates. SimilArly, 25 some of the compounds of this invention may be cryst~llic~Pd or recrys~llicecl from solvents COI-IA;~ ~ water. In such cases water of hydration may be formed. This invention in~ln~Ps within its scope stoichiometric hydrates as well as compoundsCOI-IA;~ O variable amounts of water that may be produced by processes such as lyophilisAtion. In Ad~lition, different cryst~llicAtion con-iitior c may lead to the 30 form~tinn of dirre~ polymorphic forms of crystalline products. This inventionincludes within its scope all polymorphic forms of the compounds of formula (I).Compounds of the present invention are inhibitors of the enzyme lipop.oL~in associated phospholipAcP A2 (Lp-PLA2) and as such are expected to be of use in therapy, in particular in the tre~tmpnt of atherosclerosis. In a further aspect thel~rult;
35 the present invention provides a compound of formlllA (I) for use in therapy.The compounds of formula (I) are inhibitors of lyso~ho.cph~tirlylcholinP
production by Lp-PLA2 and may therefore also have a general application in any disorder that involves endothelial dysfunction, for exAml)lP atherosclerosis, ~liA-he h~l~el~ cio~, an~ina pectoris and after icchAPmiA and l~pelfu:jion. In addition,- 8 -wo 97/02242 PCT/EP96/027~,5 compounds of formula (I) may have a general ap~ ir,n in any disol.ler that involves lipid peroxirl~tion in conju.,clion with enzyme activit,v, for e~..r.lr m ~d~1ition to conrlitinne such as atherosclerosis and ~ hetpe~ other co~ such as rhPnm~t~
arthritis, stroke, infl~mm~tory cQnrlitionC of the brain such as ~l7hPimefs Disease, myocardial infarction, ~ P. ~l~sion injury, sepsis, and acute and chronic infl~mm~tif~n Further such con~litinne include various n~u.~ ycl~ ic disol~el~, such as scnizophrenia (see Psychoph~ ology Bulletin, 31, 159-165, 1995).
Further applir~tionc include any dLso ~er that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA2. F~mplps of such disorders include psc-ri~cie Accordingly, in a further aspect, the present invention provides for a method oftreating a disease state ~ceoei~tP~I with activity of the enzyme Lp-PLA2 which metha,d involves treating a patient in need thereof with a thP.,.~ lly effective amount of an inhibitor of the enzyme. The disease state may be associated with the il~leased involvement of monocytes, macrophages or lymphocytes; with the form~ti~n of lysophoerh~tidylchr,linP and oxitli~Pd free fatty acids; with lipid pero~ tirn in con~unction with Lp PLA2 activity; or with endothelial dy~ru"~lion.
Compounds of the present invention may also be of use in treating the above mrntif)nPd disease states in combination with anti-hy~.l;~ Pmir or anti-atherosclerotic or anti-diabetic or anti-anginal or anti-infl~mm~ts~ry or anti-llyl~t;l~nsion agents. Flc~mrlPs of the above include çhnlest~prol synthesis inhihitor.c such as statins, anti-oxi-l~ntc such as ~l~ucol, insulin ~eeneiticpre~ c~lrillm ch~nnPl antagonists, and anti-infl~mm~tory drugs such as NSAIDs.
~ thel~eulic use, the compounds of the present invention are usually ~ led in a standard ph~rm~celltir~l composition. The present invention therefore provides, in a further aspect, a ph~rm~celltic~l composition compri.cing a compound of formula (I) and a ph~rm~re~ltir~lly acceptable carrier.
Suitable ph~rm~reutir~l compositions include those which are adapted for OI
or pa,~nte,dl ~lministration or as a suppository.
~he compounds of forrnula (I) which are active when given orally can he fnrm~ tP~ as liquids, for example syrups, ~ ~"cionc or Pmnlcione, tablets, c~rslllPs and l~7~n~ps~
A liquid fol~nlll~tion will generally consist of a suspension or solution of thecompound or ph~rm~reutir~lly acceptable salt in a suitable liquid ca~rier(s) forexample, eth~nol, glycerine, non-aqueous solvent, for example polyethylene glycol, ~ oils, or water with a sll~pentling agent, pl~l v~tive, flavouling or colouring agent.
A composidon in the form of a tablet can be prepared using any suitable ph~rm~reutir~l carrier(s) routinely used for p,~pa i"g solid ft~rmnl~tionc Fy~mplt~s of such carriers include m~gnecillm stearate, starch, lactose, sucrose and cellnlnsP~
g W O 97/02242 PCT~EP96/02765 A composition in the form of a capsule can be prepared using routine enr~rsul~tion procedures. For eY~mrlP, pellets eo~ the active ingredient can be prepared using standard carriers and then filled into a hard gelatin c~rsnlP
~1lP~ ;V~1Y~ a fli~pPnciQn or s~L,p~cion can be prepared using any suitable S rh~rm~rel~tir~l carrier(s), for eY~mpkP aqueous gums, c~ll~ ses, .~ilir~tPs or oils and the di~pf~n~ion or ~u.,~llsion then filled into a soft gelatin c~rslllP
Typical palell~ldl compositions consist of a sollltirn or sll~ren~ion of the compound of formula a) in a sterile aqueous carrier or palc;nt~l~lly acceptable oil, for eY~mrl~P polyethylene glycol, polyvinyl pyrroliAonP, lPcithin arachis oil or sesame oiL
10 ~ltprn~tively~ the sol~ tion can 'oe lyophili~PA and then recon~titntPd with a sllit~' lP
solvent just prior to ~A...;.~ ftic)n A typical suppository formlllation c~-mpri.c~s a compound of forrnula (I) which is active when ~r.~mini~tPred in this way, with a binding andl'or l~.h. ;.~I;..g agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synt'netic waxes or fats.
Preferably the composition is in unit dose form such as a tablet or c~psl~1P
Each dosage unit for oral ~Amini~tration cont~inC preferably from 1 to 500 mg (and for pZ~ t~.a~ minictration contains preferably from 0.1 to 25 mg) of a compound of the formula (I).
The daily dosage regimen for an adult patient may be, for eY~mrlP, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or an avf_nous, subcutaneous, or intramllcclllar dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula a), the compound being ~f1,.,;.~ f~-~ed 1 to 4 times per day. Suitably t'ne compounds will be ~fAminictered for a period of continuous therapy, for eY~mplP for a week or more.
Compounds of fcrmlll~ a) may be prepared from co-lv~nient starting m~tPri~
by adapting synthetic procedures well known in t'ne arL A suitable process compri~P,s treating an azetidone of formula (II!:
R l ZR3 o~ H
(II) in which:
n, R1, R2 and R3 are as hereinbefore dPfinPf ,';
with an aLkylating agent of the formula (IlI):

LlCR4R5xy W O 97/02242 rCT~EPg6/0276' in which Ll is a snit~hlp- leaving group such as halogen or triflate; and R4, R5, X and Y are as he~l~;nh~-ro, e ~lPfinrd, in the presence of a s~it~hlP base such as sodium hydride or ~ hydroxide 5 optionaly with a 4~ y ~mmoninm salt such tetrabutyl ~mmonillm bromide, in a suitable a71~ylating solvent such as tetrahyd-uful~n ( I~;), and at a ~ in t"e:
range -10 tO 0~C
For compounds of formula a) in which Z is S(O)n, the preceding a7kylation re~rtion is collvenielllly t~-ffPcte~7 on compounds of formula (~) in which n is 0.
Compounds of form-ll~ (I) in which one of R4 and R5 is a7kyl may a7so be prepared from corresponding compounds of formula (I) where both R4 and R5 are hydrogen by tre~tmPnt thereof with an aL~ylating agent under the contlitit~ns t7çsr7 ihed above. Such compounds may be obtained by treating a compound of formula (~) withan a7kylating agent of formula (lII) in which both of R4 and R5 is hydrogen, under 15 aL~ylating connitit ns as hereinbrfnre described.
A second aLkyl group for R4/R5 may be introduced by treating a first obtained compound of formula (I) in which one of R4 and R5 is hydrogen, with an a71cylating agent in the presence of a suitable base such as sodium hydride, pot~C~il7m hydroxide or lithium hry~mpthyll7icil~7it7e in a suitable aLkylating solvent such as ~y~ Çu~u 20 (THF), and at a ~ç.--pel~tl-re in the range -80 to 10~C.
Compounds of formula (~) in which Z is S(O)n and n is 1 or 2 can be readily prepared from cc,l,es~onding compounds of formula (I) in which n is 0 by tre~tmPnt thereof with a s~it~hlP oxiflicin~ agent such as m-chlolopell~nzoic acid. Use of chiral ~xi~licing agents such as (+)- or (~ -bi-2-n~rhth- l / til;...;~ isopropoxide (N~nm~tsu et al, J Org Chem, 1993, 58, 7624-7626) can give diastereoi.comrnc selectivity, if not chirally pure compounds.
Compounds of formula (rl) in which in which Z is S(~)n and n is 0 may be obtained by treating 4-aceto~y;-7PI ;tlinonr~ 4-benzoyloxy~7~ti-1innnP or 4-phenylsulfonyl~7Pti~linone with a thiol R3SH in the presence of a base such as sodium ethoxide, in a suitable solvent such as ethanol at a tempelat~ in the range 0 to 5~C.
When this displ~remçnt is con~lucted in the prespnre of a chiral base, such as ~hinrhc~ni~linP or cinchonine, çn~ntiomerir~lly PnrichPd compounds (II) can be obtained (J Chem Soc, Chem Commun, 1982, 1324-5).
Compounds of formula (~) in which Z is O may be obtained by treating 4-acetoxy~7Pti~linQnr 4-benzoyloxy~7pti~inrJnp or4-phenylsulfonyl-~7Pti-~inonP with a phenol/alcohol R30H in the presence of a base such as pot~ccillm t-butoxi~lP~ in a suitable solvent such as THF at a temperature in the range O to 5~C
Compounds of formula (m) may be readily prepared by ~ pting known synthetic procedures, according to the specific value of X. A convenient starting W O 97/02242 PcT/~5~276s m~tP.ri~l is an applupliately sukstitllt~Pd aryl compound which may then be elaborated to introduce the side chain LlCR4RSX-.
Compounds of formula (I) in which X denotes a group CONR6(CH2)m, CONR6X2, CONR60(CH2)m or CONR60X2 may be cc.llvt;niell~y plc~ cd by S treating an acid of the formula (IV):

R'+~",ZR3 ~N

(IV) in which:
10 Z, Rl, R2, R3, R4 and RS are as hereinbefore ~lpfinpd with an amine of the formula (V):

NHR6x5y (V) 15 or a hydroxylarnine of the forrnula (VI):

(VI) in which XS is (CH2)m or x2 and m, R6, Y and x2 are as hereinbefore tlefin~
20 in the presence of an activating agent such as ethyl chloroformate or dicyclohexylcarbodiirnide (DCC), in a suitable solvent such as chlo-ofc",l, or dirnethyl form~mirl~P~ at a temperature in the range -10 to 20~C.
An acid of formula aV) in which one of R4 and RS is hydrogen may be obtained by treating a compound of forrnula (II) with a co~ ,pollding 2-bromo ester, 25 for inct~n~e a (Cl 7) ~lk~no~tP. ester, under aLkylating conditions as hereinbefore ~losrrihe~ followed by the hydrolysis of the thus formed intp~n~ te ester using standard confii~if)nc A second group, for in.ctqsln-~e an aLtcyl group, may then be introduced by aLkylating of the first formed mono~lkyl ester.
Compounds of formula (I) in which X denotes a group COO(CH2)m or 30 COOX2 may be conveniently prepared by a tr~n.cestP.rifi~tion reaction from another ester, in particular the methyl ester of forrnula (VII):

~f ZR

~ \CR~R5--CO2CH3 (VII) in which:
Z Rl- R2, R3 R4 and R5 are as h~ ;..r~fore clP.finP.-l using con~litionC well known in the art for such rP~ction.C, for ~ e heating in S toluene in the presence of a catalytic amount of sodium mP.th~xi~1P and an ~lt'oh~l A compound of formula (VII) in which one of R4 and R5 is hydrogen may be obtained by treating a compound of fonn~ (I[) with a methyl 2-bromo(Cl 7) k~no~te under aLkylating con~itio~c as hP.~ hç~ ~lç~nhe~
.~ltP.rn~tively a compound of fonnlll~ (I) in which X denotes a group 10 COO(CH2)m or COOX2 may be prepared by treating a compound of formula (IV) with an alcohol YX50H or an activated derivative thP~eof, for inst~nre- a tosyla~e.
Compounds of formula (I) in which the linker group X contains an ether function may be prepared by a suitable ether coupling reaction, for inct~n~e treating a compound of formula (Vm):
R~ ZR3 ~~ \CR4R~--X2(CH2)pL2 (VIII) in which Z Rl R2 R3 R4 R5 and x2 are as here~nbefore ~IP.finP.d 20 with a compound of formula (lX):

L3(CH2)qY
(r~
in which one of L2 and L3 is a halogen or other sllit~hhP- leaving group such as triflate 25 or tosylate and the other is OH or a suitable salt therof and p and q are as he,cil~fc,,~
dP-finP.~; under standard ether forming coll~itionc Compounds of formula (I) in which Z is S(~)n and n is 0 may also be prepared by a process which cnmpri.ces treating a compound of formula (X):

R2 _~SAg O CR4Rs-x y (X) in which Rl R2 R4, R5 X and Y are as hereinbefore defined;
with an aL~cylating agent of the formula (XI):

W O 97/02242 PCT~EP96/02765 R3Ll ~ )in which R3 and Ll are as hereinbefore definPd;
5 under snit~khP aLkylating con~liticmc~ for inct~n~P, in a solvent such ~ ~elu..;~ P, at a ...pe~i.tllre in the region 25~C.
Compounds of formul~ (X) may be obtained from the corresponding ~
acetylthioa7Pti(linone by trÇ~tn Pnt with silver nitrate and a b~e in a suitable solvent such as mPth~nnl Mixtures of diastereoisomeric compounds of formula (I) may be resolved, if so ecire~l according to procedures well known in the a~ For ~ nce slllpho~i.1P,s (n=l) may be separated by chromatography and/or cryst~llic~tion. Chirally pure compounds may be prepared by chiral chromatography, from chirally pure intPrmP11iatPS or by chiral syll~lesis using chiral reagents or catalysis. S-litahlp chiral 15 intern~p~ tp~s may be obtained by resolution or chiral in~uction or by using chiral re~g~ntc, in particular natural chiral molecules, according to methods well known to those skilled in the art. For chiral synthesis, a convenient chiral starting m~tPri~l is a pPni~illin derivative which has the pl~Çellr d confi~llration at C~ of the ,B-lactam ring.
This is illllctr~t~d in the following scheme for the preparation of suitable intPrmPrliat~s Br S~O P(OiPr)3, Ac~O ~SAc (fl ~3. EtOAc~ -70~ Br"~c ~ ~ MB ~ (iii) aq acid O ~

Br _SAg Br ,SCH2Ph Br ,SCH2Ph NEt3. AgN03 '~~ PhCH2Br "~ (i) KOH/MeOH. 0~ '~
MeOH ~N~Coo-pMB MeCN ~N~CO~pMB (ii) HCI 0~ \~COOH

DCuHogt Br~scH2ph mCPBA, CH2C12 Br~SCH2Ph Zr~AcOHJCH2C12 F~SCH2Ph Ph(cH2)6NH2 0 N~coNH(CH2)1~Ph O N~CONH(CH2)~Ph N ,coNH(cH2)~,Ph The preparation of the starting material (4-methoxyben_yl-6-bromopenicillin~tP-1-oxide) is descr~bed by J. Chem. Soc., Perkin Trans. 1, 1994, 179-188. An alkyl sllbsSituent (R4/R5) may be introduced at a late stage in the sequence. using alkylating 25 conditions hereinbefore described.
The present invention will now be illustrated by the following PY~mpl~Ps The relative confign~tinnc of the centre at the C4 position in the ~7Pti~linone and the centre alpha to the N of the azetidinone are unknown in the two diastereoisomers (a and b) described below but are thought to be R,R/S,S (diastereoisomer a) and R,S/S,R

W O 97/02242 PCT~EP96/027C5 ctPrçoicomPr b). The relative conf~ r~tionc of the C4 and snlfo~ P centres ar~
also unknown, but are thought to be R,R/S,S (tlia~tereoi~com~r 1) or R,S/S,R
(~iactPreni~(!rnp~r 2). Such config~ tinnc were obtained initially by x-ray analysis of a limited number of colllpuu~lds and then eYsr~r)olatp-cl to the rçm~ining cc~ ds an S the basis of their lH NMR spectra Unless o~erwise speçifiP~l (e.g. isomer (-)b2) ~11 compounds are racPmir (e.g. diastereoicomPr b2). All cc,lllpollnds are pre~ y the (diastereo)isomer descAbed. All compounds are c 1 ~~- a~ ~. ;.ced by NMR and most by microanalysis and mass spec,. Melting points are uncorrected. T.comPrc and çn~ntirJmPrs are l~hPllPd as de~crrihed above to farilitatP des ,~i~lion of the s,~ leses 10 and to in~licatP prefprred collll)ounds.

W O 97/02242 PCT~EP96/0276S

lions 4(5-AllyloAy~ .ylru~ 2-~ lU,io~ 2 one a Meffiyl5-(chlo.~ 2-rulo~l~
A stiIIing mixture of p~ rO.. ~ltiehyde (25.22 g, 0.84 mol), anllydr~us zinc çhlr)ri~p~
(108.06 g), and methyl 2-furoate (100 g, 0.793 mol) were cooled to 15 ~C (ice bath) and a stream of HCl gas bubbled through with .stirring- The Ir~ e wa~s allowed to rise to 25-30 ~C, and after 1 hr the ll~A~ULC~ was poured onto ice-water. Theorganic layer was sep~ d off and the ~queolls layer further e~trActPd with 10 dichloromPth~np-~ The comhinP-d eytrArtC were dried (MgS04) and t;vapc,ld~d to a dark brown oil. Di.ctill~tion under reduced ~ ,ule gave the product as a pale yellow solid (72.5g, 52% yield ), b.p.( 88~C/0.8 mm Hg). lH NMR ~ (DMSO-d6) 3.82 (3H, s, CH3), 4.90 (2H, s, CH7), 6.75, 7.29 (each lH, d, furan-H) b. Methyl5-(ac~lylll.iomethyl)-2-lu~o~te Methyl (5-chloromethyl)-2-furoate (50 g, 0.286 mol) was dissolved in dry dimethylform~mi~lP (300 ml) and pot~ lm thin~et~tP ( 32.68 g, 0,286 mol) added with stirrino The initial exotherm was controlled by cooling ( ice bath), then the reaction was stood at room Lelllpt:,ature for 2 hr. The solvent was evaporated and the residue treated with water and thoroughly e~trA~tP-d with ether. The combinPd extracts were dried (MgSO4), evaporated and purified by flash chromatography (silica, ethyl acetate/petroleum ether) to give the product as an oil (40.9g, 67% yield). lH
NMR ~ (CDC13) 2.36 (3H, s, CH3CO), 3.88 (3H, s, CH30), 4.16 (2H, SCH7), 6.36, 7.09 (each lH, d, furan-H) ~ 4(~-(AIIYIOA~1,onyl)furan-2-~nLU.~lll~iop~ 2-one Potassium t-butoxide (12.77 g, 0.114 mol) was stirred in allyl alcohol ( 60 ml) until complPtP sol~ltio~ was obtained. Methyl 5-(acetylthiomethyl) furoate (22.17 g, 0.104 mol) in allyl alcohol (60 ml) was then added, and after 2 hr the mixture was cooled (ice bath) and a solution of 4-acelo~y~7~ 1in-2-one (13.36 g, 0.104 mol) in dry tetrahydrofuran (100 ml) added dropwise over 20 min. After a further 30 min, thecooling bath was removed, then the mixture stirred for 3 hr at room tempel~lLulc~. The solvent was evaporated and the residue treated with brine and e~ttr~ctPd with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated to give the product as a pale yellow oil (22.5g, 81% yield). lH NMR ~ (CDCl3) 2.87 (lH, m, --3a)~ 3-43 (lH, m, H3b), 3.89 (2H, m, SCH2), 4.79 (2H, m, CH20), 4.94 (lH, m, ~4), 5.38 (2H, m, CH7CH-), 6.01 (lH, m, C_CH2), 6.33, 7.13 (each lH, d, furan-H), 6.74 (lH, N~) 4(2-Fluoroph~noxy)~7eff~1in-2-one A solution of 2-fluorophenol (4.5g, 40mmol) and 18-crown-6 (5 mg) in dry THF
(lOOml) was treated with potassium t-butoxide (4.5g, 40mmol) and a solution of 4-benzoylo,.y;17P!i~lin-2-one (7.7g, 40mmol) in dry THF added. The mixture was stirred for 1 h and quçnrhP(i with aqueous citric acid and ethyl acetate. The organic layer was sPp~r~ltP(l, washed with brine, dried (Na2SO4) and evaporated. On trituration under ether/excess n-hexane and filtration the title compound was obtained as a solid (5.8g, 80%) m.p. 95-6~

CA 0222F.627 1997-12-23 lH NMR ~ (CDCl3) 3.17 (lH, dd), 3.34 (IH, m), 5.66 (lH, m), 6.59 (lH, bs), 6.93-7.18 (4H, m) The following were prepared from 4aceto~ non~ (or ~acetoxy-3-5 methyl~7Ptit1in-2-one) and the required phenol in a similar manner 4(Phenoxy)~7~ in-2-one m.p. 107-8~C
1 (2-Methylr~ nnxy)~ one m.p.105-6~C
~ 4(2-Ben_yloAy~ ,(,A~ e~ 2~onem.p. 86-7~C
4(2-MeU.ylU~iophenn~y)~ one m.p. 131-2~C
4(4Allyl~ ~Lonylrhpnnyy)h~ onem.p. 51-2~
4~4-Chlor.,~lleJ,.,~)~7PhA;n- one m.p. 115-6~C
4(4Methoxyph~n.>Yy)~7e1i~lin-~one m.p. 96-7~C
4(4Mell,~lll.iophenoxy)~ ~Dne m.p. 118-20~C
~rans-3-Methyl~(phenoxy) ~7~ffrlin_~one lH NMR o (CDC13) 1.35 (3H, d,7.6E[z), 3.55 (lH, m), 5.63 (lH, d, 4.0Hz), 6.83-7.38 (6H,m) N-(6-phenylhexyl)br~.l..o~e~ ide A cooled solution of 6-phenylhexylamine (26.6 g) (Morse M. A. et al., Cancer Research, 1991, 1846) and Hunig's base (19.5 g) in dry dichl~ J...~Ih~ne (300 ml) was treated with bromo~cetylchl- n~l~ (23.38g) in dichlorom~th~nP (50 ml) at 0-5 ~C.20 After aqueous workup and chromatog;aphy N-(~phenylhexyl)-l-bromo~ret~mi-1e was obtained as a colourless solid, 35.4 g (83%), m.p. 29-32~C.
N-(6-(4-chlorophenyl)hexyl)~ v.~ c~ ~ide ~(~Chlorophenyl)hexylamine (T ~m~ttin~ J. L. EP 138464 A2 850424 (CA
103: 142000)) was treated with bromoacetylbromide in a similar manner to give the title compound as a colourless solid, m.p 67-8~C, (93%).

4(Bc..~,~lll.io)~7Pti~in-2-one Sodium (8.1g, 0.35mol) was dissolved in ethanol (250ml) and ben_yl melca~La l (45.2g, 0.37mol) added dropwise over 20 minllt~s k~eping the Lt~lllpel~ beLweel~ 20 ~C - 25~C whilst bubbling nitrogen through the mixture. After 15 ~ r-s~ the reaction was cooled to 5~C and a solution of 4-aceto~y~7Ptitlin-2-one (45.0g, 0.35mol) in ethanol (50ml) was added dropwise over 15 min~tPs whilst m~ ;ni-~g the temperature at 5~C. The mixture was stirred at room tempel~lu~e for 60 ..~ and evaporated to dryness under reduced pressure. Water (400ml) was added, the mixture eYtr~rtPd with dichlorometh~np (2x300ml), the extracts dried (MgS04) and evaporated under reduced pressure to an oil. The oil WâS cooled to -20~C and tir~lr~tP-d with ether (400ml) to give a white solid which was i.col~tP.cl by filtration (50.2g, 79%), mp 50-51.0~C.
Methyl-(4-bel.~yltllio-2-oxo~7~ n-l-yl) acetate To a solution of ~(benzylthio)~7Ptidin-2-one (5.0g, 25mmol), methyl bromo~re (4.6g, 30mmol) and tetrabutylammonium bromide (0.9g, 0.28mmol ) in dry THF
(lSOml) was added powdered potassium hydroxide (1.7g, 30mmol). The res~llting n~ ule was stirred for two hours at room tempelalu,f before water (50 ml) was added. The solution was extracted with ethyl acetate (3xl50ml portions) and the combinP~ extracts dried (MgS04) and evapol~d. The residue was purified by flash W O 97/02242 PCTAEP96tO2765 chromatography on silica gel eluted with petroleum ether 60~-80~:ethyl acetate 4:1 to give methyl (4-ben~ylll~o-2-oYo~7Ptillin-l-yl)acetate as a yellow oil (Sg, 70%).lH NMR ~ (CDC13) 2.96(1H, dd, J=2.5, 16 H_ H3a)~ 3.24,3.99 (each lH, d, J=18.00 H_, NCH2), 3.4 (lH, dd, J=5,12.5 Hz H3b), 3.70 (3H, s, OCH3), 3.77 (2H, s, SCH2), 4.92 (lH, m, ~4), 7.28 (SH, m, Ph-_) (4-Be.~llll;O 2-Q~ Iidin-l~yl)ace'dc acid To a solution of methyl (4-benzylthio-2-oxo-~7Pti~lin-l-yl)acetate (2.5g, g.4mmol) in methanol (80ml) was added, dropwise at 0~C, a soll~ti~n of 1 N sodium hydro~cide(9.9ml, 9.9mmol). The reaction was stirred for 1 hr and eva~ulà~d to dryness. Water (50 ml) was added and the soluti~n ~Ci~lifipd to pH 3 with dilute hydrochloric acid and extracted with ethyl acetate (3xlOOml) . The combinPd eYtr~rtc were dried (MgS04), evaporated and the residue pu~ified by lt ~;ly~ li.~tinn (hexane/ether) to give (4-benzylthio-2-oxo-~7Ptitlin-l-yl)acetic acid as a white solid (1.3g, 55%), mp 110-111~
C. lH NMR ~ (CDC13) 2.99 (lH, dd, J=6.87,17.5 Hz, H3a)~ 3.27, 4.06 (each lH, d, J=18.40 Hz, NCH2), 3.39 (lH, dd, J=5,15.4 Hz, H3b), 3.77 (2H, s, SC_2)~ 4.91 (lH, m, H1), 7.27 (SH, m, Ph-_).
l-(Am~no)-6-(3-chlorophenyl)hex-1-yne a 6-(3-chlorophenyl)hexyn-1-ol A surred mixture of 3-chloroiodoben~ne (14.3g, 60mmol), tetrakis(triphel.ylrhosrhinP) p~ flinm (2.1g, 1.8mmol) and 5-hexyn-1-ol (5.9g, 60mmol) in triethylamine (120ml) was stirred at 25~C for 3h and partitioned b~n water and ether. The ether layer was ~s~p~r~tPd and the aqueous extracted with ether.
The combined ether extracts were washed with lN HCl and dried (Na2S04). The ether was evaporated and the residue purified by flash chromatography on silica using dichlorometh~n~ as eluant. Evaporation of the applu~,liate fraction~ gave the product as an oil (l l.Sg, 92%) b. 1~ o)-6-(3-chlorophenyl)hex-1-yne A solution of 6-(3-chlorophenyl)hexyn-1-ol (ll.Sg, SSmmol), triphenylphosphin~
(14.5g, 55mol) and phth~limidP (8.1g, 55mol) in dry THF (l lOml) was treated with a solution of DEAD (9.6g, 5~mmol) in THF (20ml) over several minllt~s- After 16h, volatiles were removed in vacuo and the residue treated with ether. The precir)it~ted solid was removed, the filtrate evaporated and the residue purified by flash chromatography on silica using dichloromp-th~nlo as eluant. Evaporation of the applopliate fractions gave l-(phth~limil10)-6-(3-chlorophenyl)hex-l-yne as a solid (16.5g, 89%) c 1-(An~ino)-6-(3-chlorophenyl)hex-1-yne A mixture of l-(phth~limitlQ)-6-(3-chlorophenyl)hex-1-yne (6.6 g) and hydrazine hydrate (2.24 g) in ethanol (100 ml) was heated at reflux temperature for 18 h. After cooling and filtPrin, the solvent was evaporated to give an oil which was dissolved in diethyl ether and washed with brine, dried and evaporated to give 1-(amino)-6-(3-chlorophenyl)hex-l-yne as a brown oil (3.1 g, 77%).
The following 2 amines were prepared in an analogous manner:
1-(Amino)-6-(2-chlorophenyl)hex-1-yne l~(Arnino)-6-(1-naphthyl)hex-1-yne W O 97/OZ242 PCT~EP96/02765 ~phenyl-3-heA,~
a N-(6-phenyl 3 1,~
A ~ Lulc: of phth~limi~p (8.78 g), 6-phenyl-3-hexynol (J.Dijkink, N.Sye~;~
S Tetr~hPllron~ Vol.34, 173-178, 1978) (8.0 g) and triphenylrh~).crhinP (12.04 g) in dly THF (75 ml) was cooled to 5~C u~der nitrogen. A soluti~n of diethyl ~7o~lir~rboxylate (8.0 g) in dry THF (20 ml) was added over 10 minutes m~i.~ .;..;.~p ~ the tPmrPr~tllre at 10~C. The reaction was stirred at room tP~re~,.tllre for 20h, evilpoldted to dryness, dissolved in CHC13 (250 ml) and washed with lN NaOH, brine, 10 2N HCl, saL NaHCO3, brine, dried (MgS04) and ev~ol~d to a cream solid (28. l g). pllrifir~tion by flash column chrom~to~o~r~rhy eluted with 10:1 to 2:1 petroleum etherethyl acetate and recryst~lliC~t~n from ethanol gave N-(6-phenyl-3-h~yllyl)rhth~limiti~ as a cnlol-rlPcc solid (8.25 g, 59%) m.p. 95-96~C.
b. 6-phenyl-3-heAy ~ ~
15 N-(6-phenyl-3-he~yllyl)rhth~limi~l~p (3.0 g) in ethanol (150 ml) was treated with hydld~e monohydrate (0.96ml) and st~red at reflux for 4h. The reaction was coo]~ed, evaporated to dryness and azeotroped with water. The residue was treated with lMNaOH and P~tr~ctPd with diethyl ether (x2). The organic extracts were combined a~nd e~LIa~;L~d with 2N HCl (x2). The aqueous extracts were combined and b~cifiPd with 20 NaOH(aq) and extracted with diethyl ether (x2). The organic extracts were combined, washed with water, dried (MgSO4), evaporated to give 6-phenyl-3-h~y,ld.l.il~e as ~In oil (1.52 g, 89%).
Z~phenyl-3-h~At:l.yl~...~.e a Z-N-(~phenyl-3-hexenyl)phth~
25 N-(6-Phenyl-3-hexynyl)phth~limi~i~P (4.4 g) in ethanol (140 ml) was hydrogenated at 40psi/20~C with Lindlar's cayalyst (60 mg) for 105 minlltPs The reaction was filtered and ~vapoldted to a yellow oil (4.51 g). Pl-nfi~tion by flash colurnn chromatography eluted with 6: 1 to 4: 1 petroleum ether: ethyl acetate gave ZN-(6-phenyl-3-hexenyl)phth~limi~l~P as a colourless oil (4.15g, 94%). v c=c 1656 cm~l; nmr 30 hom-)n~clP~r decoupling gives 3JH3 H4 (alkene) = 10.8Hz.
b. Z-6-phenyl-3-heA~:--yl~--~i~-e Z-N-(6-phenyl-3-hexenyl)phth~limirle (1.95 g) in ethanol (100 ml) was treated with hydrazine monohydrate (0.64 g) and the mixture was stirred at reflux for 4.5 h and stirred at room tempela~ule for 22 h. The reaction was evaporated to dryness and35 azeotroped with water. The residue was mixed with lN NaOH and eYtr~rtPd with diethyl ether (x2). The organic extracts were combined, washed with brine, dried(MgSO4) and evaporated to dryness. pll~ifir~tion by Kugelrohr ~ till~tion at 185-200~C/0.2mmHg gave Z-6-phenyl-3-hexenylamine as a colourless oil (collLa~ns 6-phenylhexylamine 10%) (0.89g, 80%).
40 E-6-phenyl-3-hexenylan~ine a, E-N-(6-phenyl-3-hexenyl)phth ~lim;~l~
A I~ Lulc~ of E-6-Phenyl-3-hexenol (J.Dijkimc, N.Spec~mp, Tetrahedron, Vol.34, 173-178, 1978) (6.35 g), phth~limicle (6.89 g) and triphenylphospin~ (9.45 g) in dry THF (50 ml) was cooled under nitrogen. Diethyl azodic~l~ylate (6.27g) in dry I~IF
45 was added over 10 minutPs m~int~inino t'ne temperature at 10~C. The reaction was W O 97/02242 PCT~EPg6/02765 stirred at room ~ lprl"hlre for 20 h and evaporated to dryness. The residue was rnixed with CH2C12 (100 ml) and washed with lN NaOH, brine, lN HCl, brine, dried(MgS04) and evaporated to dryness. pll.;r~ on by flach column chromatography eluted with 8:1 to 4:1 petroleum ethel..,Lhyl acetate gave trans-N-(6-phenyl-3-hexenyl)phth~limi~P as a colourless solid (6.96 g, 63%) m.p. 75~C. v ~=~ 1670 cm~
and nmr homrm~ P~r ~lecollpling gives 3JH3 H4 (alkene) = l5Hz.
b. E-6-phenyl-3-h-:At~ ,e E-N-(6-phenyl-3-hexenyl)phth~limitle (4.79 g) and propylamine (5 g) in ethanol (200 ml) were stirred at reflux for 2h and then at 70~C for 18h. The reaction mL~t; was evaporated to dryness and azeotroped with eth~nol The residue was mi~ed with lN
NaOH and extracted with diethyl ether (x2). The organic eAtracts were combinP-I
washed wit-h- 2N HCl (x2). The aqueous ç~tr~tc were combined, washed with diethyl ether and then basified with NaOH(aq) and eYtr~tp-d with diethyl ether (x2). Theorganic extractc were combined, wached with brine, dried (MgSO4) and eva~o,a~d to an oil. Purification by Kugelrohr rlictill~tion at 180~C/0.5mmHg gave E-6-phenyl-3-hexenylamine as a colourless oil (0.98g, 36%).

5-PhenoA~ e a S-Chlor~l-phenoA~pent~
A mixture of phenol (2.67 g, 0.028mol), 1,5-dichlolopenta~le (20 g, 0.148mol) and K2C03 (20 g, 0.144mol) in methyl ethyl ketone (300ml) was refluxed for 24 hourc.After cooling, the reaction mixture wac filtered, and evaporated to a yellow oil (37.8 g). This was purified by flash chromatography on silica gel eluted with hexane/ethyl acetate 15:1 to give a yellow oil (18 g). This was evapo,ated using a high va~;uu~l with a water bath temperature >80OC to remove the excess 1,5-dichlc~,~n~e (b.p.
63-65~C) to give a yellow oil (5.8g). The oil was further purified by flash chromatography on silica gel eluted with hexane to give 5-chloro- l-pheno~Lyl,e..~e as a yellow oil (2.50 g, 44%).
b. N-5-Ph~ Ay~ lyl ph~
5-Chloro-l-pheno~ypentane (2.50 g,l2.6mmol) was dissolved in DMF (75 ml) and pot~ m phthsllimi~iP (4.65 g, 25.13mmol) was added and the mixture stirred at 100oC overnight for 18 hours. The DMF was evaporated and the solid was partitioned between ethyl acetate (75 ml) and water (50 ml). The organic layer was washed with H2O (50ml3, dried (MgS04) and evaporated to yellow solid. The yellowsolid was purified by re cryst~llic~tiQ~ from ether/pet ether to give a white solid. The white solid was re cryst~lliced again from ether to give N-5-phenoxypentyl phth~limide as a white solid (2.50 g, 64%), m.p. 62-64~C.
c 5-Pl~ Ay~entylarl~ine N-(phenoxy)-5-pentyl phth~limidp- (2.50 g, 8.08mmol) in ethanol (200ml) and hydrazine monohydrate (1.21 g, 24.17mmol) was refluxed for 18 hours overnight.
Then filtered and evaporated, then evaporated from water a few times then evaporated from ethanol. 2M NaOH (500 ml) was added and extracted with ether (200 ml x2).
The organic layer was washed with water several times until pH of solution was neutral, then dried (MgS04) and evaporated to give 5-phenoxypentylamine as a a yellow oil (1.13 g, 78%).
2-(2-phenoAy~:ll,ylox~)ethylamine W O 97/02242 PCT~EP96/02765 Se~uential tre~tm~nt of 2,2'-dichlorodiethylether with phenol/K2CO3/2-l,.~ o..P arld pot~ccillm phth~limi-WDMF as ~esr,ribed m the previous Plr~p;l~n~ (at a and b) above gave N-(2-(2-pheno~-yt:~-yloxy)ethyl)rhth~limitle as a colourless solid.
Tre~tment of this phth~limi~P (2.99 g) with hyd~azine hydrate (1.44 g) in ethanol (2130 5 ml) by the procedure in the previous Prep~tinn (at c) gave the title amine as a yellow oil (0.81 g, 47%)/
2-(3-phr~ r~ yloxy)~ u~-e ~ FSh~nQ1~minP (1.53 g) was added to NaH (1.0 g) in di-nethyl sulfoxide (DMSO) (10 rnl) at room tompr~ , followed by l-bromo-3-ph~nylt,lo~alle (5 g) and the mi~nlre 10 stirred at room temperature for 0.5 h. After aqueous work-up the title col--poulld u~as obtained as a yellow oil (1.6 g, 36%).
~Phenylhexy~loxy~ triflate a 2-(6-Pht~ oxy)e~

6-Phenylhexyl bromide (6.10 g) and ethylene glycol (15.5g) were added tO a solution 15 of sodium hydroxide (1.08 g) in water (1.1 ml) and the mixture heated at 100~C for 30hrs. Ether (75 ml) and water (75 ml) were added, sep~aled and the ether layer was washed with water then brine, dried over MgSO4 and evaporated to an orange oil.
This was purified by Kugelrohr ~lictill~tion (225~C/0.2mm) followed by chromatography on silica gel (40-60 petroleum ether/ethyl acetate) to give a colourless 20 oil (3.04g; 54%) b. 2-(~Phenylhexyloxy)ethyl triflate 2-(6-Phenylhexyloxy)ethanol (2.88g ), pyridine (1.23 g) and DMAP (20 mg) were dissolved in dry CH2C12 (lSml), cooled to -5~C and triflic anhydride(4.37 g) in CH2C12 (10 ml) was added over 5 mins kPeping temp ~0~C. The mixture was stirr~d 25 at 0~C for 1 hr then washed with water, bnne, dried over MgSO4 and evaporated to a colourless oil (4.54g, 99%).
The following 2 triflates were prepared in an analogous manner.
2-(6-(4-Chlorophenyl)hexyloxy)ethyl triflate 30 2-(6-(4Fluorophenyl)hexyloxy)ethyl trinate 3-Phenoxy-1-trifluo,o..~ .lrhollyll"o~!a~-e A mixture of 3-phenoxypropan-1-ol (2.38 g), pyridine (1.19 g) and 4-dimethylaminopyridine (DMAP) (0.10 g) was cooled to -5~C under a N2 atrnosphere.35 TrifluoromPth~nP sulfonic anhydride (4.4 g) dissolved in dry dichloromPth~n.- (15 ml) was added dropwise over 30 mimltps between 0~C to -5~C, then stirred for 2 hours at 0~C. The mixture was poured into water and the organic layer was sep~r~tp-~l washed with water (x2), dried (MgSO4), evaporated under reduced pressure to a dark brown oil which was purified by silica gel flash chromatography, eluted with petroleum ether 40 40~C - 60~C/ethyl acetate 2:1, to give the title compound as a clear oil pale brown/orange oil (3.22g, 73%).
2-Phenoxy-1-trifluororn~Pth~nPe-llphonyleth~nP was prepared in an analogous manner from the corresponding alcohol.
(4-(4-ethoxycarbonyl)ben_ylthio)~7eff~lin-2-one 45 a. Ethyl 4(bromompthyl)ben7o~t~p W O 97/02242 PCT~EP96/02765 1 (Bromom~Athyl)benzoic acid (25.75g, 0.1197moles) was s~lspentled in thionyl ~hlori~le (50ml) and dimethylr~ e (0.25ml) was added. The lll~ALuLt~ was heated under reflux for 25 mimlt~s until clear, eva~u~ d and a~e~ ,ped with toluene (~c2).
The rç~ ting oil was dissolved in dichlorometh~n~A- (75ml) and added dlo~ ise over 10 S minutps to a soll~tinn of absolute alcohol (8.6ml, 0.1465moles), pyridine (lO.~ml, 0.1298moles) in dry dichlorom~-th~n~ (SOml), cooled to 10~C. The ice bath was removed and the re~Atif)n was stirred for 45 minllt~s, then washed with water, 2NHCl, water, sodium hydrogen carbonate solutic ~ and brine. The organic sol~ltif ~ was dried (MgS04) and evapola~ed to give a mixture of 60:40 ethyl 4-(bromollle~lyl,~ ~n -~LtA
ethyl 4-(chloromethyl)ben70~t~o- as an oil (25.6g, 94%) lH nmr ~ (CDC13) 1.40 (3H, m, CH3), 4.40 (2H, m, CH20), 4.50, 4.61 (2H, 2~s, CH2Cl/Br), 7.45 (2H, m, Ar-H), 8.01 (2H, m, Ar-H) b. Ethyl 4(a~1y! ' ~
60:40 Ethyl 4-(bromQm~thyl)b~n70~te ethyl 4-(chloromethyl)be~ ~ (25.0g, 0.11 lmoles) in dry dimethylfnrm~mi~ie (lSOml), cooled to 5~C, was treated with potassium thio~ret~t~-- (13.3g, O.117moles) and the temperature rose to 20~C. The reaction was stirred at room ~ e,~1t~lre for 2 hours, poured into water (250ml) and extracted with diethyl ether (3xlOOml). The organic extracts were combined, washed with water, dried (MgS04), charcoaled and evaporated to give ethyl 4-(acetylthiom~thyl)~-n70~t~- as a brown soild (26.0g, 99%), m.p. 36-37~C.
lH nmr ~ (CDC13) 1.38 (3H, t. J=7. lHz, C_3), 2.36 (3H, s, COC_3), 4.14 (2H, s, CH2S), 4.36 (2H, q, CH20), 7.35 (2H, d, J = 8.2Hz, Ar-H), 7.97 (2H, d, J= 8.2Hz,Ar-H) ~ 4-(4-(Ethoxy~ l,onyl)~ io)~ -~one A soluti~ n of sodium (1.87g, 0.0813moles) in absolute alcohol (300ml) was treated with a sol~lti~ n of ethyl 1 (acetylthiomethyl)ben7o~tP- (19.4g, 0.0814moles) in absolute alcohol (75ml) over 3 mimltes The reaction was stirred at room t~mpe.~--f~ for 30 minut~S, cooled to -5~C and treated with a snlllti- n of 4-acetoA~ in-2-one (lO.Og, 0.07745moles) over S min~lt~s The cooling bath was removed and reaction was stirred for 2 hours, evaporated to dryness and treated with brine (200ml) and ~t-~etecl with ethyl acetate (200ml, lOOml). The organic extracts were combined washed with brine, dried (MgS04) and evaporated to a red oil. Purified by flash column chromatography on silica gel eluted with 3:1 to 1:2 petroleum ether40-60~C:ethylacetate to give 4-(4-(ethoxycarbonyl)benzylthio)~7ptil1in-2-one as an orange oil(18.64g, 91%).
lH nmr ~ (CDC13) 1.38 (3H, t, J=7. lHz, C_3), 2.82, 2.89 (lH, 2xm, _3), 3.29, 3.35 (lH, 2xm,_3), 3.88 (2H, s, CH2S), 4.37 (2H, q, C 2~)~ 4.70 (lH, m,_4), 5.70 (lH,bs, N_), 7.40 (2H, d, J = 8.3Hz, Ar-_), 8.00 (2H, m, Ar-H) F,~

7~Y~7rr7p~ 1 N-t6-(4-chloro~ "~ exyl)~ t1 b~ lU,io~ idin-1.
yl]propionz77n~ n~ b) a Methyl 2.~be,~ylll~io~ in-l-yl)propionate A mixture of 4-bel~y~ o~7ptirlin-2-one (1.93 g, 0.01 mol), methyl DL-2-bromopropionate (1.23 ml, 0.011 mol) and tetra-n-buty1~7mmQni-7m bromide (0.32 ~"
0.001 mol) in dry tetrahydluru~n (50 ml) was treated with freshly powdered po!~c~ l hydroxide (0.62 g, 0.011 mol) and stirred at ~mhi~nt ~ ; for 1 10 hour. Following trP~tmPnt with ethyl acetate and water, an in.col~lble yellow solid ~as removed by fillr~tion and discarded, and the filtrate sep~ 7 The aqueous layer ~vas extracted again with ethyl acetate and the c~ mhined PY~,7-~t~ dried (MgSO4) andevaporated to a brown oil. p~lrifir~tion by flash chromatography (silica, ethyl acetate/petrol) gave the title co,~ nd as a mixture of diastereoicom~rs (coloorless 15 oil), 0.5 g, 18% yield.
lH NMR o (CDC13) 1.55 (2x3H, d), 2.93 (2xlH, m), 3.29(2xlH, m), 3.74 and 3.7'5 (each 3H, s), 3.80 and 3.84 (each 2H, s), 3.91 and 4.41 (each lH, q), 4.70 and 4 96 (each lH, m), 7.30 (2x'5H, m) b. 2-(4.B~yla~io~ o~ ;..-l-yl)~ acid A st7rred solution of methyl 2-(4-ben~ylLhio-2-o~o~7Pt~ n-l-yl)propionate (1.39 g, 0.005 mol) in m~.th~nol (12 ml) was treated with 1 molar pol~c~ .. hydroxide (5.4'7 ml). After 2 hours, the mçth~nol was evaporated and the residue diluted with water and extracted twice with ether. The aqueous layer was ~ ih~Cl with cooling (ice bath) and the oil which precipitated was eYt~ ted into ether. The combined extracts were dried (MgS04) and evaporated to give the title compound as a white solid (mixture of diastereoi.~omers), m.p. 78-82~C, 0.98 g, 74% yield.
lH NMR o (CDC13) 1.58 (2x3H. d), 2.94 (2xlH, m), 3.29(2xlH, m), 3.80 and 3.83 (each 2H, s), 3.80 and 4.39 (each lH, q), 4.73 and 4.95 (each lH, m), 6.94 (2xlH, s), 7.30 (2x~H, m) c N-[6-(~chlorophenylhexyl)]-~t~be~ la,io-~oxo~7~ff~lin-l-yl]propionamlide (dia~, ~;somer b) A mixture of 6-(4-chlorophenyl)hexylamine (0.54 g,0.00256 mo1 r ~m~ttin~ J. L. El?
138464 A2 850424 (CA 103:142000)), 1-hyd~o~yben7ofri~7ole hydrate (0.35 g, 0.00256 mol), 2-(4-benzylthio-2-oxo~7Ptitlin-l-yl) -propionic acid (0.68 g, 0.00256 mol) and dicyclohexylcarbodiimide (0.53 g, 0.00256 mol) in dimethylÇ~ e (1() ml) was stirred for 16 h at ambient tempe~tllre. The solvent was ~vapul~Led and the residue treated with ethyl acetate. The insoluble dicyclohexylurea was filtered off and discarded, and the filtrate washed with saturated sodium hydrogen carbonate solution, dried (MgSO4) and evaporated tû an oil. The diastereomeric mixture was separatedby flash chromatography (silica, tert. butyl methyl ether/petrol) and fractions c-",~ -ing the more slowly eluting diastereoisomer were combined and evapoldLed to give the title compound as an oil (0.14 g, 11.8% yield) 1H NMR ~ (CDCl3) 1.32 (4H, m), 1.51 (3H, d), 1.53 (4H, m), 2.55 (2H,t), 2.87 (lH, dd), 3.24 (3H, m), 3.82 (2H, s), 4.06 (lH, q), 4.69(1H, dd), 6.51 (lH, m), 7.06-7.33 (9H, m)-F ~ ? 2 N-[6-(4chlo.o~ lhe~1)]-2-t41~-~
yl~lù, ~ sl~ - a) Evaporation of the fractions CO~IA;~ the faster eluting ~ ct~reoi~compr in the above eY~mrlP gave the other diastereoi.~P~ as a colourless oil (0.54g, 46% yield) S lH NMR ~ (CDC13) 1.33 (4H, m), 1.53 (3 H, d), 1.57 (4H, m), 2.55 (2H, t), 2.83 (lH, dd), 3.26 (3H, m), 3.84 (2H, s), 3.92( lH, q~, 4.77 (lH, dd), 6.58(1H, m), 7.05-7.36(9H, m).
EY~nple 3 N-t6-(4chlorophenylhexyl)l-2-t4l~e~ bul}~hinyl-? ~~ Un-l-yl]~lu, '~ lel~oisomers bl &b2) A solution of N-[6-(4-chlon~phel,ylhexyl)]-2-[4 bel~ylll~io-2-0~0~7Pti~lin-l-yl]propic)n~mi-l~P ((li~ctPreoicomPr b) (0.96 g, 0.0021 mol) in di.,llo~o.-.Pth~nP (25 ml) was cooled to -65 to -70~C and a solution of m-chlo,u~ll,el~oic acid (0.43 g, 0.0025 mol) in dichloromPth~nP- (10 ml) added dropwise over 15 min. After 45 min the ule was washed with a mixture of saturated sodium hydrogen carbonate and .c~tllr~tPd sodium s~llrhitP, dried (MgSO4) and evapolated to an oil. Cryst~lli.c~tion from ethyl acetate - ether gave the title compound as a 40:60 mixture of dia_tereoisomers bl:b2, m.p. 70-73~C
F.Y~mp~e 4 N-t6-(4-chlorophenylhexyl)]-2-t4b~ y~;nyl_~
yl]propiQn~m;~l~ (isomer (-)b2) The solid was purified by chromatography (HPLC, Ch~ PIl OJ column, ethanol/hexane), followed by silica, ethanol/hexane) to give the title compound, a white solid, as a single enantiomer.
[a]D20 = -41.6~ (c 0.11, ethanol) lH NMR ~ (CDC13) 1.33 (4H, m), 1.55 (4H, m),l.61 (3H, d), 2.56 (2H, t), 2.76 (lH, dd), 3.12 (lH, dd), 3.23 (2H, m), 3.96, 4.09 (each lH, d), 4.45 (lH, q), 4.58 (lH, dd), 7.07-7.39 (9H, m) The other 3 components of the mixture (FY~mrl~s 5-7) were obtained by the same chromatographic procedure.
F.Y~lmp~e S N-[6-(4-chlorophenylhexyl)]-2-t4bt:~r~ k~ 2--J~
yl]propion~mi-le (isomer (+)b2) [a]D20 = +345~ (c 0.112, ethanol); 99.2% pure.
lH NMR ~ (CDC13) 1.33 (4H, m), 1.55 (4H, m),l.61 (3H, d), 2.56 (2H, t), 2.76 (lH, dd), 3.12 (lH, dd), 3.23 (2H, m), 3.96, 4.09 (each lH, d), 4.45 (lH, q), 4.58 (lH, dd), 7.07-7.39 (9H, m) F.Y~mrle 6 N-t6-(4-chlorophenylhexyl)]-2-t4-~ yh~ 2 ~ ;Air 1-yl]propior ~mi~le (isomer (+)bl) [a]D20 = +80.7~ (c 0.03, ethanol); 96.2% pure.
lH NMR ~ (CDC13) 1.32 (4H,m), 1.42 (3H, d), 1.55 (4H, m), 2.55 (2H, t), 2.90 (lH, dd), 3.20 (2H, m), 3.45 (lH, dd), 3.88, 4.06 ( each lH, d), 4.34 ( lH, q), 4.48 (lH, dd), 6.g5 ( lH, m), 7.08-7.41 ( 9H, m) F.Y~mrle 7 N-t6-(4-chlorophenylhe~y~yl)~-2-t4-b~ h;nyl-2~ n yl]prorio~mi~l~ (isomer (-)bl) [a]D20 = -95 5~ (c 0.11, ethanol); 99.4% pure.

.

W O 97/02242 PCT/~1f.S/~2765 lH NMR ~ (CDC13) 1.32 (4H,m), 1.42 (3H, d), 1.55 (4H, m), 2.55 (2H, t), 2.90 ( IH, dd), 3.20 (2H, m), 3.45 (lH, dd), 3.88, 4.06 ( each lH, d), 4.34 ( lH, q), 4.48 (lH, dd), 6.95 ( lH, m), 7.08-7.41 ( 9H, m) FY~, le 8 N-~6-(4~orophenylheYyl)] 2 [~1 ~n7y~ finy 5 yl]~rv~ m~ al) Tr~-~tmP-nf of N-[~(4-chlw ~ hellylhexyl)]-2-[4-bel~ylll~,o-2~o~7Pti~in- 1 -yl]propion~mi~P (diastereoic-)mpr a) with mCPBA as rlPs~rihecl m Fy~mrle 3 gave the title colllpouIld as a mixture of diastere~ nmPn~ Recryst~lli~ti-)n of this mL~ture from ethyl acetate gave N-t6-(4-chlorophenylhexyl)]-2-[~b~l~yl~ulfmyl-2-o~o~
yl]prorion~mitl~ (diastereoicomPr al) as cQIo-lrlPss crystals, m.p. 168-170~C.
lH NMR ~ (CDC13) 1.32 (4H, m), 1.49 (2H, m), 1.55 (3 H, d), 1.60 (2H, m), 2.56 (2 H, t), 2.83 (lH, dd), 3.20 (2H, m), 3.38 (lH, dd), 3.88, 3.97 (each lH, d), 4.08 (ll:I, q), 4.67 (lH, dd), 6.38 (lH, m), 7.08-7.40 (9H, m) Example 9 N-[6-(4chlorophenylhexyl)~-2-[4-b~ ulrl~ ~n~o~ lin-l-15 yl]propinr ~m~ (di~le~
Tre~tmPnt of the mother liquors form the above le~cly~l~lli.~tion with petroleum ether (b. p. 40-60) gave the title compound as a white cryst lline solid, m.p. 79-81~C.
lH NM~ ~ (CDC13) 1.33 (4H, m), 1.52 (4H, m), 1.61 (3H, d), 2.56 (2H, t), 2.77( lH, dd), 3.15 (lH, dd), 3.24 (2H, m), 4.01 (lH, q), 4.01. 4.12 (each lH, d), 4.58 (lH, dd), 20 7.08-7.41 (9H, m) FY~n-ple 10 N-~6-(4-nuorophenylhexyl)l-2-~ io-2-nYn~7~t; 1in.
yl]propiQn~ liaslt:l ~isomer b) a Methyl-~benzylthio-2-o~ ..-1-yl)acetate To a solution of 4-(benzylthio)~7~tir~in-2-one (S.Og, ~Smmol), methyl brom~ce 25 (4.6g, 30mmol) and tetrabutylammonium bromide (0.9g, 0.28mmol ) in dry'l'~' (lSOml) was added powdered potassium hydroxide (1.7g, 30mmol). The resnlting mixture was stirred for two hours at room temperature before water (50 ml) was added. The solution was extracted with ethyl acetate (3xlSOml portions) and the combined extracts dried (MgS04) and evaporated. The residue was purified by flash 30 chromatography on silica gel eluted with petroleum ether 60~-80~:ethyl acetate 4: 1 to give methyl (4-benzylthio-2-oxo~7Pti~in-l-yl)acetate as a yellow oil (Sg,70%).
lH NMR ~ (CDC13) 2.96(1H, dd, J=2.5, 16 Hz _ 3a)~ 3.24,3.99 (each lH, d, J=18.00Hz, NCH2), 3.4 (lH, dd, J=5,12.5 Hz H3b), 3.70 (3H, s, OC_3), 3.77 (2H, s, SCH[2), 4.92 (lH, m, H1), 7.28 (SH, m, Ph-H) 35 b. Methyl 2-(1 benzylthio-2-o~o~t~Ain-l-yl)propionate A stirring solution of methyl (4-benzylthio-2-oxo~7p-ti~lin-l-yl) acetate (13.27 g, 0.05 mol) in dry tetrahydrofuran was cooled to -70~C (acetone-cardice bath) and a 1 molar srlution of lithium bis(trirnethylsilyl)amide (60 ml) was added under nitrogen over 15 min, followed by 1~3-dimethyl-2-im~ 7olone (33 ml). After 30 min, iodompth~n~ (5.6 ~ 40 ml, 0.09 mol) was added dropwise. After a further hour, the reaction temperature was allowed to Ase to -20~C, then the mixture recooled to -70~C and glacial acetic acid (5.6 ml) added dropwise. The reaction was qllench~d with water and e,~ d three times with ether. The combined extracts were dAed (MgS04) and evaporated to an oil , W O 97/02242 PCT~EP96/02765 which was purified by flash çhromatography (fine silica~ ethyl acetatetlight petrol) to give the product as a mixture of diastereoisomers, co~ tecl with 9% of the dimethylated product, as a yellow oil, 13.7 g, 89% yield lH NMR ~ (CDC13) 1.55 (2x3H, d), 2.93 (2xlH, m), 3.29(2xlH, m), 3.74 and 3.75 (each 3H, s), 3.80 and 3.84 (each 2H, s), 3.91 and 4.41 (each lH, q), 4.70 and 4.96 (each lH, m), 7.30 (2x5H, m) c. 2-(4Be-~ylll,io-2-oxfi~ yl)propionic acid A stirred solntion of methyl 2-(4-b~l~yllllio-2-oxo~7Pti~lin-l-yl)propionate (1.39 g, 0.005 mol) in m~th~nol (12 ml) was treated with 1 molar pol~ hyd~ ide (5.47 ml). After 2 hours, the mPth~nt)l was evaporated and the residue diluted with water and extracted twice with ether. The aqueous layer was ~ ih~ci with cooling (ice bath) and the oil which plC;~ ;ril~tPd was eYtr~ct~od into ether. The combined es~ctc were dried (MgSO4) and evaporated to give the title compound as a white solid (mixture of diastereoicomPr.~), m.p. 78-82~C, 0.98 g, 74% yield.
1H NMR q (CDC13) 1.58 (2x3H, d), 2.94 (2xlH, m), 3.29(2xlH, m), 3.80 and 3.83 (each 2H, s), 3.80 and 4.39 (each lH, q), 4.73 and 4.95 (each lH, m), 6.94 (2xlH, s), 7.30 (2xSH, m) d. N-[6-(4-fluorophenylhexyl)~-2-t4-1 e~ ylll~io~ e~ -l-yl]l"~r ~ ~ ude ,...o;c~ . b) A mixture of 6-(4-~luoll~phenyl)hexylamine (3.0 g, 0.0154 mol,), 1-hydroxybenzotriazole hydrate (2.08 g, 0.0154 mol), 2-(4-benzylthio-2-oxo~7Pti-lin-l-yl)-propionic acid (4.08 g, 0.0154 mol) and dicyclohexylcarbo~liimi-le (3.17 g, 0.0154 mol) in dimethylfonn~mi-le (60 ml) was stirred for 16 h at ambient temrer~tl-re The solvent was evaporated and the residue treated with ethyl acetate. The in~Qhlbledicyclohexylurea was filtered off and d~c~ded, and the filtrate washed with s~t~lr~ted sodium hydrogen carbonate soll~tion, dried (MgSO4) and evaporated to an oil. Thediastereomeric mixture was sepala~d by flash chromatography (fine silica, ter~ butyl methyl etherlpetrol) and fraction~ corl~inin~ the more slowly eluting diastereoisomer were combined and evaporated to give the title compound as an oil, yield 1.89 g (28%) lH NMR (CDC13) ~ 1.33 (4H, m), 1.51 (3H, d), 1.53 (4H. m), 2.55 (2H,t), 2.87 (lH, dd), 3.24 (3H, m), 3.82 (2H, s), 4.06 (lH, q), 4.69(1H, dd), 6.51 (lH, m), 6.91-7.33 (9H, m).
F,Y~ r 11 N-[6-(4-nuorophenylhexyl)]-2-[1 ben_ylthio-2-oY~7el;~1; -1-yl]propio~n~: le (~ co~ a) The more rapidly eluting diastereoisomer was also obtained from the above columnchromatography as an oil, yield 2.8 g (41%) 1H NMR ~ (CDC13) 1.33 (4H, m), 1.53 (3 H, d), 1.57 (4H, m), 2.55 (2H, t), 2.83 (lH, dd), 3.26 (3H, m), 3.84 (2H, s), 3.92( lH, q), 4.77 (lH, dd), 6.58(1H, m), 6.91-7.36(9H, m).
F.Y~mrle 12 N-[6-(4-fluorophenylhexyl)]-2-[4-benzylsulphinyl-2-o~
yl]propiq~r: le (.lia~h,~vicc~ bl+b2) A sollltion of N-[6-(4-fluorophenylhexyl)]-2-[4-benzylthio-2-oxo~7Ptidin-l-yl]propionamide (diastereoisomer b) (Fx~mrl~ 11) (1.82 g, 0.0041 mol) in dichoromethane (30 ml) was cooled to -65 to -70~C and a solution of m-chlolup~.l~llzoic acid (0.85 g, 0.0049 mol) in dichlorometh~nt- (30 ml) added , W O 97/02242 PCT/~ 765 dropwise over 30 min. After 2 h the mixture was washed with a mixture of .ca sodium hydrogen carbonate and s~t~lr~qted sodium slllphitP, dried (MgSO4) and e~vapoldL~:d to an oil. Crysf~ c~tirm from ethyl acetate - light petrol gave a mi-Atun~ of diastereomers (1.18 g) (bl:b2, 1:3), m.p. 75-78~C.
S FY~r~rl~P 13 N-t6-(4fluoroph~lyll-~A~1)]-? [4~~ 1-2 ~ idin~
yl3~1V~ P (~ (-)b2) The above mixfure of diacfereoi.cnm~r.C bl + b2 wac sep~ Pd by HPLC (Dynama~;
silica col~nn, ethanol/hexane) into bl and b2. Di~tP.e.oi.comPrb2 was then .CI~y~ tP( into its co.llyonent çn~nti~mPrs by ciral HPLC (C~hir:llr~l OD column, 10 etnanoVhexane) to give the title coll,pouud as a white solid, 0.06 g lH NMR ~ (CDC13) 1.33 (4H, m), 1.55 (4H, m),l.61 (3H, d), 2.56 (2H, t), 2.75(1H,dd), 3.11(1H, dd), 3.23 (2H, m), 3.96, 4.09 (each lH, d), 4.45 (lH, q), 4.58 (lH, dd), 6.92-7.40 (9H, m) [a]D20 = -36.2 (c 0.46, ethanol) FY~mrle 14 N-[6-(4-fluorophenylhexyl)]-2-14-~.. ~.yl~ inyl-2 yl~prop:or- '?(~ ~so~ (+)b2) ALco obtained was the (+) en~ntiomP-r as a white solid, yield 0.06 g.
lH NMR ~ (CDC13) 1.33 (4H, m), 1.55 (4H, m), 1.61 (3H, d), 2.56 (2H, t), 2.75(1H, dd), 3.11(1H, dd), 3.23 (2H, m), 3.96, 4.09 (each lH, d), 4.45 (lH, q), 4.58 (lH, dd), 6.92-7.40 (9H, m) [a] D20 = +32.7 (c 0.42, ethanol) Tre~tmen~ of N-[6-(4-fluorophenylhexyl)]-2-[~ber~zyllllio-2--)xo~7Pti~in-l-yl]propionamide (1.15 g) (diactereoicomP-r a, FY~mplP 10) with mCPBA (0.54 g) bythe procedure ~le-s~ribed in Fy~mrle 12 gave the following two dia~ coic4---Prc after chromatography (Examples 15, 16) FY~mrle 15 N-t6-(4-fluorophenylhexyl)]-2-[4~ JAua~lidin l-yl]l~ù~i<J .~m ~lP (~ Q;~ .Pr al) 0.5 g, white solid, m.p. 165-7~C, lH NMR d (CDC13) (selPcf~d tli~gnosti- peaks) 4.11 (lH, q, a-H), 4.70 (lH, m, H4); Found: C, 65.2; H, 6.7; N, 5.8% C2sH31FN2O3S
requires: C,65.5; H,6.8; N,6.1%
F~ le 16 N-~6-(4-fluorophenylhexyl)]-2-t4b~ ..ll,hinyl 2-~n~ffA n..l-yl]propion~ e (~ ~oico~
0.28 g, white solid, m.p. 73-5~C, lH NMR d (CDC13) (sPlPcted ~ gnosti~ peaks) 400 (lH, q, a-H), 4.58 (lH, m, H4); Found: C, 65.3; H, 6.65; N, 5.7% C2sH21FN2O3S
requires: C, 65.5; H, 6.8; N, 6.1%
F~Y~mrle 17 N-[6-(4-fluorophenylhexyl)]-2-[4-b~ honyl-2-o~o~ in~-l-yl]propion~m~ ,eoiso~-~er a) Tre~tmPnt of N-t6-(~fluorophenylhexyl)]-2-t4-benzylthio-2-oxo~7Pti~lin-l-yl]propionamide (2.7 g) (diastereoisomer a, Example 10) with mCPBA (2.43 g) at room t~mpçr~tllre gave the title compound as a white solid (2.43 g), m.p. 85-7~C; lH
NMR d (CDC13) (selected diagnostic peaks) 3.96 (lH, q, a-H), 4.75 (lH, m, H4);
Found: C, 63.2; H, 6.45; N, 5.9% C2sH31FN2O4S requires: C, 63.3; H, 6.6; N, 5.9%
F.Y~rle 18 N-l6-(4-Fluorophenylhexyl)]-2-t4~ y~ o~yl-2-o~o~ ;m-l-45 yl]propion~mi-le (dia~le~ ~isomer b) W O 97/02242 PCT/~r,''~765 Tre~tmPnt of N-[6-(4-fluo~,phe,.ylhexyl)]-2-t4-be,~yllllio-2-o~o~7Pt~ n-l-yl]propion~mi~l~P (0.39 g) (diasterenicomPr b, FY~mrl~. 113 with mCPBA (0.22 g) at room Ir-IIpP.I~ gave the title compound as a white solid (0.29 g), m.p. 90-2~C; lH
NMR d (CDC13) (SPlP-ctpd fli~gnnstir- peaks) 4.27 (lH, q, a-H), 4.64 (lH, m, H4);
Found: C, 63.0; H, 6.4; N, 5.85% C2sH31PN2O4S l~Ui~ C, 63.3; H, 6.6; N, 5.9%
Example 19 N-(Benzyl)-2-[41~,~11hio-~ .,~ yl]propionamide (did~ oi~~ r a) Tre~tmPnt of 2-(4-benzylthio-2-oxo~7Ptitlin-l-yl)p~opionic acid (F~mple lOb) with benzylamine under the cnnrlitinnc ~lese~ibP-~l in FY~mplP lOc gave the title compound as the higher rf product after chromatog.aphy: 1.19 g, clear oil; lH NMR d (CDC13) (SPlPctP-d fli~gnostic peaks) 4.27 (lH, q, a-H), 4.80 (lH, m, H4);
FY~n~P'~ 20 N-(Benzyl)-2-[41~ io-2~ yl]propionan~ide From the above chromatographic sep~r~tion the lower rf fT~ctionc were combined to give the title compound as a colourless solid, m.p. 70-2~C, 1.44 g; lH NMR d (CDC13) (SPhPCtpd rli~onnstiC peaks) 4.10 (lH, q, a-H), 4.69 (lH, m, H4);
Example 21 N-[6-(4Fluorophenylhexyl)]-2-r4(allyloA~ l,v~ e ~L~lll~io~-2-,~"~ .- l yl]prv~ lia~ - a) a Allyl4(~v~.~o~thyl)b~ o~lt ~(BromomPthyl)benzoic acid (103 g, 0.48 moles) was sncpPnt1P~ in thionyl chln~ P(200 ml) and dimethylform~mi-lP- (1 ml) was added. The ~ t; was heated under reflux until clear, evaporated and azeotroped with toluene (2 x 150 ml). The res~lltin~
oil was dissolved in dichloromPth~nP and added d~ wise to a cooled solution of pyridine (42 ml) and allyl alcohol (40 ml) in dichlolo~ nP. The mixture was stirred at room temperature for 1 hour, then washed with water, 2M hydrochloric acid, sodium hydrogen carbonafe solufion and brine. The organic solution was dried andevaporated to give allyl 4-(bromomethyl)be-n70~tP as a clear oil (98g, 84% yield). lH
NMR d (CDC13) 4.61 (2H, s, CH2), 4.82 (2H, m, C_2~)~ 5.34 (2H, m, C_2CH-), 6.05 (lH, m, CHCH2), 7.45 (2H, d, Ph-H), 8.03 (2H, d, Ph-H).
b. Allyl 4-(aeelylll~iol~eu~yl)~ o~fe Allyl 4-(bromomethyl)ben7o~t~p (98 g, 0.4 moles) in dry dimethylf~-rm~mi~e (100 ml) was added dropwise to a cooled suspension of potassium thio~-~et~tP (46 g, 0.4 moles) in dry dirnethylform~midP- (200 ml). The cooling bath was removed and the mixture was sfirred overnight. The rection mixture was poured into water and extracted with efhyl acetate (x3). The combined extracts were washed with water and brine. The mixture was dried and evaporated to give allyl 4-(aceLyl~l.iomethyl)~.~o~ as an orange oil (lOOg, 100% yield). lH NMR d (CDC13) 2.36 (3H, s, COCH3), 4.13 (2H, s, CH2), 4.82 (2H, m, C_2~)~ 5 32 (2H, m, CH2CH-), 6.05 (lH, m, CHCH2), 7.35 (2H, d, Ph-H), 7.98 (2H, d, Ph-H).
c. 4-~4-(Allyloxycarbonyl)be,~yl~llio)~ ;..-2-one Allyl alcohol (27 ml) in dry tetrahydloîulan (50 ml) was added dropwise to a solution of pot~c~ m tert-butoxide (4.93 g, O.W4 moles) in dry tetrahydrofuran (100 ml).
After stirring for S mimltPs a solution of allyl 4-(acetylthiomPthyl)bç..7.0~tP (10.1 g, 0.04 moles) in dry tetrahydrofuran (100 ml) was added dropwise. After stirring for 15 W O 97/02242 PCT~EP96/0276S

...;...,I~s a sohltion of 4-aceto~y~ in-2-one (5.16 g, 0.04 moles) was added dropwise. The ~ was stirred for 1 hour and ev~pol~d. The residue was partitioned be~wt;en ethyl acetate and water and the a~luevu~, was ~ d w~th ethyl acetate. The c~)mbinPd extracts were washed with brine, dried and ev~o,~t~d. Flash 5 chromatography (silica gel, ethyl acetate-petrol) gave 4-(4-Allylo~ye~bonylbel~yllllio)~7P-ti~in-2-one as an oil (9.lg, 82% yield). lH NMR d(CDC13) 2.84 (lH, dd, H3a), 4.31 (lH, dd, H3b), 3.88 (2H, s, S-CH2), 4.68 (lH, dd, ~ H4), 4.78 (2H, m, CH2O), 5.35 (2H, m, C_2CH-), 6.05 (lH, m, CHCH2), 6.07 (lH, br. singlet, N-H), 7.40 (2H, d, Ph-H), 8.03 (2H, d, Ph-H).
10 d. Methyl 4~1 (Allyl~ ~bonyl)l~,~ltl..o)~ r l-~To a stirring solution of 4-(4-(allylo~-yc~l,ollyl)l~llzylll~~o)~7P~;A;i.-2-one (2.55 g, 9.:~
mmol), tetrabutyl~mmoni-lm bromide (0.33 g, 1.02 mmol) and methyl br mo~r~et~tP
(1.06 ml, 11.2 mmol) in dry tetrah~ .r~ (40 ml) was added powdered pol ~
hydroxide (0.63 g, 11.2 mmol) kP.epin~ the reacdon tPml~..,,l...c~ below 30 by means of a cold water bath. After 2 h, the mixture was diluted with water and çxt~ctP~ three times with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated and the residue chromatogr~rhpd (fine silica, ethyl acetate-petrol) to give the title compound as a clear oil, yield 2.66 g (83%).
lH NMR o (CDC13) 2.97 (lH, dd, H3a), 3.26. 4.07 (each lH, C_2CO, d). 3.42 (lH~.
dd, H3b), 3.70 (3H. s, C_3O), 3.81 (2H. s, SC_2)~ 4.83 (2H, m, C_2~)~ 4-93 (lH, dd, H4), 5.35 (2H, m, C_2CH), 6.03 (lH, m, C_CH2), 7.39 (2H, d, Ph-H), 8.02 (2H,d, Ph-H) e. Methyl 4(4(allylo~eal1,onyl)bel~y' ' ~)-2-o~ r~, ~nate Methyl 4(4(allyloxycarbonyl)benzylthio)-2-oxo~7ptitlin-l-ylacetate (23.8 g, 68 mmolps) was stirred at -65~C in dry tretahy~orul~ under nitrogen and treated with lithium bis(trimethylsilyl)amide (81.6 ml of a 1.0 molar solution in hexane), lrPepin~ Ithe temperature to -65~C. The mixture was stirred for 5 minlltP~, then treated with 173-dimethylimi-l~7olitiinonP (44.6 ml) dropwise Pn~nrin~ the ~l,lpelaLult: did not nse.
This m~lul~ was stirred for 30 mimltPs then methyl iodide (7.6 ml) was added dropwise. The llli~ was stirred for a further 1 hour then allowed to warm to -20~C.
After re-cooling, the mixture was treated with acetic acid (7 ml), poured into water and extracted with ethyl acetate (x6). The combined extracts were dried and ev~polated to an orange oil. Flash chromatography (fine silica, 20% ethyl acetate in petrol) gave the required methyl ~(4-(allyloAy~;~bonyl)bel-~ylLhio)-2-oxo~7Pti(lin-2-ylpropionate as a yellow oil as a mixture of diastereoisomers (15.2 g, 62%).
lH NMR o (CDC13) 1.56 (3H, d), 2.85-2.96 (2H, m, diastereomer A and B, H3a)~
3.24-3.35 (2H, m, diastereomer A and B, H3b), 3.74 (3H, s), 3.76 (3H, s), 3.87 (2H, d), 3.97 (lH, q, diastereomer B, N-C_), 4.43 (lH, q, diastereomer A, N-C_), 4.71(lH, m, diastereomer B, H4), 4.82 (2H, m), 4.97 (lH, m, diastereomer A, H4), 5.27-5.46 (2H, m), 5.96-6.10 (lH, m), 7.39 (2H, d), 8.02 (2H, d).
f. 4-(4-(Allyloxy~l l,onyl)~ ylll~,o)-2-v~ 2~ acid 29.7 ml of 1 M potassium hydroxide solution was added dropwise over 20 mimltes IO
a sol-lti-)n of methyl 4-(4-(allyloxycarbonyl)benzylthio)-2-oxo~7Pti~lin-2-~ pi~(9.0 g, 0.0248 moles) in te~ahydrofuran (100 ml), keeping the temperature to 0-5~C.
The ~ Lul~ was stirred for a further 20 minut,qs then diluted with water and e~rart~

W O 97/02242 PCT/~~ 276s with ether (x2). The aqueous so1~ltion was recoolP-d and ~ri~ifiPd with dilute lly~lloel~loric acid then PYtr~e~d with ether (x2). The comhinPd ex~acts were dried and eva~O~atedtO give the title compound as a yellow oil, 8.5g, 98% yield lH NMR ~ (CDC13) 1.50-1.6 (3H, m), 2.86-2.98 (2H, m, di~lGlco,~er A and B, H3a)~3.24-3.35 (2H, m, diastereomer A and B, H3b), 3.87 (2H, d), 395 (lH, q, diastereomer B, N-CH), 4.45 (lH, q, diastereomer A, N~_), 4.75 (lH, m, diastereomer B, H4), 4.82 (2H, m), 4.98 (lH, m, diastereomer A, H4), 5.27-5.46 (2H, m), 5.96-6.10 (lH, m), 7.39 (2H, d), 8.02 (2H, d).
g. (+/-)-N-t6-(4-Fluorophe~ Yyl)~- 2-t4(allylo~ bo...~lbel~;l'h,~)-2-10 ~Yo~ ;.- l-yl]~"u~ , a) Dicyclohexylcarbo-liimidP (4.75 g, 23 mmol~~) in dry dimG~IylÇ~ e (50 ml) was added dropwise to a cooled sol-ltio~ of 4-(4-(allylu~y~l,onyl)l,el~yl~lio~2-oxo~7etidin-2-ylpropionic acid (8.0 g, 23 mmnlPs), l-hydro~y~ 7~ 7o1P hydrate (3.11 g, 23 mmoles) and 6-(4-fluorophenyl)hexylamine (4.5 g, 23 mmoles) in dry 15 dimethylformamide (S0 ml). Cooling was removed and the mixture was stirred overnight. The dimethylf~3rm~midP was evaporated and the residue was purified byflash chromatography (fine silica, ter~-butylmethyl ether then ethyl acetate) to provide samples which were predo...i..~ y diastereoisomer a (4.6 g), d~a~,eoicomP~ b (2.7 g) and mixed fr~rtionc Diastereoisomer a: yellow oil, 4.6 g, 38% yield lH NMR o (CDC13) 1.23-1.63 (llH, m), 2.55 (2H, t), 2.81 (lH, dd, H3a)~ 3.20-3.30(3H, m, CH2 and H3b), 3.90 (2H, d), 4.04 (lH, q, N-CH), 4.78-4.84 (3H, m, C_2 and H4), 5.27-5.45 (2H, m), 5.95-6.09 (lH, m), 6.50 (lH, br. triplet, NH), 6.90-6.98 (2H, m), 7.06-7.26 (2H, m), 7.40 (2H, d), 8.02 (2H, m).
F-Y~ 22 (+/ ) N t~(4FI -= ol,henylheYyl)]-2-[4(a~lylo~ onyl-l~l~ylll~io)-2--~Yo~ in-l-yl]propionamide (di~h.~.30mer b) From the above chromatography diastereoicomP-r b was obtained as a yellow oil, 2.7 g, ~% yield lH NMR ~ (CDC13) 1.23-1.63 (llH. m), 2.55 (2H, t), 2.85 (lH, dd, H3a)~ 3.19-3.23(2H, m), 3.28(1H, dd, H3b), 3.91 (2H, s)t 4.09 (lH, q, N-C_), 4.69 (lH, dd, H4),4.82 (2H, d), 5.25-5.45 (2H, m), 5.95-6.09 (lH, m), 6.43 (lH, br. triplet, NH), 6.90-6.98 (2H, m), 7.06-7.26 (2H, m), 7.40 (2H, d), 8.02 (2H, m).
FY~mrl~q 23 (+/-)-N-t6-(4-Fluorophenylhey-yl)]- 2-14-(4-allyl~l~onyl)~ y~ rhinyl)- 2-oy~7~ n-l-yl]~lr~)~ ~n~ide (diasterec icO~ b2+bl 3:2) A solution of (+I-)-N-[6-(4-fluorophenylhexyl)]- 2-[4-(allylo~y~ l~uIlylbel~yllllio)- 2-oxo~7Pti~lin-l-yl]propion~mirle (diastereoisomer b) (2.5 g,4.75 mmoles) in dichloromPth~nP (50 ml) was stirred at -65~C and treated with a solution of m-chlorope~l,en~oic acid (1.0 g, 5.7 mmoles) in dichloromP-th~nP (30 ml). The mixture was stirred for 1 hour, poured into a solution of sodium hydrogen carbonate and sodium s~llphi~p7 separated and the a~ueous eytr~ctp~l with dichlorome-th~nP. The combined extracts were washed with brine, dried and evà~Jo~ated to an oil which was purified by flash chromato~raphy (fine silica, ethyl acetate) to give the title compound as a yellow oil, 1.3 g, 50% yield as a 3:2 mixture of sulfoxide diastereoisomers 2 and 1.

F~ '- 24 (+/-)-N-[~(4Fluo.(i~,henylhexyl)]- 2 t4(4 allylc,~ 2 c~ 1-yl3~ de (~lia~h.~ , b2) The sulfoxide diastereoi~omPr~ above were sep~rated by HPLC to give the ~dtle - S compound as a yellow oil, 100 mg lH NMR ~ (CDCl3) 1.32-1.34 (4H, m), 1.4~1.63 (4H, m), 1.61 (3H, d), 2.55 (2H, t), 2.84 (lH, dd, H3a)~ 3.15-3.31 (3H, m, H3b and CH2), 4.01 and 4.09 (lH each, d), 4.50 (lH, q, N-CH), 4.61 (lH, dd, H4), 4.83 (2H, d), 5.29-5.45 (2H, m), 5.95-6.0S' (lH, m), 6.90-6.98 (2H, m), 7.06-7.26 (2H, m), 7.37 (2H, d), 8.08 (2H, m).
FY~mr~ 25 (+/-~N-t6~(4-Eluo~v~l~e~ h~A~ _t~4 allyloA~LonYl)bw~ Yl)-2 Q~ l-yllpropionamide (~5isl~n ;o~ . bl) The above chromatography also gave ~e title col,.~und as an oil, 50 mg lH NMR ~ (CDC13) 1.32-1.34 (4H, m), 1 4~1.63 (4H, m), 1.45 (3H, d), 2.54 (2H, t), lS 2.90 (lH, dd, H3a)~ 3.18-3.22 (2H, m, CH2), 3.43 (lH, dd, H3b) 3.94 and 4.02 (lH
each, d), 4.34 (lH, q, N-CH), 4.53 (lH, dd, H4), 4.83 (2H, d), 5.29-5.45 (2H, m), 5.95-6.09 (lH, m), 6.80 (lH, br. triplet, NH), 6.90-6.98 (2H, m), 7.06-7.26 (2H, m), 7.37 (2H, d), 8.08 (2H, m).
FY~mrle26 (+/-)-N-[6-(4-fluorophenylhexyl)~ 2 t4 (4 (allyloxy~l,onyl)bel~Ly~ hinyl)-2-o~ lir l-yl]propionamide (~li~l~.eo;30mer al) TrP~tmPnt of N-t~(1 fluorophenylhexyl)]- 2-~4-(allylu~y~l,o"ylben_yl~lllrhinyl)- 2-oxo~7~Pti(1in-l-yl]propion~mi-le (diastereoisomer a, FYZImpl'' 21) with mCPBA by th~e method (~çscrihed in Example 23 gave the title compound as white crystals after chromatography and le~,y~ s~tiQ~ from ethyl acetate, m.p. 175-177~C, 27% yiel~
lH NMR ~ (CDC13) 1.32-1.34 (4H, m), 1.38-1.65 (4H, m), 1.54 (3H, d), 2.55 (2H, t), 2.82 (lH, dd, H3a)~ 3.20 (2H, dt, CH2), 3.35 (lH, dd, H3b) 3.94 (2H, d), 4.17 (lH[, q, N-CH), 4.78 (lH, dd, H4), 4.83 (2H, d), 5.29-5.45 (2H, m), 5.95-6.09 (lH, m), 6.35 (lH, br. triplet, NH), 6.90-6.98 (2H, m), 7.06-7.26 (2H, m), 7.37 (2H, d), 8.08 (2H[, m)-FY~rl~P 27 (+/-)-N-t6-(4-ilu~l u~JhenylheYyl)~ 2-[4-(4-(ally~ du~onyl)be~l~..l~hinyl)-2-n~A~ _yl]~ ?
(~li&~h. ~;so...er a2) From the above reaction (Example 26) the title compound was obtained as off-white crystals after chromatography and recryst~ nn from diethyl ether, m.p. 75-76~C, 22% yield lH NMR ~ (CDC13) 1.32-1.34 (4H, m), 1.38-1.65 (4H, m), 1.62 (3H, d), 2.56 (2H, t), 2.82 (lH, dd, H3a)~ 3.17-3.30 (3H, m, CH2 and H3b), 4.00-4.15 (3H, m, CH2 and N-- CH), 4.63 (lH, dd, H4), 4.83 (2H, d), 5.29-5.45 (2H, m), 5.95-6.09 (lH, m), 6.90-6.98 (2H, m), 7.06-7.26 (3H, m), 7.37 (2H, d), 8.08 (2H, m).
F~y~mple 28 (+/-)-N-[6-(4-fluorophenylheYyl)]- 2-[4-(4-(carboxy)be..~ h nyl)_2_oYn~7Pff~lin-l_yl]propiQn~m;~le (lli&l~:leu~ nPrs b2+bl 3:2) Trç~t~nPnt of (~/-)-N-[6-(4-fluorophenylhexyl)]- 2-[4-(4-allyloxycarbonyl)-45 benzyl.~ rhinyl)-2-oxoazetidin-1-yl]propionamide as the mixture of diastereoisomers W O 97/02242 PCT~EP96/0276 produced in FY~mrlP 23 (b2+bl 3:2) (0.32 g) with triphenylrhosphin~ (0.165 g), pyrrolidine (0.045 g) and tetrakis triphellylphocp~ p~ m(o) (0.02 g) in dichlor~mP-th~nP (40 ml) under nitrogen for 16 h, followed by aqueous work-up gave the title compound as a white solid, m.p. 122-150~C, 0.155 g, 51 % yield as a 3:2 S mixture of diastereoi.com~rs b2 and bl.
lH NMR - some rii~gnostio peaks: ~ (CDC13) 4.7 (m, H4 of dia b2) 4.6 (m, H4 of dia bl).
Example29 (+/-)-N-[6-(4Fluo.~ l)heY~yl]-2-(4-be~ lll.io~2-oYn~7~tidin-l-yl-3-(3-furyl)~ c n~m;~le (~l~a~ eGi~mers a and b) 10 a 4-(Benzylthio~ ;..-2-one Sodium (8.1g, 0.35mol) was dissolved in ethanol (250ml) and benzyl mel-;d~l (45.2g, 0.37mol) added dropwise over 20 minlltos k~epin~ the ~Ill~la~ belwe~ll 20 ~C - 25~C whilst bubbling nitrogen through the .~ After 15 Ill;lllll~S, thereaction was cooled to 5~C and a solution of ~acetoxy~7P~ti~iin-2-one (45.0g, 0.35mol) 15 in ethanol (50ml) was added d.~.p~ise over 15 minntPs whilst m~ g the temrer~tllre at 5~C. The mixture was stirred at room l~lll~ldlUlt~ for 60 minntes and evaporated to dryness under reduced pl~S~ c;. Water (400ml) was added, the ç~rtr~etPd with dichlor mPth~nP (2x300ml), the eYt~c'tc dried (MgSO4) and evapo.a~d under reduced p.~s~u,e to an oil. The oil was cooled to -20~C and ~o titnr~t-~d with ether (400ml) to give a white solid which was isolated by filtration (50.2g, 79%), mp 50-51.0~C.
lH NMR ~ (CDC13) 2.86(1H, m, H3a)~ 3.30 (lH, m, H3b), 3.85 (2H, s, SCH2), 4.68 (lH, m, H,l), 7.31 (SH, m, Ph-H).
b. Methyl-(4-benzylthio-2-o~ ;..-l-yl) acetate To a solution of 4-(bel"ylLhio)~7~ti~1in-2-one (5.0g, 25mmol), methyl bromo~cet~to (4.6g, 30mmol) and tetrabutylammonium bromide (0.9g, 0.28mmol ) in dry THF
(150ml) was added powdered pot~c~jnm hydroxide (1.7g, 30mmol). The res~llting ule was stirred for two hours at room te~r pPr~tllre before water (50 ml) was added. The solution was extracted with ethyl acetate (3xl50ml portions) and the combined extracts dried (MgS04) and evaporated. The residue was purified by flash chromatography on silica gel eluted with petroleum ether 60~-80~:ethyl acetate 4: 1 to give methyl (4-benzylthio-2-o~o~7P-ti~in-l-yl)acetate as a yellow oil (5g, 70%).lH NMR ~ (CDC13) 2.96(1H, dd, J=2.5, 16 Hz H3a)~ 3.24,3.99 (each lH, d, J=18.00 Hz, NCH2), 3.4 (lH, dd, J=5,12.5 Hz H3b), 3.70 (3H, s, OCH3), 3.77 (2H, s, SCH2), 4.92 (lH, m,_4), 7.28 (SH, m, Ph-H) c 3-Bro~ -yllu~d~-A solution of triphenylphosphine (8.45g, 0.0322moles) and 3-(llyd~u~yl~lethyl)-furan (2.93g. 0.02987moles) in dry dichloromethane (30ml) at 0~C was treated with N-br~!mosurrinimi-l~P (5.74g, 0.03225moles) in solid portions over 10 minlltes Thereaction was stirred at 0~C for 30 minutes and the allowed to warm to 15~C over 1.5 hours. The reaction was then purified by flash column chromatography on silica gel eluted with petroleum ether 40-60~C to give 3-bromomPthylfuran as a pale yellow oil (3.25g, 68%).
d. Methyl 2-(4be~ o-2-oyo~7~ffAin-l-yl)-3-(3-furyl)propionate)~

W O 97/02242 PCT~EP96/02765 A solution of methyl-(4-benzylll-io-2~ o~7Pt~ n-l-yl)~et~t~P (3.0g, 0.01131moles) in dry tetra~ly~ ,Çu~an (60ml) at-78~C under r~itrogen was treated with a lM s~ tion of lithium bis(tnmethylsilyl)amide in 1~ (13.8ml, 0.0186moles) over 10 mimlte~
kPepin~ the temr~Pr~ lre below-74~C. 1,3-Dim~ yl~ 7~ in-2~ne (7.5mL
0.0687moles) was added kpeping the ~ below -74~C. The r~snltin~
s~ cion was stirred at -78~C for 30 .--i----l~s and then treated with a solution of 3-bromomethylfuran (3.0g, 0.0186moles) in dry THF (lOml) over 10 ~ s k~Ppi~
the le~ tnre below -73~C. The reaction was stirred at -78~C for 1 hour and then allowed to warm to -20~C over 30 mim~tPs The r~tion was cooled to -75~C and q~len~h~od with glacial acetic acid (l.~ml), partititionp~ ~Lw~,. brine (150ml) and ethyl acetate (lSOml). The organic layer was washed with water, dned (MgS04) arld evaporated to a coloured oil (7.81g). Purified by flash column chromatography onsilica gel eluted with 2:1 petroleum e~er 40-60~C:ethyl acetate to give methyl 2-(4-be ,zyl~.io-2-oxo~7Pti~lin-1-yl)-3-(3-~uryl)propionate as yellow oil (2.35g, 60%, 85: 15 d.~L~lGoicom~r A:B) lH NMR ~ (CDC13) 2.83, 2.90 (dd, J=2.4, lS.S Hz, 1 Of _3A)~ 3.17 (m, CH2-furyl, --3B 3A)~ 3.54, 3.80 (2H, 2xs, SCH2A+g), 3.77 (3H, s, C02CH3), 3.95,4.26 (lH, 2xm, C_A+B), 4.60, 4.64 (lH, 2xm, H,lA+g), 6.30 (lH, m, furyl-H), 7.30 (6H, m, Ph-_, furfyl-H) e. 2-(4-be.. ~ylU~io-2~Yo~7~ in-1-yl~3-(3-furyl)~ acid A sol--tinn of methyl 2-(4-benzyl~.io-2-o~ro~7Pti~lin-l-yl)-3-(3-furyl)propionate (2.93g, 0.00848 moles) in meth~nQl (SOml) at 10~C was treated with a lN sodium hydroxidesolution (8.5ml, 0.0085moles) over 30 ...;.~ es The cooling bath was removed andthe reaction was stirred for 1 hour. lN NaOH (l.Oml) was added and the reaction was stirred for 30 minut~s~ diluted with water (SOml) and evaporated to remove m-oth~nt)l The residue was mixed with water (SOml) and extracted with diethyl ether (SOml). The aqueous was ~ ifiPd with dilute Hcl and e~t~r-t~-d with diethyl ether (2x75ml). The organic extracts were combined, washed with brine, dried (MgS04), and t;vapOl~d to give 2-(4-benzylthio-2-oxo~7~ti~1in-1-yl)-3-(3-furyl)propionic acid as a cream soliid m.p. 77-80~C (2.73g, 97%, 50:50 distereoi~omt~r A:B) lH NMR o (CDC13) 2.86, 2.92 (dd, J=2.3, 15.4 Hz, H3), 3.10 (m, CH2-furyl, H3), 3.54, 3.79 (2H, m+s, SCH2A+g), 3.89 (m, C_B)~ 4.19 (m, C_A)~ 4.23 (lH, bs, C~2_), 4.57, 4.64 (lH, 2xm, H4A+g), 6.30, 6.37 (lH, 2xbs, furyl-HA+g), 7.30 (6H,m, Ph-H, furfyl-_) f. N-t6-(4Fluorophenyl)hexyl]-2-(1 bel~ylll-io~2-oYo~e~ l-yl-~(~
furyl)propi~ e (dia~ rs a and b) 6-(4-Fluorophenyl)hexylamine (l.S9," 0.00814moles) in dry DMF (75ml) was added to a mixture of 2-(4-benzylthio-2-oxo~7~t~ n-l-yl)-3-(3-furyl)propionic acid (2.7g, 0.00814 moles), 1-hydroxybenzotriazole (l.lg, 0.00814moles), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluene sulfonate (3.5g, 0.00826moles) and the r~snlting solution was stirred at room IP~ tllre for l9h. The ~ cicn was partitioned between aq.NaHC03 (175ml) and diethyl ether (75ml). The layers were sep~r~t~d and the aqueous layer was washed with diethyl ether (75ml). The organic:
extracts were combined and washed with brine (x2), dried (MgS04) and evaporated to an orange oil (3.76g). Purified by flash column chromatography on silica gel eluted W O 97/02242 PCT~EP96/02765 with 2:1 petroleum ether 40-60~C:ethyl acetate to give the title compounds as colourless oils.
Diastereoi.eomer a, 1.17g, 28% (coll~ins 20% dia~etereoi~eo-mpr b) lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xC_2)~ 2.55 (2H, t, J=7.9 Hz, CH2Ph), 2.75, 2.80 (dd, H3), 3.15 (m, C_2-furyl, H3), 3.75 (3H, m, CH, SC_2)~ 4-30 (lH, m, H1), 6.23 (lH, bs, furyl-_), 6.85 (lH, m, N_), 6.9-7.4 (1 lH, m, pF-Ph-H, Ph-H, furyl-H) Diastereoieomer b, 1.36g, 33% (cont~ine 20% diastereoieompr a) lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.55 (2H, t, J=7.9 Hz, CH2Ph), 2.81, 2.87 (dd, _3), 3.15 (m, C_2-furyl, H3), 3.70 (2H, s, SC_2)~ 4.12 (lH, m, C~), 4.57 (lH, m, Hl), 6.25 (lH, bs, furyl-_), 6.4 (lH, m, NH), 6.9-7.4 (1 lH, m, pF-Ph-_, Ph-_, furyl-H) Example 30 (+/-)-N-[6-(4Fluorophenyl)hexyl]-~ (4~,~
oY~P~ yl-3-(3-furyl)~ ude A sQllltinn of (+/-)-N-[6-~fluorophenyl)hexyl]-2-(4-bell~ylthio)-2-oxo~7ptirlin-l-yl-3 (3-furyl)propio~mi~lP (80% diastereoisomer b) (0.30g, 0.00256moles) in dichlorometh~nP (25ml), cooled to -70~C, wae treated with a solution of 3-chloroperoxy benzoic acid (0.80g, 0.00255moles) in dichloromp~th~np (25ml) over 1 hour m~int~ining the ~Illl e~ature at -70~C. The cooling bath was removed and the reaction mixture was stirred for 1 hour giving a colourless solution. The reaction mixture was diluted with dichlorompth~np (SOml) and washed with 10% aq sodium slllI-hitP solution, sodium hydrogen carbonate solution, water, dried (MgS04), and evapoldted to a colourless oil which cnnt~inP-d a mixture of diastereoieomPre bl+b2.
~lrific~tion by repeated flash column chromatography on silica gel eluted with 1:1 to 3:1 petroleum ether 40-60~C: ethyl acetate followed by recry~st~llie~tion from ethyl acetatelpetroleum ether 40-60~C gave (+/-)-N-[6-(4-fluorophenyl)hexyl]-2-[4-benzylelllrhinyl]-2-oxo~7Pti~lin-l-yl-3-(3-furyl)propionamide (di~l~oisomer b2) as colourless solid. (0.38g, 28%) m.p. 90-91~C.
lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.57 (2H, t, J=7.6Hz, C_2Ph), 2.67, 2.73 (lH, dd, J=2.5, 15.4Hz,_3), 2.94, 3.01 (lH, dd, J=5.5, 15.4Hz,_3), 3.22 (4H, m, C_2-furyl, CH2NH), 3.92, 4.05 (each lH, 2xd, J=13.1Hz, SOC_2)~ 4.41 (lH, m, H1), 4.58 (lH, dd, J=6, 10 Hz, C_), 6.29 (lH, d, J=0.77Hz, furyl-_), 6.9-7.4 (12H, m, pF-Ph-_, furyl-H, Ph-H, N_) F~y~mple 31 N-[6~ Fluorophenyl)hexyl]~ l b~ ~oY~ idin-l-yl-3-(3-furyl)pr~
A solution of N-[~(4-fluorophenyl)hexyl]-2-(4-benzylthio)-2-oxo~7pti(lin-l-yl-3-(3 furyl)propio~-mitle (80% diastereoisomer a) (1.13g, 0.00222moles) in dichlorometh~nP (25ml), cooled to -70~C, was treated with a solution of 3-chlolupelu,.y benzoic acid (0.70g, 0.00223moles) in dichlorompth~np (25ml) over 1 hour m~int~ining the temperature at -70~C. The cooling bath was removed and the reaction was stirred for 1 hour giving a colourless sollltion The rP~ctinn mixture was diluted with dichloromPth~ne (SOml), washed with 10% aq sodium sulphite solution, sodium hydrogen carbonate solution, water, dried (MgS04), and evaporated to a colourless oil which ct nt~inPd a mixture of diastereoisomers. pnrific~tion by flash column chromatography on silica gel eluted with 1:1 to 4:1 petroleum ether 40-60~C:ethyl acetate gave (+J-)-N-[6-(4-fluorophenyl)hexyl]-2-(4-benzylqllrhinyl)-2 W 0 97/02242 PCT~EP96/02765 oxc ~7Pti~in- l-yl-3-(3-furyl)propion~mi~lp (dliastereoisomer a2) as colourless oiL
(0.31g, 26%).
lH NMR o (CDCl3) 1.2-1.6 (8H, m, 4xCH2), 2.57 (2H, t, J=7.6Hz, CH2Ph), 2.76, 2.79 (lH, dd, J=2, 15.2Hz, H3), 3.00, 3.04 (lH, dd, J=5.2, 15.2Hz, H3), 3.30 (4H, m, S CH2-furyl, CH2NH), 3.93, 4.08 (4H, 2xm, CH, H4, SOC_2)~ 6.29 (lH, s, furyl-H)D
6.9-7.4 (llH, m, pF-Ph-_, furyl-H, Ph-H), 7.88 (lH, m, N~
F.Y~mpl~ 32 (+/-)-N-[6-(4-Fluorophenyl)heYyl]-2~ lll.io}2~Y~ idin-l-Yl-3-phenyl)pr~ (9S% ~lia~ r a a Methyl 2-(1 be~ l,io-~-)Y~>~7~t;~in 1-yl) 3 ~
A solution of methyl-(4-be,l~ylt~lio-2-oYr~7pti~1in-l-yl) acetate (2.03g, 0.00765moles) in dry tetrahydrofuran (40ml) at -75~C under nitrogen was treated with a lM sol~ltion of lithium bis(trimethylsilyl)amide in hP~ ~n~-s (9.2ml, 0.0092moles) over 5 ...i~
keeping the temperature below-68~C. 1,3-Dimethylimi~l~7~ n-2-one (5.0ml, 0.0457moles) was added keeping the te.mpr..~ below -70~C. The resnltin~
snCI~çn.cion was stirred at -75~C for 30 min-ltPs and then treated with a solution of benzyl bromide (2.36g, 0.0138moles ) over 5 min-ltes kPeping the ~ below -70~C. The reaction was stirred for l.S hours during which time it reached -20~C.The reaction was cooled to -75~C and quenrh~cl with glacial acetic acid (l.Oml),partititionPd beLween brine (lOOml) and ethyl acetate (lOOml). The organic layer was washed with water, dried (MgS04), and evaporated to a coloured oil. pllrifi~tion by flash column chromatography on silica gel eluted with 2: 1 petroleum ether 40-60~C:ethyl acetate gave methyl 2-(4-benzylthio-2-oYo~7Pti~in-l-yl)-3-phe"yl~ )ionate as yellow soild (1.78g, 65%, 9:1 diastereoi.~omPr a:b) m.p. 66-67~C.
lH NMR o (CDCl3) 2.83 (lH, m, H3), 3.12 (lH, m, H3), 3.35 (2H, m, CH2Ph),3.76 (5H, m, OCH3, SC--2)~ 4.06 (m, CHg), 4.75 ( m, H/l, C_A)~ 7.23 (lOH, m, 2xPh-H) b. 2-(4-benzylthio-2-oY.~ in-l-yl)-3-pl~ r~ io. ic acid A solllti-~n of methyl 2-(4-benzylthio-2-oxo~7Ptiflin-l-yl)-3-phenylpropionate (1.75~, 0.00492 moles) in mPth~nol (75ml) at 10~C was treated with a lN sodium hydroxidesolution (4.92ml, 0.00492moles) over 40 minll~Ps The cooling bath was removed ;md the reaction was stirred for 2 hour. lN NaOH (0.2ml) was added and the reaction was stirred for 60 minlltps~ diluted with water (SOml) and evaporated to remove mPth~nol The residue was mixed with water (75ml) and extracted with ethyl acetate (SOml). The aqueous was ~ri~lifipd with lNHCl and extracted with ethyl acetate (2x75ml). Theorganic extracts were combined washed with brine, dried (MgS04), and evaporatedl to give 2-(4-benzylthio-2-oxo~7Ptitlin-l-yl)-3-phenyl)propionic acid as a cream solid m.p.
125-131~C (1.37g, 82%, 40:60 distereoisomer a:b) lH NMR ~ (CDC13) 2.8 (lH,m, H3), 3.15, 3.35 (3H, 2xm, CH2-furyl, H3), 3.53 (m, SCH2g), 3.73 (s, SCH2A), 4.0, 4.15 (lH, 2xm, C_A+B)~ 4-07. 4.59 (lH, 2xm, ~,1), 5.47 (lH, bs, C02H), 7.08-7.37 (lOH, m, 2xPh-H) c. (+/-)-N-t6-(4-Fluorophenyl)hexyl]-2-(4-b~-~yllllio~2 ~ 1-yl-3-phenyl)propi~ A~
~(4-Fluorophenyl)hexylamine (0.76g, 0.00389moles) in dry DMF (40ml) was added to a mixture of 2-(4-benzylthio-2-o7~o~7ptillin-l-yl)-3-phellylpl~3pionic acid (1.33g, 0.00389moles), l-hydroxybenzotriazole (0.52g, 0.00385moles), N,N'-dicyclohexylcarbodiimide (0.8g, 0.00388moles) and was stirred at room Lelnpel~L~ Le W O 97/02242 PCT~EP96/02765 for 4h. The ~"s~en~ion was diluted with ethyl acetate (lOOml) and filtered to remove urea The hltrate was evaporated to remove ethyl acetate and the residue was miAed with aq.NaHC03 (125ml) and washed with diethyl ether (2x75ml). The organic extracts were combinP~i and washed with brine, dried (MgS04), and evapo ~d to anoil. This was com~inP~ with product from sep~ rÇS7~tionC (from 0.33g, 0.96g of 2-(4-b~l~yl~lio-2-oxozt7Pti~lin-l-yl)-3-phellyl~opionic acid) and purified by repeat flash column chrom~togr~rhy on silica gel eluted with 3:1 P.E.:ethyl acetate to give the title compound as a waxy colourless solid, 0.79g, 20% (conts7inc 5% ~ oi~...Pr b), nmr for a:
lH NMR o (CDC13) 1.2-1.6 (8H, m, 4xC_2)~ 2.56 (2H, t, J=7.8 Hz, C_2Ph), 2.68, 2.74 (lH, dd, J=2.3, 15.4Hz, H3), 2.99, 3.05 (lH, dd, J=5.2, 15.4Hz, H3), 3.26 (4H, m, NHCH2, CH2Ph), 3.70 (2H, s, SC_2)~ 3.81 (2H, m, C_, H,,), 6.9-7.4 (lSH, m, pF-Ph-H, 2xPh-_,N_) FY~7mple 33 (+/-)-N-[6-(4-7~uJlo~henyl)hexyl]-2-(47De~ ;o)-2~ lin-l-15 yl-3-phenyl)~ , A~P (98% ~li;~cl~eo~ .-. b) The above chromatography gave the title compound as a colonrlP-ss soi d, l.Olg, m.p.
78-80~C, 25% yield (cont~inc 2% diastereoisomer a) lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.56 (2H, t, J=7.8 Hz, C_2Ph), 2.76, 2.80 (lH, dd, J=2.4, 15.6Hz, H3), 3.06, 3.10 (lH, dd, J=5.2, 15.6Hz,_3), 3.24, 3.34 (4H, m, NHCH2, CH2Ph), 3.51 (2H, s, SC_2). 4.16 (lH, dd, J=5.6, 10.4 Hz, C_), 4.54(lH,m,H1),6.35(1H,m,N_),6.9-7.4(14H,m,p.~-Ph-_,2xPh-_) l~Y~77~rlP 34 N-t6-(4-Fluorophenyl)heAyl]-2-(4-benzy sulphinyl)-2-~A )a~lidin-l-yl-3-phenyl)~ P (lia~
A soltltion of N-[6-(4-fluorophenyl)hexyl]-2-(4-ben~ylthio)-2-oxozt7Ptil1in-l-yl-3-phenylpropion~mi~le (0.76g, 0.00147moles) in dichlorornPthztnP (25ml), cooled to-70~C, was treated with a solution of 3-chl(Jlu~luAy benzoic acid (0.46g, 0.00147moles) in dichlorornP-th~nP- (25ml) over 1 hour ...~i.-t~ o the te~ llle at-70~C. The cooling bath was removed and the reaction was stirred for 2 hour giving a colourless solution. The reaction was washed with 10% aq sodium s~llrhitp solution, sodium hydrogen carbonate ~olntion, water, dried (MgS04), and evaporated to a colourless oil (0.89g). Purification by repeat flash column chromatography on silica gel eluted with 1: 1 to 2:3 petroleum ether 40~-60~C:ethyl acetate followed by recyst~lli ~ti-)n from diethyl ether / pelroleum ether gave N-r6-(4-fluorophenyl)hexyl]-2-(4-benzylc-llrhinyl)-2-o~ 7Pti~lin- l-yl-3-phenylpropion~mi-le (diastereoisomer a2) as colonrl~s solid. (0.26g, 33%) m.p. 62-63~C.
lH NMR o (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.57 (2H, t, J=7.6Hz, CH2Ph), 2.77, 2.87 (lH, dd, J=2.2, 15.3Hz, 3~, 2.88, 2.93 (lH, dd, J=5.2, 15.3Hz, _3), 3.38 (4H, m, CH2Ph, C_2NH), 3.61 (lH, m, Hl), 3.83, 4.05 (each lH, 2xd, J=13Hz, SOC_2)~
3.99 (lH, m, C_), 6.9-7.4 (14H, m, pF-Ph-H, 2x Ph-_), 8.06 (lH, m, NH) v ~=0 1785 cm~l; Found: C, 69.3; H, 6.5; N, 5.3%; C31H3sFN203S requires: C, 69.6; H, 6.6; N, 5.2%
F~ lc 35 N-t6-(4-Fluorophenyl)hexyl]-2-(4-l,e~ L~ f~p~ ..f;~
yl-3-phenyl)propio~ e (79% dia~ - al) W O 97/02242 PCTAEP96tO276S

Evaporation of column fractions from the above chrnm~to~r~rhy gave the title compound as a colourless foam, 0.21g, 27% yield, (Cont~in~ 22% clia~ i.c~mPr a2);
nmr for al:
lH NMR o (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.57 (2H, t, J--7.8 Hz, CH2Ph), 2.62, 2.68 (lH, dd, J--~1.7, 14.8Hz, H3), 3.3 (5H, m, H3, CH2-Ph, CH2NH), 3.80 (4H, m,H1, SOCH2, CH), 6.60 (lH, m, N~), 6.9-7.4 (14H, m, pF-Ph-H, 2xPh-H) F.Y~mpl e 36 (+/-)-N-t~(4Flu~vl.henyl)hexyll-~ (4benzyl~ h;~yl)-2-oYo~ -yl-3-pht~ io~ ~ somer bl) A sol~ltio~ of (+J-)-N-[6-(4-fluoluphe.,yl)hexyl]-2-{4-bG.~ylll.~o]-2-oxo~7~titlin-l-yl-3-phenyl)propio~mi~iP (diastere~ omPr b) (0.95g, 0.00183mnlPs) in dichloromPth~nP
(25ml), cooled to -70~C, was treated with a solntion of 3-chlo,upel~o~y bel~oic acid (0.57g, 0.00182moles) in dichloromp-th~np (25ml) over 45 ~ -~ m~ the tPmpçr~tllre at -70~C. The cooling bath was removed and the reaction was stirred for 2 hour giving a colourless soh~tio~ The reaction was washed with 10% aq sodium sulphite solution, sodium hydrogen carbonate solution, water, dned (MgS04), and evaporated to a colourless oil (0.89g). Purified by repeat flash column chromatography on silica gel eluted with 1:1 to 1:3 petroleum ether 40-60~C: ethyl acetate lo separate the diasterenic~ mPr products. Cooling the higher running isomer in diethyl ether gave N-t6-(4-nuoluphenyl)hexyl]-2-(4 benzylcnlrhinyl)-2-oxo~7~ti~in-l-yl-3-phenyl)propion~m~ (diactereoisomer bl)ascolo~lrl~-ccsolid.
(0.071g, 7%) m.p. 128~C. (contains 4.8% diactereoisomer b2) lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.56 (2H, t, J=7.8 Hz, CH2Ph), 2.62, 2.68 (lH, dd, J-1.9, 14.7Hz, H3), 2.85 (lH, m), 3.25 (2H, m, C_2NH), 3.36, 3.42 (lH, dd, J=2.2, 14.7Hz, H3), 3.52 (lH, m, 1 of CHC_2)~ 3.70. 4.05 (each lH, 2xd,J=lOHz, SOC_2)~ 4.20 (lH, m, H4), 4.67 (lH, dd, J=S, 1 lHz, CH), 6.7-7.4 (lSH, m, pF-Ph, 2xPh-H, NH) Found: C, 68.9; H, 6.5; N, 5.1%; C31H3sFN203S requires: C, 69.6; H, 6.6; N, 5.2%Example37 (+/-)-N-t6-(4-Fluorophenyl)hexyl]-2-(4-bt~ nyl)-2-oY~7P~in-l-yl-3-phenylpropio~miAp(~ia~ ~nic~ rb2) The lower lunning isomer fr~rtio~ from the above chromatography were ~ d from ethyl acetate/diethyl ether to give N-[6-(4-fluorophenyl)hexyl]-2-(4-benzyl.clllrhinyl~-2-o~o~7P~itlin-l-yl-3-phenyl)propion~mi-le (diastereoisomer b2) as colourless solid. (0.328g, 33%) m.p.84-85~C.
lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.56 (2H, t, J=7.8 Hz, CH2Ph), 2.60, 2.65 (IH, dd, J=2.4, 15.6Hz,_3), 2.84, 2.87 (lH, dd, J=5.6, 15.6Hz,_3), 3.21 (3H, m, 1 of PhCH2CH), 3.53, 3.59 (lH, dd, J=6.4,14.9Hz, 1 of PhC_2CH ), 3.91, 4.02 (each lH, 2xd, J-13.1Hz, SOC_2)~ 4.34 (lH, m, Hl), 4.70, 4.74 (lH, dd, J=6.4, 10, CH), 6.9-7.4 (lSH, m, pF-Ph-H, 2xPh-H, N_) Found: C, 69.0; H, 6.5; N, 5.1%; C3lH3sFN203S.1.0%H20 requires: C, 68.9; H, 6.6; N, 5.2%
FY~mple 38 (+)-N-[6-(4-Fluorophenyl)heYyll-2-(4l*~ rhinyl)-2 oY~7eff~lin-l-yl-3-ph~ ;on~m ~ ~r~~ r (+)-b2) The above b2 diastereoisomer was se~a~d by chiral HPLC to give the title compound as a Oum lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xC_2)~ 2.56 (2H, t, J=7.8 Hz, CH2Ph), 2.60, W O 97/02242 PCT~EP96/02765 2.65 (lH, dd, J=2.4, 15.6Hz, H3), 2.84, 2.87 (lH, dd, J=5.6, 15.6Hz, H3), 3.21 (3H, m, 1 of CH2NH), 3.53, 3.59 (lH, dd, J=6.4,14.9Hz, 1 of C_2Ph), 3.91, 4.02 (each lH, 2xd, J=13. lHz, SOCH2), 4.34 (lH, m, H1), 4.70, 4.74 (lH, dd, J=6.4, 10, C~), 6.9-7.4 (lSH, m, pF-Ph-H, 2xPh-H, N_) S aD = +35.8~ (c=0.4%w/v ethanol) at 20~C
FY~mrl~ 39 (-)-N-t6~(4-Fluorophenyl)he~y-yl~-~ (4~ ~
;..-l-yl-3-~ (dia~l~.eoisomer (-)-b2) The title compound was a so obtained from the b2 diastereoicomPr by chiral HPLC and was icol~tPd a gum lH NMR o (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.56 (2H, t, J=7.8 Hz, C_2Ph), 2.60, 2.65 (lH, dd, J=2.4, 15.6Hz, H3), 2.84, 2.87 (lH, dd, J=5.6, 15.6Hz,_3), 3.21 (3H, m, 1 of CH2NH), 3.53, 3.59 (lH, dd, J=6.4,14.9Hz, 1 of CH2Ph), 3.91, 4.02 (each lH, 2xd, J=13. lHz, SOCH2), 4.34 (lH, m, H1), 4.70, 4.74 (lH, dd, J=6.4, 10, C_), 6.9-7.4 (15H, m, pF-Ph-H, 2xPh-_, NH) lS aD = -43.7~ (c=0.3%w/v ethanol) at 20~C
FY~mp'~40 (+/-)-N~[6-(4-Flu~ enyl)heYyl]-2-(4-l)e~ lU~io~2~ idin-1-yl-2-all~lac~.~ide (diactere~ico-n~r a) a Methyl 2-(4-l~el~ylU~io-2-~ in-l-yl)-2-allyl~
A solution of methyl-(4-benzylthio-2-oyr~7pti~lin-l-yl) acetate (5.0g, 0.01884moles) in dry tetrahy l~oru~ (lOOml) at -75~C under nitrogen was treated with a lM
sol~lti()n of lithium bis(trimethylsilyl)amide in THF (23.0ml, 0 02~molPs) over 10 mimltPs keeping the tPmpPr~tllre below -68~C. 1,3-Dime~lyli...;~ in-2-one (12.5ml, 0.1143moles) was added keeping the tPmrer~tllre below -70~C. The resnlting suspension was stirred at -75~C for 30 Illil.lllPS and then treated with aUyl iodide (3.1ml, 0.0339moles) over 5 minlltPs . The tempeialule rose to -65~C. Thereaction was stirred at -78~C for 30 ...i....~Ps and then aUowed to warm to -20~C over 30 mimltPc The reaction was cooled to -75~C and ~llen~hPd with glacial acetic acid (Sml), par~ititionpcl between brine (lSOml) and ethyl acetate (175ml). The organic layer was washed with brine, dried (MgS04), and evaporated to a coloured oil.
30 pnrifi~tiQn by flash column chromatography on silica gel eluted with 4:1 petroleum ether 40-60~C:ethyl acetate gave methyl 2-(4-benzylthio-2-oxo~7Pti~in-l-yl)-2-allylacetate as yellow oil (4.48g, 78%, 85:15 diasterPoicQmP- a:b) lH NMR ~ (CDC13) 2.7 (2H, m, C_2)~ 2.90 (lH, m, _3), 3.27 (lH, m, H3), 3.80 (SH,m, C02C_3,SCH2), 3.92, 4.23 (lH, 2xm ,C_A~C B)~ 4.55, 4.90 (lH, 2xm, H1), 5.16 (2H, m, CH=C_2)~ 5.80 (lH, m, CH=CH2), 7.31 (SH, m, Ph-_,) b. 2-(~be..~y~ io-2-o~Q~7~H~l:n-l-yl)-2-allyl acetic acid A solutio~ of methyl 2-(4-benzylthio-2-oxo~7~ti~lin-l-yl)-2-allyl acetate (4.38g, 0.01434 moles) in methanol (lOOml) at 10~C was treated with a lN sodium hydroxide solution (14.3ml, 0.0143moles) over lS minut~Ps The cooling bath was removed and40 the reaction was stirred for l.S hour. lN NaOH (2.0ml) was added and the reaction was stirred for 30 mimltes, diluted with water (lOOml) and evaporated to remove meth~nol. The residue was extracted with diethyl ether (lOOml). The aquous was aei~lifi.od with dilute HCl, and extracted with diethyl ether (lOOml, SOml). The extracts were combined, washed with brine, dried (MgS04), and evaporated to give 2-(~

WO 97/02242 pcTlEps6lo2765 l~n~yl~~~o-2-o~o~7pt~ n-l-yl)-2-allylacetic acid as a yellow oil (3.97g, 95%) 60:40 distereoi.~omPr a:b lH NMR o (CDC13) 2.7 (2H, m, CH2), 2.90 (lH, m, H3), 3.27 (lH, m, H3), 3.80 (m, CHg, C02CH3,SCH2), 4.12 ( m ,CHA), 4.65, 4.85 (lH, 2~cm, H1), 5.16 (2H, m, CH=CH2), 5.80 (lH, m, CH=CH2), 7.31 (5H, m, Ph-H,) G (+/-)-N-~(4Fluorophenyl)hexy1]-2-(4 bt~ llluo)-~ yl-2-allylAr~ ude (90% ~ a) 6-(4-Fluorophenyl)hexylamine (2.5g, 0.0128moles) m dry DMF (75ml) was added ItO a u~i~LLul~ of 2-(4 benzylthio-2-o~oA7~ n-l-yl)-2-allylacetic acid (3.73g, O Ol'~gmol~s), 0 l-hydl~yl~e~.0~ 7.Clf' (1.75g, 0.0129moles), 1-cyclohe~yl-3-(2-morphnlin~thyl)carbo~liimi-l~ metho-p-toluene sulfonate (5.42g, 0.0128moles) andwas stirred at room temperature for 19h. The ~sl~,nc~ was partitioned between sodium hydogen carbonate sollltion (300ml) and diethyl ether (lSOml). The layerswere se~ d and the aqueous was washed with diethyl ether (lOOml). The organic ~ ;ls were combined washed with water, dried (MgS04), and evaporated to an oil (5.92g). Purified by repeat flash column chrom~togr~phy on silica gel eluted with :2:1 petroleum ether 40-60~C:ethyl acetate to give the title colllpol"ld as a colourless oil, 1.27g, 21 %yield lH NMR ~ (CDC13) 1.35-1.6 (8H, m, 4xC_2)~ 2.56 (2H, t, J=7Hz, CH2Ph), 2.65 (2H, m, CH2), 2.79, 2.85 (lH, dd, J=2.4, 15.4Hz, _3), 3.25 (3H, m, _3, NHCH2)9 3.71 (lH, dd, J=6Hz, CH), 3.82 (2H, s, SCH2), 4.65 (lH, m, ~4), 5.15 (2H, m, CH=C_2)~
5.72 (lH, m, CH=CH2), 6.85 (lH, m, N_), 6.9-7.3 (9H, m, Ph-_, Ar-H) Example41 (+/-)-N-[6-(4-Fluo~ l)hexyl]-2-('1 be~ io~2 yl-2-allyl~f ~ P (80% .lia~ b) From the above chromatography the title compound was isolated as a colourless oil, 1.1 lg, 19% yield lH NMR ~ (CDC13) 1.25- 1.6 (8H, m, 4xC_2)~ 2.56 (2H, t, J=7Hz, C_2Ph), 2.78 (2H, m, C_2)~ 2.84, 2.91 (lH, dd, J=2.3, 15.3Hz, H3), 3.25 (3H, m, H3, NHCH2), 3.82 (2H, s, SC_2)~ 4.03 (lH, dd, J=6Hz, C_), 4.65 (lH, m, ~4), 5.08 (2H, m, CH=CH2)~
5.72 (lH, m, C_=CH2), 6.51 (lH, m, N_), 6.9-7.3 (9H, m, Ph-_, Ar-H) F ~ e 42 (+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-(41~~
~Y ~7~ n-l yl-2-ally~ *~ ?(~ oiSO~ a2+al) Tre~tmPnt of 1.2g (0.00256moles) of (+/-)-N-[6-(4-Fluolophellyl)hexyl]-2-(4-benzylthio)-2-oxo~7Pt~ n-l-yl-2-allyl~Rt~mi~lP (90% diastereoisomer a) with mCPBA
using the procedure described in F~mr)l~ 34 gave, after similar work-up and chromatography the title compound as a colourless oil, 0.41g, 33% yield lH NMR (diastereoisomer a2) ~ (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.56 (2H, t, J=7Hz, CH2Ph), 2.7-3.3 (6H, m, CHCH2,_3, NHC_2)~ 3.80-4.20 (3H, m, SOCEI2, CH), 4.48 (lH, m, _4), 5.13 (2H, m, CH=CH2), 5.72 (lH, m, CH=CH2), 6.9-7.4 (lOH,m,Ph-_,Ar-H),7.46(1H,m,N~
FY~nP'e 43 (+/-)-N-[6-(4-FIUOrOPhenYI)heXYI]-2-(4-b~ UIPhinYI)-2 o~ -yl- 2-ally~ et~

W O 97/02242 PCT~EP96/02765 Tre~tmPnt of l.O5g of (+/-)-N-[6-(4-Fluorophenyl)he~cyl]-2-(4-bel~ylll~io)-2-oxo~7pt~ n-l-yl-2-ally~ e~ A~p (80% diastere~icomp-r b) with mCPBA using the procedure ~P-sr~ihed in FY~mrlP 34 gave, after similar work-up and ~ 1Q~ Y
the title co~ ol.lld as a pale yellow oil, 0.38g, 35% yield lH NMR ~ (CDC13) 1.2-1.6 (8H, m, 4xCH2), 2.56 (2H, t, J=7Hz, C_2Ph), 2.6-3.3 (6H, m, CHCH2,_3, NHCH2), 3.95, 4.09 (each lH, 2xd, J=11.6 Hz, SOCH2), 4.47 (lH, m, C_), 4.57 (lH, m, H4), 5.11 (2H, m, CH=C_2)~ 5.72 (lH, m, CH=CH2), 6.9-7.4 (lOH, m, N_, Ph-H, Ar-H) F~ e 44 (+/-)-N-[6-~1 Fluor~ lhexyl)]-2 [4L~
~ n~l-yl]l~ul,~ ~ide a Methyl 2-(4-l>~ lll,io-2-~ l-yl)butanoate A mixture of methyl 2-(4-bel~yll~io-2-r,Y~)~7Pti~lin-l-yl)~et~tP(l~2 g, 0.0045 mol) in dry tel.~hydloru.di~ (20 ml) was treated with lithium hP~mPthyl-licil~AP sollltil-n (1 Mol solution in hPY~n~ ~ 4 ml, 0.0054 mol) and stirred at -78~C for 30 ~ s forming a pl~ci~ te which was broken up with vigorous stirring. Following tre~tmPns with ethyl iodide (0.64 ml,O.008 mol) at -78~C, the incoln~lP yellow solid dissolved forming a yellow sollltion The reaction ~ was then left 16 hours at -20~C.
After cooling to -78~C the sollltion was treated with acetic acid (0.5 ml) followed by partitiong belween ethyl acetate and water. The aqueous layer was e~ P~ again with ethyl acetate and the combinP-d extracts dried (MgS04) and ~val.olaL~d to abrown oil. pnrifir~tion by flash chrom~tography (silica, ethyl acetate/petrol) gave the title componn-l as a miYture of diastereoicom~rs (colourless oil), 0.3 g, 23% yield.
lH NMR ~ (CDC13) 1.02 (3H, d of d, CH_C~), 2.07 (2H, m, SCH2), 2.92 and 3.25 (each lH, m, H4s), 3.76 (2H, d, CH2), 3.83 (2H, d, C_2)~ 3.67, 4.16 (lH, m, CH),4.64 and 4.94 (lH, m, H3), 7.28 (2xSH, m, Ph) b. 2-(~B~ l.io-2-oYo~eti~' l-yl)L~ -o:~ acid A stirred solution of methyl 2-('1 bel~yl~io-2-oxo~7p-ti~lin-l-yl)but~no~tp (1.40 g, 0.0047 mol) in meth~nol (12 ml) was treated with 1 molar pot~ccinm hydroxide (5.47 ml). After 16 hours, the meth~nol was evaporated and the residue diluted with water.
The aqueous layer was ~ci~lifi~d with cooling (ice bath) and the oil which pl~eipi~d was eYtr~rtPd into ethyl acetate. The combined extracts were dried (MgS04) and evaporated to give the title compound as a white oily solid (Uli~ t; of diastereoicomPr.c), 1.36g, 100% yield.
lH NMR ~ (CDC13) 1.02 (3H, m, CH_C~), 2.07 (2H, m, SCH2), 2.92 and 3.35 (each lH, m, H4s), 3.74 (2H, s, CH2), 3.84 (2H, s, CH2), 3.53, 4.10 (lH, m, CH),4.71 and 4.94 (lH, m, H3),6.99, ~lH,bs, OH), 7.28 (2xSH, m, PhH) c N-~6-(4-Fluorophenylhexyl)]-2-t4-be~ io-2-oYo~ff~lin-l-yl]b~ ide ixlul.: of ~lia~le~;com~rc a + b) A mixture of 6-(4-fluorophenyl)hexylamine (0.9Sg,0.0048 mol,T ~m~ttin~ J. L. EP
138464 A2 850424 (CA 103:142000)), l-hydroxybenzotriazole hydrate (0.56g, 0.0042 mol), 2-(4-benzylthio-2-oxo~7ptitlin-l-yl)-butanoic acid (1.2 g, 0.0043 mol) and dicyclohexylcarbo-iiimi-ie (0.89 g, 0.0043 mol) in dim~Lhylr~ mi-le (50 ml) was stirred for 16 h at ambient temperature. The solvent was evaporated and the residue treated with ethyl acetate. The insoluble dicyclohexylurea was filtered off and discarded, and the filtrate washed with ~tnr~t~d sodium hydrogen c~ul,onatP sol~ltir~n dned (MgS04) and evaporated to an oil. This w~ pnrified by flash chrom~t~ ~rh y (silica, ethyl acetatelpetrol) to give the title compound as an oil (1.47 g, 75% yield) lH NMR ~ (CDC13) 0.83-.98,(3~,m C-H3),1.1-17(~T~,m ~'~2),1.8-2.15(4~,m,~
2.55 (2H, t,CH2),2.88 (l~,m ~'H2), 2.99,(~,m ~ 2), 3.46,(1~,q,C~2), 3.85, 4.12(1~,q ~), 3.85 (2H,s,C_2)~ 3.86 (lH,d,CH2), 4.65(1~,m,~4), 6.5(1H,t,NH~, 6.75(1H, t,N_), 6.9-7.33(9H, m,Ph ).
F.~ r 45 N-[6-(4-Fluorophenyl)heAyl]-2-[41~b~ ,hinyl~2~Aoa2L~din-1-yl]l~ ide, A solnti~n of N-[6-(4-fluoluphenylhexyl)]-2-~beliLyllli~o-2-o~ 7~ti-1in-l-yl]bulyl~llide (diastere~ i.comt~rs a &b) (1.27 g, 0.0028 mol) in dicholo..~ h~nP. (50 1~) was cooled to -65 to -70~C and a solution of m-chlc~l-)pe~ Loic acid (0.58 g, 0.0033 mol) in dichlorom~-th~n~ (20 ml) added dropwise over 15 m~n. After 3 hours the mixture was washed with a mixture of saturated sodium hydrogen carbonate and 1~ c~nlr~t~d sodium SnlIlhit~ dried (MgSO4) and evaporation gave the title co-llpoulld as a mixture of diastereoi.com~rs al, a2, bl. b2 as an oil, 1.47g 100% yield.
lH NMR ~ (CDCl3) 0.93-1.04,(3H,m,CH2C_3),1.1-1.7(6H,bm,-CH2),1.8-2.25(~,m -'H3CH2) 2.55 (2H, t,CH2Ar),2.6-3.0 (l~,m,~H), 3.05-3.55 (3H,m,CH2,_3),3.7 (lH,q,CH),3.85,4.12(1H,q,C_),3.85-4.25(2H,m,SCH2), 4.5-4.85(1H,m,H4),6.45(1H,t,N_), 6.85(1H, t,N_), 6.9-8.1(9H, m,PhH).
0.8g of the above oil was purified by chrom~to~r~I)hy (HPLC, Re~l~m~n silica column, ethanol/hexane), to give the i.corn~rs described in F~m~ s 4~48.
F~ .'e 46 (+/-)-N-t6-(4-Fluorophenyl)hexyl]-2-[4be-~yl~
oyn~ ; l;.. 1 yl]~ le(Isomeral) Isomer al, oil, (0.05g) lH NMR ~ (CDC13) 0.83-.98,(3H,t,C 3),1.2-1.7~(6H,m,C_2)~ 1.99 (2H, q,CH3C_2),2.56 (2H,m,C 2Ar) 2.78,3.34,(2H,m,_3)3.21,(2H,m,NHC_2)~ 3.87 (3H,m,CH,PhCH2), 4.71(1H,m,H4),6.25(1H,t,NH), 6.9-7.39(9H, m,PhH).
FY~mple 47 (+l-)-N-t6-(4-Fluorophenylhexyl)]-2-t4be.~ h;~ 1-2-oY~ -1-yl]l~ P (isomer bl and b2, 1:3) The above procedure yielded 0.05g of the title compounds (bl:b2, 1:3) as an oil lH NMR ~ (CDC13) 0.93,(3H,t,C_3),1.01,(3H,t,C_3),1.22-1.38(6H,m,C_2)~ 1.99-2.1 (2H, m,CH3C_2)~ 2.1-2.25 (2H, m,CH3CH2), 2.56 (2H,m,C_2Ar), 2.55,3.08,(2H,m,_3) 2.68,3.55,(2H,m,_3),3.18,3.25,(~ ~ym,NHC_2j, 3.87-4.25 (3H,m,C_,PhCH2), 4.45,4.51(1:3)(1H ~ym~H4)~6~7s(lH~t~N_), 6.9-7.40(9H, m,PhH).
Example48 N-t6-(4-Fluorophenyl)hexyl]-2-t4-bel~yl~
yl]~ P (isomer a2) The above procedure yielded 0.05g of the title compound as an oil lH NMR ~ (CDC13) 098,(3H,t,C_3),1.3-1.61(6H,m,C_2)~ 2.08 (2H, q,CH3CH2),2.56 (2H,m,C_2Ar),2.75,3.19 (each lH,m,_3),3.26 (2H,m,NHC_2)~
3.85 (lH,m,CH,), 4.05 (lH,d of d,ArCH2), 4.54(1H,m,H4), 6.92-7.40(9H, m,PhH).
FY~mp'e 49 (+/-)-N-t6-(4-Fluorophenylhexyl)]-2-t41,e-~ l-2-~Y~ l-yl]pe~ P
a Meffiyl 2-(4-benzylthio-2-- Yo~7e~lin-l-yl)p~p~ Q~te W O 97/02242 PCT~EP96/02765 Sub~ g propyl iodide (4g, 0.023 mol) for ethyl iodide and using the collG~ g amounts of the other lta~gell~ in FY~mrlP 44a gave after pllrifir~tion by flash chromatography (silica, ethyl acetate/petrol) the title ccllu~oul-d as a ll~i~ G of dia~lGl~oico.~.Pr.s (colollrlPss oil), 1.05 g, 25.3% yield.
S lH NMR ~ (CDC13) 0.96 (3H, d of d, CH2C~), 1.36 (2H, m, CH3CH2),1.96 (2H, m, CH2CH2),2.90,3.29 (each lH, m,_3s), 3.74 (3H, d, OCH3,), 3.79 (2H, d, SCH2), 4.27 (lH, m, CH), 4.64 and 4.94 (lH, m, H4), 7.29 (SH, m, Ph) b. 2-(4Be~lll 'o ~ o~.~a~ yl)pentanoicacid .SIlbs~ g methyl 2-(4-bGll~ylLl~iO-2-o~ Pl;l1in-l-yvppnt~nn~tp (1.04g, 0.0033 mol) for methyl 2-(4-ben~yllllio-2-oxo~7Pti~lin-l-yl)b~ r and using the corresponding ~mountc of the other l~agen~ in FY~mrlP- 44b gave the tide CO-ll~Ou ld as a mixture of diastereoisomers (colourless oil), 0.8 g, 82% yield.
lH NMR ~ (CDC13) 0.96 (3H, d of d, CH_C 3), 1.40 (2H, m, CH3CH2),1.91 (2H, m, CH2CH2),2.90,3.29 (each lH, m, _3s), 3.64 (lH, m, OC_3,), 3.84 (2H, d, lS SCH2), 4.24 (lH, m, CH), 4.64, 4.94 (lH, m, H4),6.4(1H,bs,OH),7.29 (SH, m, Ph) ~ (+/-)-N-[6-(4-Fluoroph~:..;lht:A,~1)]-2-[1 1~t~ n-l-yl]y. u~.~l~ide S~stitllting 2-(1 bel~yllllio-2-oxn~7pti~lin-l-yl)propanoic acid (0.8g, 0.0027 mol.) for 2-(4-ben~ylLl~io-2-oxo~7pti(lin-l-yl)butanoic acid and using corresponding 4~n~ s of 20 the other reagents in FY~mrlP 44c gave the title compound as an oil, 1.4g 100%yield lH NMR (complPY spectrum) ~ (CDC13) 0.93,(3H,m,CH3),1.2-1.6(4H,m,CH2),1.8-2.15(4H,m,CH2) 2.55 (2H, t,CH2),2.88 (1H,m,CH2) 2.8,3.3 (lH,d of d,3_) 2.9,(~ ,CH2) 2.95,(2H,s,CH2)3-28.(~ m,C~2)~ 3.85 25 (~ m,CH2),4.62(1H,q,C_),4.74(1H,m,_4),6.5(1H,t,NH), 6.76(1H, t,NH), 6.9-7.3 (9H, m,Ph_).
Example ~0 (+/-~N-[6-(4chlol~op~~~ylhexyl)]-~ t1 ~ ..lyh;~.,~1-2-~o~ ,._t~ - l-yl]y~
A ~solllti-~n of N-t~(4-fluorophenylhexyl)]-2-[4-benzylthio-2-oxo~7Pti~lin- 1 -yl]pçnt~n~mi~e (diastere~isompr~s a &b) (0.2g, 0.00042 mol) in dichoromPth~nP (S ml) was cooled to -65 to -70~C and a solution of m-chloropelbenzoic acid (0.09 g, 0.00051 mol) in dichloromethane (5 ml) added dropwise over 15 min. After 1 hour the mL~ was washed with a mixture of ~rnr~tP~1 sodium hydrogen carbonate and saturated sodium snlrhitp~ dried (MgS04) and t;vapolation gave the title compound as a mi~ of diastereoicomprs al, a2, bl, b2 as an oil, 0.2g 100% yield.
H NMR (complex spectrum) ~ (DMSO d6) 0.83-0.95,(3H,m,CH2CH3), 1.1-1.7(6H,bm,-C_2) 2.7 (2H, s,CH2Ar), 2.9 (2H, s,CH2Ar), 3.05-3.55 (3H,m,CH2,H3), 3.7 (lH,q,CH), 3.85, 4.12 (lH,q,CH), 3.70-4.25 (2H,m,SC_2)~ 4.6-S.lS (lH,m's,H4), 7.0-8.2 (9H, m,PhH).
Example ~1 N-(Ben_yl)-2-[4-be~ l-2~o~ n-1-yl]propionamide (dia~l~.. ~o;coln~- bl&b2 l:l.S) Tre~tmPnt of N-(benzyl)-2-[4-benzylthio-2-oYo~7Pti-lin-l-yl]propton~mi~lP
(diastere-)icc-mPr b, FY~mrlP 20) (1.31 g) with mCPBA under the Con~litiQn~ described in FY~mrlP 12 gave the title compound as a mixture of diastereoisomers (b 1 :b2 1: l.S) 1.14 g, colourless solid, m.p. 110-3~C

W O 97/02242 PCT~EP96/0276;5 F~ample52 N-(Benzyl)-2-[4 b~ lphfnyl-2~ idfn-l-yllpropionamide (89% ~ ~.~ eo~ . al) T~ç~l.nP.I~ of N-(benzyl)-2-[4-bel~y~ o-2~o~7p-t~ n-l-yl]~ P
(diastereoi.somPr a, FY~mplP. 19) (1.31 g) with mCPBA under the con-lition.c des~ ed - ~ in F.Y~mrlP. 12 gave the title compound a,, a mi~cture of ~ cte~o~ which were sP,p~r~tP~ by cryst~lli.c~tion to give pred~ hlly diastereoic~mpr al as a colollrlpcc:
solid, m.p. 150-3~C
FY~rle 53 N-(Benzyl)-_-['l benzylsulphinyl-? ~ lidin-l-yllpropiona nfde (82% li~ ~n' ~ a2) 10 The mother liquors from the above ~ ,lya~lli.c~tion were ~ p~ (l and l~
to give the title conlpound a_ pre(lc,...;.-~..lly the dia~t~,eoi.cl mP!r a2, 0.67 g, m.p. 134-~~C.
F,Y~ple S4 R-Me~yl~[(4-allyloAy~bv~l)bel~y~ i 15 a (-)-(R)-4-(4-(Allylo~y~l,onyl)bt~ y' ' ~)-2-o~oa~- ~idfn-l-;lzc&~cacid 4-(4-(Allyloxycarbonyl)benzylthio)-2-oxo~7Pti~lin-l-ylacetic acid ( 3.41 g, 10.2mmol) and cin~ho~ nP (2.99 g, 10.2 mmol) in ethanol (40 ml) were heated to boiling when a clear sollltion was obtamed. On st~n~in~ for 90 mm, the crystalline salt which had precipit~ted was fltered off, and lG~ 71~lli~,~ from ethanol (20 ml).
20 The solid obtained was s~irred vigorously with ether and water whilst acidify~ng with dil. hydrochloric acid, and when complete solution was obtained the layers were sep~d and the aqueous layer further ~ rtPd with ether. The cornhinP~ extracts were dried (MgS04) and evaporated to an oil which crystallised on tritllr~tion wit'r light petrol to give the title compound as white crystals, m.p. 74-6~C, 6.7 g, 50%
25 yield ~ D25 = -24.2 (c. 0.7 w/v CHCl3, 25~C) 'H NMR ~ (CDC13) 2.97 (lH, dd, H3a), 3.26, 4.07 (each lH, CH2CO, d), 3.42 (lH, dd, H3b), 3.70 (3H, s, CH30), 3.81 (2H, s, SCH2), 4.83 (2H, m, CH20), 4.93 (lHl,dd, H4), 5.35 (2H, m, CH2CH), 6.03 (lH, m, CHCH2), 7.39 (2H, d, Ph-H), 8.02 (2H,30 d, Ph-H) b. R-methyl-4[(4-allylox~c~l,onyl)b~ 111,io] 2~ r~ r ~ t~
A sn~pencion of anhydrous potassium carbonate (8.88g), R-4-[(4-allylo,~y~ onyl)bell~yl~lio~-2-oxo~7p-titlin-l-ylacetic acid (21.55g) in N-metllyl~.yl.,lli~linonP (lOOml) was t eated with methyl iodide (10.94g) and stir~ed at 35 room ~p~ t; for 2 hours. After a further (l.Og) methyl iodide was added the reaction was stirred for 30 minl~tP~, partitioned between brine (SOOml) and diethyl ether (SOOml). The aqueous layer was washed with diethyl ether (SOOml) and the organic extracts were combined, washed with water (x2), brine, dried (MgS04),andevaporated to an orange oil (22. lg). Purified by flash column chromatography on40 silica gel eluted with [1:1] P.E. 40-60~C: ethyl acetate to give R-methyl-4-[(~
allyloxycarbonyl)benzylthio]-2-oxoazetidin-1-yl~-et~te as a yellow oil (20.0g, 89'~).
lH NMR ~ (CDC13) 2.94, 3.01 (lH, dd, J=2.2, 15.3Hz, H3), 3.26 (lH, d, J=18.1Hz, 1 of NCH2), 3.39, 3.46 (lH, dd, J=S.1, 15.3Hz, H3), 3.7 (3H, s, C02CH3), 3.81 (2]H, W O 97/02242 PCT~EP96/02765 S7 SC~2), 4.03 (lH, d, J=18.1Hz, 1 of NCE~2), 4.83 (2H, m, C02C~I2), 4.93 (lH, m, ), 5.37 (2H, m, C~12=CH), 6.04 (lH, m, CH2=C~D, 7.39 (2H, m, Ar-~D, 8.02 (2H, m, Ar-~) ~ R,R.Methyl-2-(4-t(4allylox~c~Lonyl)b~ lll,-o]-2 o~ idin-l-y~ r~ and S,R- Methyl-2-(4[(4-allylox~rl,onyl)be ~ylll~;o]-2- -u~Q~ -l-yl)t,.o~:Qn~t~ solnt~ of R-methyl~[(4 allylc~yc~l onyl)benzylthio]-2-o~c0~7Ptitlin-l-yl~et~t~p (13.2g) in anhydlous tetrahydrofuran (250ml), cooled to -75~C under nitrogen, was treated with a lM
solution of lithium bis(trimethylsilyl)amide in THF (46.3ml) over 10 ...;.~ s keeping the temperature below -70~C. The red sollltion was cooled back to -75~C and 1,3-dimethyl-imi~oli~linonP (30.5ml) was added kPPping the t ~"~ below -70~C.
The r~-sulting snsl-çn~ion was stirred at -75~C for 30 ~ e-s and then treated with methyl iodide (4.3ml) over 1 minute and the ~m l.e. ~ t; rose to -68~C. The reaction was stirred at -75~C for 1.5 hours and ~hen allowed to warm to -20~C over 30 minlltps- The reaction was cooled to -75~C and quen~hPd with glacial acetic acid(3.5ml), partititio~pd between water (300ml) and diethyl ether (250ml). The ~queou~
was washed with ether (250ml) and the organic extracts were combined washed withbrine (x3), dried (MgSO4) and evaporated to a coloured oil (7.81g).1H nmr inr~ tP~
- a ratio of al)plv~ ately 50% R,R (diastereoi~()mPr a): 35% S,R (diastereoisomer b):
15% starting m~ttori~l Purified by repeat flash column chromatography on silica gel eluted with [2:1] petroleum ether 40-60~C:ethyl acetate to give the products as various mixtures (12.06g, 88%).
d. R,R-2-{4-[(4-allyloxycarbonyl)be:J.Lylll.io]-~o~ yl}propionic acid and S,R-2-{4-[(4-allyloAycal l,onyl~e~ ;o]-~oy~7~HAin l -yl}propionic acidA solution of methyl-2- {4-[(4-allylo~ycdll,onyl)bell~yl~lio]-2-ox- ~7Pti~lin-l-yl}propionate (2.65g) in tetrahydrofuran (50ml) was cooled to 3~C and treated with lN sodium hydroxide solution (7.5ml) over 1 hour. The cooling bath was removed and reaction mixture was stirred for 30 ~ P-S and a further l.Oml of lN sodium hydroxide solution was added. The reaction was stirred for 30 minllt~s~ brine (75ml) was added and the reaction mixture was extr~ct~d with diethyl ether (75ml). The aqueous was ~ ifiPd with 2NHCl and extr~ct~d with diethyl ether (2x75ml). the extracts were combined, washed with water, dried (MgS04), and evaporated to give a Lule of (R,4-R) and (S,4-li~)-2-~4-[(4-allyloxycarbonyl)bel-~yl~-io]-2-oxo~7Ptil1in-l-yl}propionic acid and des a-methyl analogue as an orange oil (2.50g, 98%).e. (S,4-R~N-[6-~4-Fluorophenyl)hexy1]-2-t(4 allyo~ l~--yl)~e,~yl ' ~]-2~ ;n-l-yl~ ion~
A mixture of 6-(4-fluorophenyl)hexylamine (1.38g), 2-~4-[(4-allylo~yca~l ol~yl)benzylthio]-2-oxo~7ptirlin-l-yl~propionic acid (mixture of diasteroisomers) (2.47g), 1-hydroxybenzotriazole (0.95g) and dicyclohexylcarbodiimide(1.46g) in dimetl-ylÇo, ~ mi(le (50ml) was stirred at room L~-l-~el~tult: for 4 hours. The reaction mixture was treated with diethyl ether (lOOml) and filtered to remove dicyclohexylurea. The filtrate was washed with saturated sodium hydro_en carbonate solution, brine, dried (MgS04) and evaporated to dryness.
Purified by flash column chromatography on silica gel eluted with [2: 1] P.E. 40-60~C

W O 97/02242 PCT~EPg6/0276S
-to give S,R-N-t6-(~fluolophenyl)hexyl]-2-~(1 ally~Ay-,~L.ollyl)be-~ylll~o]-2-o~u~ ;..-l-ylplu~;o~ P, (~lis ~tPreoieo~ b) as a yellow oil (0.479g, 13.4%)lH NMR ~ (CDCl3) 1.32-1.6 (13H, m, CEI3. 4xC~12), 2.56 (2H, t, J=7.6Hz, CH2Ph)~
2.8~, 2.87 (lH, dd, J=2.3, 15.3Hz, 1~3). 3.1-3.3 (3H, m, NHC~2, ~13), 3.86 (2H, s, - S SCH2), 4.10 (lH, q, C~CH3), 4.69(1H, m, 314), 4.83 (2H, m, C02C~I2), 5.37 (2H, m, C_2=CH), 6.02 (lH, m, CH2=C~), 6.43 (lH, m, N~D, 6.94 (2H, m, p-F-Ph-~), 7.10 (2H, m, p-F-Ph-~), 7.37 (2H, m, Ar-~), 8.09 (2H, m, Ar-~) FY~mplc ~ S,4-R,SS,~N-t6-(4Fluo..~ yl~heYyl]-'~ t(4 allylu~,~ul,onyl)l~L.~.~l~-.lrh;nyl]-2~ a, ~ lyr~
10 A sollltion of S,R-N-[6-(~Fluol~phenyl)heAyl]-2-[(~ally-3Ay-,dLbonyl)l>el~ylll.io]-2-v~n~7~ in-l-ylplupiot.,....i-l~ (1.20g) in dichloromPthstnP (25ml), cooled to -75~C, was treated with a sollltion of mcpba (0.7lg, 1Pq~ in dichloromP-thS~n~P (25ml) d~0~. ise over 1 hour. The cooling bath w~ removed and the reaction .~ w~ stirred for 2 hours, diluted with dichloromPthS,nP- (25ml) and washed with 10% aqueous sodium 15 s~llphite (SOml), saturated sodium hydrogen carbonate ~olntion (SOml), water. dried ~MgS04) and evaporated to an orange oil. Intially purified by flash column chromatography on silica gel eluted with ethyl acetate and then by IJlGpaldLiV~ hplc to give S7R~s-N-[6-(4-fluorophenyl)hexyl]-2-t(~allylu~y~ lyl)benzylclllphinyl]-2 tl~o~7pti~iin-l-ylpropion~mirlp (diastereni~omp-r b2) as colourless oil. Soli~lifips on 20 st~n-ling (0.24g, 19.4%).
lH NMR o (CDCl3) 1.32-1.6 (13H, m, C~3, 4xCE12), 2.56 (2H, t, J=7.6Hz, C~I2Ph) 2.83, 2.87 (lH, dd. J=2.4, 15.3Hz, ~3), 3.1-3.3 (3H. m, NHC~2, H3), 3.96, 4.08 (2H, 2xd, J=13Hz, SOCH2), 4.4 (lH, q, CHCH3), 4.60 (lH, m, ~4), 4.84 (2H, m, C02CH2), 5.,37 (2H, m, CH2=CH), 6.04 (lH, m, CH2=C~), 6.94 (3H, m, NH, p-F-25 Ph-~), 7.10 (2H, m, p-F-Ph-~), 7.37 (2H, m, Ar-~), 8.09 (2H, m, Ar-~) F-Y~ ,'~ S6~ S~4-R~SS)-N-t6-(4~FIUOIU~h~ I)heXYI]-2~4 carb~yl.~,~y~ l]-2~ ;Ain-l-yl~lul i~nan~ide A solntion of (oc-S, 4-R, SS)-N-t6-(4-Fluorophenyl)hexyl]-2-t(4-allyoxycarbonyl)benzyl~nlrhinyl]-2-07co~7Pti~in-l-yipropionamide (FY~mrlP 55, dia 30 b2) (0.24g), terakis(triphenylphosphinP)p~ rn (O) (lSmg) and triphenylphosphine (6mg)i in dry dichloromp-th~np (Sml) was treated with pyrollidille (0.039ml) and the reaction was stiired at room temperat~lre for 20 hours. The rP~etion mi~Lulc~w~s treated with dichlorompth~np (50ml) and water (25ml) and lifiPd with 2NHCl. Brine (75ml) was added to the emnlci~n the layers were 35 separated and the aqueous was washed with dichloromPth~nP (2x50ml). The organic extracts were dried (MgS04) and evaporated to a yellow gum (0.22g) and purified lby flash column chromatography on silica gel eluted with 50:50: 1 dichlorom~Pth~nP:~retonP ~eetic acid to give (oc-S, 4-R, SS)-N-[6-(4-fluorophenyl)hexyl]-2-[(4- allyoxycarbonyl)7~ll~yllllio]-2-oxo~7pti~lin 40 ylpropion~mi~le as a brown foam (0.123g, 56%).
lH NMR o (CDC13) 1.32-1.6 (13H, m, CH3, 4xCH2), 2.55 (2H, t, J=7.6Hz, CH2Ph), 2.84, 2.88 (lH, dd, J=2.4, 15.2Hz, H3), 3.1-3.3 (3H, m, NHCH2, H3), 4.04, 4.10 (2H, 2xd, J=13Hz, SOCH2), 4.4 (lH, q, CHCH3), 4.68 (lH, m, Hl), 6.94 (3H, m. NH, p-F-Ph-~), 7.10 (2H, m, p-F-Ph-H), 7.39 (2H, m, Ar-H), 8.06 (2H, m, Ar-~) W O 97/02242 PCT/~~ 2765 Example 101 - (+/-)-4(Pyrid-2 yl~ )-1-(4phenyl-2 one a) (+/-)-4(Pyrid-2~ ..eU.~ .o)azetidin-2-one Sodium (0.935 g, 40 mmol) was dissolved in etnanol (100 ml), then 2-S (m~L.lo~Pthyl)pyridine (5.0 g, 40 mmol) was added and stirred 10 min at room ~ ela~u~~ A solution of 4-ac~tu~yi~7~ n-2-one in ethanol (50 ml) was added dropwise, and stirring contimlP~d for a further 30 min. The solvent was evaporated, water was added, and the product eY I . ~ d into ethyl acetate. Drying and ~apolalion gave an oil which slowly cryst~lli.cP~ and was l~ -d with petroleum ether to give the title compound (5.3 g), m.p. 99-100~C. IH NMR (CDC13) ~ 2.84 (lH, dd), 3.34 (lH, dd), 3.95 (2H, s), 4.86 (lH, dd), 6.58 (lH, br s), 7.17-7.34 (2H, m), 7.65-7.72 (lH, m), 8.50-8.53 (lH, m).
b) (+/-)-4(Pyrid-2-yl~ ll.ylll~io)-1-(4-phenyl- oxobutyl)~7~ti~1ir 2 one A mixture of (+/-)~(pyrid-2-ylmethylthio)~7pti~lin-2-one (5.3 g, 27 mmol), l-bromo-4-phenyl-2-bnt~nonP (6.8 g, 30 mmol), tetrabutyl~mmoninm bromide (0.87 g, 2.7 mmol), finely powdered KOH (1.7 g, 30 mmol) and dry THF (100 ml) was stirred at room temperature for 2 hours, then poured into water and extracted with ether.
Chromatography (silica, dichloromPth~n~) of the organic extracts and cry.~t~lli.~tion from ether gave the desired product (2.5 g), m.p. 56-58~C. 'H NMR (CDC13) o 2.70(2H, t), 2.90 (2H, t), 3.01 (lH, dd), 3.43 (lH, dd), 3.57 (lH, d), 4.11 (lH, d), 3.84 ( 2H, s), 4.98 (lH, dd), 7.15-7.32 (7H, m), 7.60-7.67 (lH, m), 8.48-8.51 (lH, m).
Example 102 - (+/-) 1-(Pyrid-2-ylmell~ hinyl)-1-(4phenyl-2-oxobutyl)~Pti-l;n-2-one (diastereomer 1) A sol~ltion of (+/-) 1 (pyrid-2-ylmethylthio)-1-(4-phenyl-2-oxobutyl)~7Pti~iin-2-one (2.4 g, 7 mmol) in dichlorometh~n~o (50 ml) was cooled to -60~C and a solution of m-chlo,o~lo~ybenzoic acid (1.46 g, 8.4 mmol) in dichloromPth~ne (50 ml) was added dropwise. Stirring was continued at this tPmrPr~mre for 1 hour, then the ~ Lulc: was poured into an aqueous solution of sodium sulphite and sodium bicarbonate. The organic layer was dried and evaporated, and the residue trinlratPd with ethyl acetate.
Recryst~lli.c~ti~n from ethyl acetate gave a single diastereomer (0.66 g), m.p. 123-125~C. IH NMR ~ (CDC13) 2.74 (2H, t), 2.92 (2H, t), 3.01 (lH, dd), 3.33 (lH, dd), 3.84 (lH, d), 3.98 (lH, d), 4.13 (lH, d), 4.40 (lH, d), 4.92 (lH, dd), 7.15-7.35 (7H, m), 7.70-7.80 (lH, m), 8.56 (lH, m). v~=O 1785 cm~l (CCL) Found: C, 63.63; H, 5.62; N, 7.97%
ClgH20N203S requires: C, 64.02; H, 5.66; N, 7.86%
F.Y~mple 103 - (+/-)~(Pyrid-2-ylmell~ yl)-1-(4phenyl-2-oxobutyl)~-7Pt--l;n 2-one (diastereomer 2) The mother liquors from the ethyl acetate trihl~tinn in e~mrlP 102 were y~ ced twice from ethyl acetate/ether to obtain a sample of the second diastereomer, cont~min~t~-d with 20% of diastereomer 1 (0.34 g), m.p. 70-72~C. IH
NMR o (CDC13) 2.69-2.77 (2H, m), 2.77 (lH, dd), 2.90 (2H, t), 3.26 (lH, dd), 4.17 (2H, s), 4.22 (lh, d), 4.37 (lH, d), 4.79 (lH, dd), 7.14-7.34 (7H, m), 7.69-7.74 (lH, m), 8.56-8.57 (lH, m).
vc=O1785cm~l(CC14) Found: C, 64.07; H, 5.65; N, 8.22%

W O 97102242 PCT~EP96/0276S

ClgH20N2O3S req~ s: C, 64.02; H,5.66; N,7.86%
Exa nple 104 - (+/-)-N-(6-Phenylhex-l-yl)- 4 (~ ylm~ lU~.o)-2 l yls.~
a) (+/-)~(Pyrid-~ .,t;ll,rlUIio)~7~ 2-one S The synthesis was carried OUt as in e-~mrlP la, using 20 mmol each of 4 (a~lyl~o-methyl)pyridine and 4 act;Lo~yi17~ in-2-one~ Chromatography (silica,0~% MeOH in CH2Ck) gave the title compound as an oil (2.7 g). lH NMR ~ (CDC13) 2.87 (lH, dd~, 3.34 (lH, dd),3.g0 (2H, s),4.70 (lH, dd),7.03 (lH br. singlet),7.26-7.30 (2H, m), 8.51-8.59 (2H, m).
10 b) (+/-)-N-(~Pht ,.~' -l-yl)~(~ tl.r! ' ~ !idin-l-~ylac~,l~-lide The syn~esis was carried out as in eY~mrlp 101b, using 8.5 mmol of (+/-) 4 (pyrid-2-ylmethylthio)~7Pti-lin-2-one (8.5 mmol), N-(6-phenylhex-1-yl~2-brnmo~.~e~ P (9 4 mmol), tetrabutylammonium bromide (0.94 mmol) and powdered KOH (9.4 mmol) in dry 1~ (50 ml). Chromatography (silica,0-2% MeOH in EtOAc) gave the tide compound as an oil (2.2 g). IH NMR ~ (CDCl3) 1.27 (4H, m), 1.46-1.66 (4H, m), 2.59 (2H, t), 2.91 (lH, dd),3.22 (2H, m), 3.39 (lH, dd), 3.47, (lH, d), 3.72-3.89 (31H, m), 4.91 (lH, dd), 6.23 (lH, br. triplet), 7.14-7.30 (7H, m), 8.53-857 (2H, m).
F - ~'e 105- (+/-~N-(6-Phenylhex-l~yl) 1 (~ yll~eû~yl~,ulphinyl)-2-~~Yn~ .-l-yl~ ~ t ~ eomer 1) The synthesis was carried out as in pY~mr)lP 102, using (~-)-N-(6-phenylhex-1-yl) 4 (pyrid-4-ylm~ yl~,io)-2-oxo~7rli~1in-l-yl~ret~mitlP (2.1 g, S.1 mmol).
Recryst~llic~tion of the crude product from ethyl acetate/ether gave a single diastereomer (0.55 g), m.p. 126-127~C. 'H NMR ~ (CDC13) 1.31-1.35 (4H, m), 1.48-1.64 (4H, m), 2.59 (2H, t), 3.01 (lH, dd), 3.23 (2H, dt), 3.46 (lH, dd), 3.82-3.90 (3H, m), 4.03 (lH, d), 4.70 (lH, dd), 6.36 (lH, br triplet), 7.15-7.29 (7H, m), 8.64 6.66 (2H, 7m). vC=O 1794, 1745cm~l (CC14) Found: C, 64.37; H, 6.74; N, 9.75%
C23H2sN3O3S requires: C, 64.61; H, 6.84; N, 9.83%
Example 106 - (+/-~N-(6-Phenylhex-l-yl)~(pyrid 1 yl~ l)-2, in_1_y~ ...;A~(~L~ omer2) The mother liquors from eY~mplP- 105 cry~st~ ce~ from ethyl acetate/ether to give a sample col-t~ g 86% of the second diastereomer (0.5 g), m.p. 89-91~C. IH NMR o (CDC13) 1.33-1.37 (4H, m) 1.50-1.60 (4H, m) 2.60 (2H, t), 3.00 (lH, dd), 3.21-3.33 (3H, m), 3.95-4.03 (3H, m), 4.18 (lH, d), 4.71 (lH, dd), 6.70 (lH, br. triplet), 7.15-7.29 (8H, m), 8.64-8.66 (2H, m). n~O (CCl~) 1795, 1766.
Found: C, 64.53; H, 6.72; N, 9.84%
C23H29N3O3S requires: C, 64.61; H, 6.84; N, 9.83%
Example 107 - (+/-)-N-(6-Phenylhex-l-yl~4-(1-ox ~ 1-4~ U~yl:,ull~honyl)-2'-~ n l yl~r~
A solution of (+/-)-N-(6-phenylhex-1-yl)-4-(pyrid 4 ylmethyls--lrhinyl)-2-0~0~7Ptitlirl-l-yl~et~mi~le (0.2 g, 0.47 mmol) and m-chlol~Jpelo~y-henzoic acid (exces~s) in dichlorom~th~nP (30 ml) was stirred at room ~~ dture for 2 hours, then worked upas in e~mplP 102. Chromatography (silica, 0-5% MeOH in CH2Ck) gave the title compound (0.17 g), m.p. 72-74~C. 'H NMR ~ (CDC13) 1.33-1.37 (4H, m), 1.'50-1.6'5 -W O 97/02242 PCT~EP96tO2765 (4H,m).2.60(2H, t), 3.24-3.30(2H,m),3.38(lH, dd), 3.86(lH, d), 4.06(lH,d), 4.30(lH,d),4.54(IH, d), 5.00 (lH, dd), 5.76(lH, br. ~plet), 7.15-7.20(3H,m) 7.26-7.30(2H,m),7.40(2H, d), 8.22(2H, d). vc~ 1780cm~l (KBr) Found: C 59.41;H6.18;N9.05 C23H29N3O5S;0.2H20 requires: C 59.64;H6.41;N9.07 FY~plel08-(+/-)-N-(6-Pheny~ex-l-yl)1(~ru~ -ylU-io~ ;Un-l-y~ce~de a) (+/-)-(~F~ .io)~-F~ one The synthesis was carried out as in eY~mrl~ 101a, using furfuryl me~ (42.5 10 mmol) and 4-ace~oAy~P~ n-2-one(38 mmol). Chromatography (silica, 1:1 pet.
ether/CH2Ck) gave the title compound as an oil (5.5 g). 'H NMR ~ (CDC13) 2.86(lH, dd), 3.36(lH, dd), 3.86(2H,s),4.79(lH, dd), 6.06(lH, br. singlet), 6.21-6.23(lH,m), 6.33-6.35(1lH, m), 7.37-7.39(lH,m).
b) (+/-)-N-(6-Phenylhex-l-yl)-1 (2-lu~ U~ylU~io)-2 15 yl~ Pt~m;~lP
The synthesis was carried out as in eY~mplP 101b, using (+/-)~(2-fulyl~ ylLhio)-~7pti~lin-2-one (10 mmol), N-(6-phenylhex-1-yl)-2-bromo~-et~mitle (10 mmol), tetra-butylammonium bromide (1 mmol), and powdered KOH(ll mmol) in dry- THF (150 ml). Chromatography (silica, EtOAclpet. ether) gave the title compound as an oil (3.4 g). lH NMR~(CDC13) 1.31-1.40(2H, m), 2.60(2H, t), 2.97(lH, dd), 3.19-3.28 (2H, m), 3.43(lH,dd),3.65(lH,d),3.83 (lH, d), 3.84(2H, d), 4.91 (lH, dd), 6.13 (lH, br. triplet), 6.22(lH, m), 6.31(lH, m), 7.14-7.36(6H, m).
F~y~plelO~-(+/-)-N-(6-Pheny~ex-l-yl)1(2-~ e~
o~ e~ ;..-l-ykc '~ omerl) The synthesis was carried out as in PY~mrl~lo2~ using (tJ-)-N-(6-phellyll.c;A-l-yl)~
(2-furylme~,yl~lio)-2-oxo~7Pti~in-l-yl~et~mide(2.9 g, 7.2 mmol). Recryst~lli~ti~n of the crude product from ethyl acetate gave a sample cont~inin~ about 99% of diastereomer 1 (0.2 g), m.p. 160-161~C.'H NMR~(CDC13)1.32-1.36(4H, m) 1.50-1.63(4H, m), 2.60(2H, t), 3.01(lH,dd),3.18-3.30(2H, m), 3.42(lH,dd),3.76(lH, d),4.00(lH,d),4.10-4.16(2H, m), 4.60(lH, dd), 6.42(2H, m), 6.55(lH, br.
triplet), 7.16-7.19(3H, m), 7.25-7.29(2H,m),7.43(lH, m). n~ 1748,1791cm~
(CC14) Found: C, 63.18;H,6.59;N,6.77%
C22H28N2O4S requires: C, 63.44;H,6.78;N,6.73%
FY~mpl~ 110~ N-(6-Phenylhex-l-yl)~ e~
n l ~ ide (.li~c~ -er2) The mother liquors from ex~mpl~- 109 were purified by chromatography (silica, 0-2%
MeOH in CH2C17) and recryst~llic~ti-~n from ether/ethyl acetate to give a sample of diastereomer 2 cont~ining 5% of diastereomer 1 (1.08 g), m.p. 61-62~C. IH NMR ~ -(CDC13) 1.33-1.37 (4H, m), 1.51-1.63 (4H, m), 2.60 (2H, t), 3.00 (lH, dd), 3.23-3.30 (3H, m), 3.98 (lH, d), 4.29 (lH, d), 4.12 (lH, d), 4.24 (lH, d), 4.61 (lH,dd), 6.42 (2H, m), 7.15-7.18 (3H, m), 7.25-7.31 (3H, m), 7.44-7.45 (lH, m). vc~01793cm~
(CC14) Found: C, 63.41; H, 6.63; N, 6.80%
C22H28N2O4S requires: C, 63.44; H, 6.78; N, 6.73%

F~ (+/-)-N-(6-Ph~ lh~-1-yl) 1(2~ruu~ 2 lin l_~ t---~ide The synthesis was carried out as in eY~mrlP 107, using N-(6-P1Ie~IY1I1GA-1-Y1) 4 (2-furylmethylsulrhinyl)-2-oxo~7Pti~1in-l-yl~fet~mirl~ (0.10 g). Tri~ration vith ether S gave the title compound (0.065 g), m.p. 102-104~C. 'H NMR ~ (CDC13) 1.32-1.36(4H, m), 1.49-1.64 (4H, m), 2.60 (2H, t), 3.12 (lH, dd), 3.22-3.29 (3H, m), 3.94 (l~i[, d), 4.03 (lH, d), 4.38 (lH, d), 4.45 (lH, d), 4.89 (lH, dd), 6.00 (lH, br. triplet), 6.4 6.46 (lH, m), 6.55-6.56 (lH, m), 7.1~7.19 (3H, m), 7.25-7.29 (2H, m), 7.4~7.47 (lH, m). vOO 1797 cm~l (CCI4) 10 Found: C, 60.15; H, 6.32; N, 6.50%
C22HzgN2O5S Ø3H20 ~c;~luil ;:s. C, 60.34; H, 6.58; N, 6.40%
Example 112- (+/-)-N-(6-[4 Fluorophenyl]hex-l-yl)~ fu~ U~ )-2-~Yo~7-~ti~1in.l.yl~ret~ni~1P
The synthesis was carried out as in PY~mphp 101b, using (+I-) 4 (2-ru~ hyllLio)-~7Pti~lin-2-one (15 mmol), N-(6-~fluorophenyl)hex-1-yl)-2-bromo~ce~ P* (15 mmol), f~-tr~blltylammonium bromide (1.5 mmol), and powdered KOH (16.5 mmol) im dry THF (100 ml). Chromalography (silica, 0-2% MeOH in CH2Ck) gave the title compound as an oil (3.4 g). 'H NMR o (CDC13) 1.25-1.64 (8H, m), 2.~7 (2H, t), 2.9~8 (lH, dd), 3.23 (2H, dt), 3.43 (lH, dd), 3.67-(lH, d), 3.76-3.91 (3H, m), 4.90 (lH, dcl), 6.10 (lH, br. tr~plet), 6.22 (lH, d), 6.31 (lH, dd), 6.90-6.98 (2H, m), 7.08-7.18 (2H,m), 7.36 (lH, m).
*obtained by treating of 6-(4-fluo~ophe-lyl)hexylamine (2.0g) and Hunig's base (1.33g~) in dry dichloromP,th~ne (2~ ml) with bromoacetylbromide (2.07g) in dichloromPth~nP
(10 ml) at 0-5 ~C.
F ~'e 113 - (+/-)-N-(6-t4-Fluorophenyl]hex-l-yl)-4(2-r~ ~ lphinyl)-2-~Y~7et~ n-l-yl~r~t~m~ t omer 1) The synthesis was carried out as ~n eY~mI~lp 102, using ~+l-)-N-(6-(4-fluorophenyl)-hex-l-yl) 1 (2-furyl~ yllllio)-2-oxo~7pt~ n-l-yl~et~mi~l~(2~og~4~8mmol)~
Recryst~ ation of the crude product from ethyl acetate gave a sample Cc--~t~
about 93% of diastereomer 1 (0.3~ g), m.p. 157-8~C. 'H NMR ~ (CDC13) 1.31-1.3~
(4H, m), 1.~0-1.~8 (4H, m), 2.56 (2H, t), 3.02 (lH, dd), 3.20-3.26 (2H, m), 3.42 (lH, dd), 3.74 (lH, d), 4.00 (lH, d), 4.10-4.17 (2H, m), 4.59 (lH, dd), 6.42 (2H, m), 6.65 (lH, br. triplet), 6.92-6.97 (2H, m),7.09-7.13 (2H, m), 7.43-7.44 (lH, m). n~=~, 1791 cm~l Found: C, 58.85; H, 6.00; N, 6.36%
C22H27FN2O4S Ø68H20 requires:C, 59.14; H, 6.40; N, 6.27%
Example 114 - (+/-)-N-[6-(4-Fluorophenyl)hexy]~(2-furylmell-yl~ nyl)-2-oY- ~et~ n-l-yl~cet~mide (~ eomer 2) Evaporation of the mother liquors from e~r~mpl~ 113 and cryst~llic~tion from ethyl acetate/ether gave a sample c~ nt~inin~ 97% of diasteromer 2 (0.62 g), m.p. 100-101~C. tH NMR ~ (CDC13) 1.33-1.35 (4H, m), 1.50-1.60 (4H, m), 2.56 (2H, t), 3.01(lH, dd), 3.22-3.31 (3H, m), 3.98 (lH, d), 4.11 (lH, d), 4.23 (lH, d), 4.29 (lH, d), 4.60 (lH, dd), 6.41-6.42 (2H, m), 6.92-6.96 (2H, m), 7.09-7.13 (2H, m) 7.26 (lH, br.
triplet), 7.44-7.45 (lH, m). nc=O 1794 cm~l Found: C, 60.70; H, 6.22; N, 6.44%

W O 97/02242 PcTr~l~Gl~2765 C2~H27FN204S requires: C, 60.81; H, 6.26; N, 6.45%
Example 115- (+/-)-N~(6-[4Eluorophenyllhex-l-yl}4~ r~u,~ ulphonyl)-The synthesis was carried out as in ey~mrlp 107, using N-(~(4-fluolvpht;l",l)he~-l-S yl) 1 (2-rulyl~ yl~lllrhinyl)-2-oYn~7ptitlin-l-yl~ icle (1.0 g). Tnt~lr~tion of the crude product with ether and ~t;e~ c~ti~n from ethyl acetate/pet. ether gave ~e title compound (0.29 g), m.p. 114-115~C. IH NMR ~ (CDC13) 1.31-1.35 (4H, m), 1.4~-1.60 (4H, m), 2.57 (2H, t), 3.12 (lH, dd), 3.22-3.29 (3H, m), 3.95 (lH, d), 4.03 (lH, d), 4.38 (lH, d), 4.45 (lH, d), 4.88 (lH, dd), 6.01 (lH, br. triplet), 6.446.45 (lH, m), 6.55-6.56 (lH, m), 6.93-6.97 (2H, m), 7.09-7.13 (2H, m), 7.46-7.47 (lH, m).
nOO 1797 cm~l Found: C, 58.27; H, 5.96; N, 6.20%
C~2H~7~205S requires: C, SX.65; H, 6.04; N, 6.22%
F~ 116- (+1-)-N-(6-t4-Chlorophenyl]hex-l-yl) 1 ('~ fur~ ylU~io).~-The synthesis was carried out as in e~r~mrle 101b, using (+/-)~(2-~u~yl~ ylthio)-in-2-one (12 mmol), N-(6-(~chlorophenyl)hex-1-yl)-2-bromoE~t~ e (12 mmol), tetrabutyl~mmonillm bromide (1.2 mmol), and powdered KOH (13.2 mmol) m dry TH~ (100 ml). Chromatography (silica, 50-100% EtOAc in pet. ether) gave the title compound as an oil (3.9 g). 'H NMR ~ (CDC13) 1.23-1.61 (8H, m), 2.56 (2H, t), 2.g7 (lH, dd), 3.23 (2H, dt), 4.05 (lH, dd), 3.62-3.91 (4H, m), 4.91 (lH, dd), 6.18 (lH, br. triplet), 6.22 (lH, d), 6.30 (lH, dd), 7.08 (2H, d), 7.20-7.26 (2H, m), 7.36 (lH, d).
F~ 117- (+/-)-N-(6-[4 Chlorophenyl]hex-l-yl)-4(2-ru}~lJ~ y' ~ nyl)-25 2~o~ ;-l-y~ ,e- 1) The synthesis was carried out as in exarnple 102, using (+/-)-N-(~(4-chlorophenyl)-hex-1-yl)~(2-furylmethylthio)-2-oxo~7Pti~in-1-yl~et~mi~e (3.8 g, 8.7 mmol).
Tritnration of the crude product with ether gave a sample of diastereomer 1 (0.4g g), m.p. 171-2~C. IH NMR ~ (CDCl3) 1.31-1.34 (4H, m), 1.49-1.61 (4H, m), 2.56 (2H, t), 3.02 (lH, dd), 3.20-3.26 (2H, m), 3.42 (lH, dd), 3.75 (lH, d), 4.00 (lH, d), 4.10-4.17 (2H, m), 4.60 (lH, dd), 6.42 (2H, m), 6.60 (lH, br. triplet), 7.08-7.10 (2H, m), 7.22-7.26 (2H, m), 7.43-7.44 (lH, m). n~=O 1791 cm~l Found: C, 58.16; H, 5.91; N, 6.25%
C22H27ClN204S requires: C, 58.59; H, 6.03; N, 6.21%
FY~ 118 - (+/-)-N-(6-[4-Chlorophenyl~hex-l-yl)~ U~ e~ }~
2~o~q~tiA;n-l-yl~rPt ~ el~omer 2) The mother liquors from e~mple 117 were evaporated and cryst~lli.~ec~ from ether to give a sample of diastereomer 2 (1.2 g), m.p. 92-3~C. IH NMR ~ (CDCl3) 1.32-1.34(4H, m), 1.50-l.S9 (4H, m), 2.56 (2H, t), 3.01 (lH, dd), 3.24-3.31 (3H, m), 3.98 (lH, d), 4.11 (lH, d), 4.25 (lH, d), 4.27 (lH, d), 4.60 (lH, dd), 6.41-6.42 (2H, m), 7.08-7.10 (2H, m), 7.21-7.26 (2H, m), 7.35 (lH, ~r. triplet), 7.44-7.45 (lH, m). nOO 1794 cm~l Found: C, 58.32; H, 5.95; N, 6.23%
C22H27ClN204S requires: C, 58.59; H, 6.03; N, 6.21%

.

W O 97/02242 PcT/~~ 276;5 F.Y~mr~ 119 - (+/-)-N-(6-[4 C~ I)hex-l-yl)~(2-r.,. ~ lphonyll)--yl~'Pt~ ?
The synthesis was carned out as in eY~mrle 107, using N-(6-(4-ch~ol.)phe..yl)he~yl)~(2-furylmethyl.~ r)hinyl)-2-oxQ~7Pti~in-l-yl~ret~mitle T.;I...,.t;.~n ofthecmde product with etner gave the title compound (0.6 g), m.p. 107-8~C. 'H NMR ~
(CDC13) 1.31-1.35 (4H, m), 1.49-1.60 (4H, m), 2.57 (2H, t), 3.12 (lH, dd~, 3.22-3.29 (3H, m), 3.95 (lH, d), 4.03 (lH, d), 4.38 (lH, d), 4.45 (lH,d), 4.88 (lH, dd), 6.03 (lH, br triplet), 6.44 6.46 (lH, m), 6.55-6.56 (lH, m), 7.08-7.11 (2H, m) 7.21-7.26 (2H, m), 7.45-7.47 (lH, m). n~=O 1797 cm~l Found: C, 56.54; H, 5.74; N, 6.02%
C22H27ClN2OsS requires: C, 56.58; H, 5.83; N, 6.00%
FY~mpl? 120- (+/-)-N-(6-14-Chlorophenyl]hex-l-yl) 1 (3-rur,~ .eU-g~ 2 ~y~7~h'- 1-yl~
a) (+/-)-4(3-Fu~ -e~ io)~7et~ n-~one The synthesis was ca~,Tied out as in ~Y~mple 101a, using 3-(acetylthi()mPthyl)furan (64 mrnol) and 4-accL~y,.7Pti~lin-2-one (64 mmol). Cyst~1li.~tion from ell-cJI,cL ethLer gave tne title compound (10 g), m.p. 60-61~C. IH NMR o (CDC13) 2.90 (lH, dd), 3.35 (lH, dd), 3.68 (2H, d), 4.70 (lH, dd), 6.14 (lH. br s), 6.42 (lH, m), 7.38-7.42 (2H,m).
b) (+~-)-N-(6-[4-Chlorophenyllhex-l-yl)-4(3-fu~ ' ~C ~ 7- ~;din-1-yl-- ?
The synthesis was CalTiedOUt as in e7c~mplP 101b, using (+/-)~(3-ru~ io)-~7Pti ~in-2-one (13.6 mmol), N-(6-(4-chlorophenyl)hex- 1 -yl)-2-bromo~ret~mi(~e (13.6 mmol), tetrabutylammonium bromide (1.36 mmol), and powde,cd KOH (14 mmol) iin dry THF (100 ml). Chromatography (si'lLica, 50-100% EtOAc in pet. e~Ler) gave the title compound as an oil (4.0 g). IH NMR ~ (CDCl3) 1.25-1.36 (4H, m), 1.40-1.68 (4H, m), 2.56 (2H, t), 2.96 (lH, dd), 3.20-3.28 (2H, m), 3.41 (lH, dd), 3.61-3.73 (3H, m), 3.85 (lH, d), 4.84 (lH, dd), 6.12 (lH, dd), 6.39 (lH, m), 7.06-7.10 (2H, m), 7.21-7.26 (2H, m), 7.37-7.39 (2H, m).
FY~mrle 121 ~ (+/-)-N-(6-t4L-Ch~orophenyl]hex-l-yl)-4-(3-lu, ~ll-,etl.~l~.ullJhLinyl'~
7~ n-l yl~et~m~ (dia~.l~.~...~ 1) The synthesis was carried out as in ex~mple 102, using (+/-)-N-(6-(4~hlol.,phel.yl)-hex-l-yl)~(3-furylmethylthio)-2-oxo~7.~ti-1in-l-yl~et~mitle (2.5 g, 5.7 mmol).
Cryst~llis~tion of the crude product from ethyl aceLate gave a sample ~ont;~ 98 of diastereomer 1 (0.6 g), m.p. 162-163~C. IH NMR ~ (CDC13) 1.30-1.34 (4H, m), 1.49-1.59 (4H, m), 2.55 (2H, t), 3.04 (lH, dd), 3.20-3.26 (2H, m), 3.55 (lH, dd), 3.7~3.78 (2H, m), 3.86 (lH, d), 4.13 (lH, d), 4.59 (lH, dd), 6.37-6.38 (lH, m), 6.l50 (lH, br. triplet), 7.08-7.10 (lH, m), 7.21-7.26 (2H, m), 7.46-7.47 (2H, m). n~=O 17~92 cm~l Found: C, 58.52; H, 5.94; N, 6.20%
C22H2,ClN204S requires: C, 58.59; H, 6.03; N, 6.21%
FY~mrle 122- (+/-)-N-(6-[4-Chlorophenyl]hex-l-yl) 4 (3 ~u,,~l~"~ll,yl Ip~;nyl?-2-~ e~ n-l-y~ et~mi~l~ (diastereomer 2) The mother liquors from example 121 were evaporated, L~ ated with ether, and 45 recryst~ e~ from ethyl acetate to give a sample cont~ining 98% of diastereomer 2 W O 97/02242 PCT~EP96/0276 (0.7 g), m.p. 95-96~C. IH NMR ~ (CDC13) 1.32-1.34 (4H, m), 1.50-1.60 (4H, m), 2.56 (2H, t), 3.03 (lH, dd), 3.20-3.32 (3H, m), 3.86-3.98 (3H, m), 4.24 (lH, d), 4.66 (lH, dd), 6.38-6.39 (lH, m), 7.08-7.10 (2H, m), 7.14 (lH, br. triplet), 7.21-7.26 (2H, m), 7.46-7.48 (2H, m). n~=O 1794 cm~l S Found: C, 58.53; H, 5.94; N, 6.20%
C22H27CIN2O4S requires: C, 58.59; H, 6.03; N, 6.21%
FY~mp'e 123- (+/-)-N-(6-14-Chlorophenyl]hex-l-yl)-4(3-ru~ ls~ onyl)-~ Y~ 7 ~;rl;n l_yl5~c~t~ ide The synthesis was carried out as in eY~mplp 107, using N-(6-(4-chl~,loplle..yl)he~
10 yl)~(3-furylrnethyl~nlrhinyl)-2-ol~o~7~ti~in-l-yl~ P. Tritl-~tion of the crude product with ether gave the tide co.~poul-d, m.p. 95-96~C. IH NMR ~ (CDC13) 1.31-1.35 (4H, m), 1.48-1.61 (4H, m), 2.56 (2H, t), 3.20-3.27 (4H, m), 3.87 (lH, d), 4.02 (lH, d), 4.18 (lH, d), 4.25 (lH, d), 4.91 (lH, dd), 5.98 (lH, br. triplet), 6.53-6.54 (lH, m), 7.08-7.11 (2H, m), 7.21-7.26 (2H, m), 7.47-7.48 (lH, m), 7.57 (lH, d). n~=O
lS 1795 cm~l Found: C,55.41;H,5.61;N,5.83%
C22H27ClN2O5S ØSH20 requires:C, 55.51; H, 5.93; N, 5.89%
F ,~.e 124 - (+/-)-N-[6-(~Chlorophenylhexyl)] 1 (~Illi~"~ llh;o~2--yl~c~t ' ~e 20 a) (+/-)-4-(2-Thienylm~ ylU.io)azetidin-2-one The synthesis was carried out as in example 101a, using 2-(acetylthio...~l~.yl)thiophene (71 mmol) and 4-acetoxy~7Pti~lin-2-one (71 mmol). Chromatography (silica, 50-70%EtOAc in pet. ether) gave the title colllp~3und as an oil (9.1 g). lH NMR ~ (CDC13) 2.88 (lH, m), 3.35 (lH, m), 4.06 (2H, m), 4.75 (lH, m), 5.82 (lH, m), 6.96 (2H, m), 7.24 (lH, m) b) (+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(~thi~ Ilhio~
1-ylacetamide The synthesis was ca~rried out as in eY~mplP 101b, using (+/-)-4-(2-~ie.lyhllell,yl~.io)-~7p-titlin-2-one (5 mmol), N-(6-(4-chlolophenyl)hex-1-yl)-2-bromo~ce~ le (S.S
mmol), tetrabutylammonium bromide (0.5 mmol), and powdered KOH (5.25 mmol) in d.~ THF (25 ml). Chromatography (silica, 30-80% EtOAc in pe~ ether) and trituration with ether/pet. ether gave the title compound (0.66 g), rri.p. SS-7~C. IH
NMR ~ (CDC13) 1.33 (4H, m), l.SS (4H, m), 2.56 (2H, t), 2.97 (lH, dd), 3.23 (2H,m), 3.41 (lH, dd), 3.63 (lH, d), 3.79 (lH, d), 4.05 (2H, m), 4.88 (lH, m), 6.05 (lH, m), 6.89-7.26 (7H, m).
F~Y~mp~? 12~- (+J-)-N-t6-(4Chlor~ yll._A~1)]-~(2-thi~ -etl~yl~ hinyl)-~
The synthesis was carried out as in eY~mple 102, using (+I-)-N-(~(4-chlorophenyl)-hex-l-yl)-4-(2-thienylmethylthio)-2-oxo~7P-ti~lin-l-yl~ret~mi~e (3.0 g, 6.65 mmol).
Cryst~ ti~)n of the crude product from ethyl acetate and recryst~llic~tion from acetonitrile gave a sample cont~ining 97% of diastereomer 1 (0.73 g), m.p. 161-2~C.
IH NMR ~ (CDC13) 1.33 (4H, m), 1.51-1.61 (4H, m), 2.56 (2H, t), 3.01 (lH, dd), 3.23 (2H, m), 3.4~ (lH, dd), 3 74 (lH, d), 4.13 (lH, d), 4.13 (lH, dd), 4.25 (lH, dd), 4.57 (lH, dd), 6.59 (IH, m), 7.03-7.35 (7H, m). nOO 1791 cm~
Found: C, 56.51; H, 5.71; N, 6.06%
- ~2-W O 97/02242 PCT~EP96/02765 C22H27ClN2~3S2 requires: C, 56.58; H, 5.83; N, 6.00%
F , '~ 126 - (+/-)-N-[6-(4-Chl~ ~y'' yl)] 1 ('~ thie~ yl)-2-The ethyl acetate mother liquors from pY~mrl~ 125 gave further crystals on ~t~nrlin~, S wnich cQnt~inP~ g8% of diastereomer 2 (0.57 g), m.p. 93-5~C. IH NMR ~ (CDC13) 1.34 (4H, m), l.SS (4H, m), 2.56 (2H, t), 2.98 (lH, dd), 3.25 (3H, m), 3.89 (lH, d), 4.25 (lH, d), 4.25 (lH, d), 4.33 (lH, d), 4.65 (lH, dd), 7.04-7.35 (7H, m). n~=O 17!33 cm~l Found: C, 56.41; H, 5.72; N, 5.99%
C22Hz7ClN2O3S2 requires: C, 56.58; H, 5.83; N, 6.00%
FY~mple 127 - (+/-)-N-[6~ h~ ylhexyl)]-4('~ ie~h~-ell~ylsulphonyl) '~
f,y,~7.c~;~lin_~
The synthesis was carried out as in eY~mpl~ 107, using N-(6-(4-chlo.~,l)l~llyl)he~c-1-yl) 4 (2-thienylmethylsulphinyl)-2-oxo~7P.ti-lin-l-yl~P.t~mirie (1.1 g). Cyst~lli.~titm lS from ethyl acetate/pet. ether gave the title compound (0.9 g), m.p. 108-110~C. IH
NMR ~ (CDC13) 1.33 (4H, m), 1.55 (4H. m), 2.57 (2H, t), 3.09-3.28 (4H, m), 3.88 (lH, d), 3.97 (lH, d), 4.53 (lH, d), 4.60 (lH, d), 4.91 (lH, dd), 5.98 (lH, m), 7.05-7.41 (7H, m). n~=O 1795 cm~l Found: C, 54.59; H, 5.52; N, 5.80%
C22H27ClN2O4S2 requires: C, 54.70; H, 5.63; N, 5.80%
FY~mple 128 ~ (+/-)-N-[6~(4-ChlorophenylheYyl)]~(3-U,it~ l",ell,ylU~io)-2-~Y~ yl~c~et~mirl~
a) (+1-)-'1 (3-thienylmeU~ylU,io)~7~ti~;n-2-one The synthesis was carried out as in eY~mrllo 101a, using 3-(acetylthiom~-thyl)thiophene (85 mmol) and 4-ace~u~yi~et~ n-2-one (85 mmol). Chrom~tography (silica7 50-70%
EtOAc in pet. ether) and trituration with pet. ether gave the title compound (8.65 g), m.p. 41-45~C. ~H NMR ~ (CDC13) 2.85 (lH, m), 3.32 (lH, m), 3.88 (2H, m), 4.68 (lH, m), 5.72 (lH, s), 7.01-7.15 (2H, m), 7.33 (lH, m) b) (+I-)-N-[6-(4-Chlorophenylhexyl)] 1 (~tlhie,-yl,~ U-ylU.io)-2-oYo~7~ffdirl-l-y~
The synthesis was carried out as in ey~mrle 101b, using (+/-)-4-(3-thie..yllllelhyl~lio)-~7~oti~lin-2-one (5 mmol), N-(6-(4-chlorophenyl)hex-1-yl)-2-bromo~eet~mi~o- (5.5mmol), tetrabutylammonium bromide (0.5 mmol), and powdered KOH (5.25 mmol) in dry THF (25 ml). Chromatography (silica, 40-90% EtOAc in pet. ether) and trituration with pet. ether gave the title compound (0.85 g), m.p.54-57~C. IH NMR.
(CDCl3) 1.32 (4H, m), 1.53 (4H, m), 2.56 (2H, t), 2.93 (lH, dd), 3.22 (2H, m), 3.38 (lH, dd), 3.56 (lH, d), 3.76 (lH, d), 3.84 (2H, m), 4.81 (lH, m), 6.07 (1 H, m), 7.0 7.82 (7 H, m) FY~mple 129- (+/-)-N-t6-(4ChlorophenylheYyl)]-4(3-thie,~h,.eLI,~
oYn~7~ti~lin l~yl~et~m;rle(~ Lt:Leo."er 1) The synthesis was carried out as in e~r~mple 102, using (+/-)-N-(6-(4-chloluphenyl)-hex-1-yl)-4-(3-llliel.yl,llethylthio)-2-oxo~7Pti~in-1-yl~er~mi~le (4.12 g, 9.1 mmol).
Cryst~lli~tion of the crude product from ethyl acetate and recryst~lli~tion fromacet~ o gave a sample of diastereomer 1 (0.57 g), m.p. 158-9~C. IH NMR ~
(CDC13) 1.33 (4H, m), 1.55 (4H, m), 2.56 (2H, t), 2.94 (lH, dd), 3.23 (2H, m), 3.44 - ~3 -W O 97/02242 PCT~EP96/02765 (lH, dd), 3.73 (lH, d), 3.98 (lH, d), 4.11 (lH, d), 4.06 (lH, d), 4.51 (lH, dd), 6.61 (lH, m), 7.01-7.41 (7H, m). nc=O 1791 cm~l Found: C, 56.45; H, 5.62; N, 6.02%
C~H27ClN203S2 requ~res: C, 56.58; H, 5.83; N, 6.00%
S Example 130 - (+/-)-N-t6-(4Chl~ JI,e,-,ylheAyl)]-4(3-ffiienyln-t U-y' ~'phinyl~
o~ f ~ n l-yk~ .ude (dia~ ,o~ 2) The mother liquors from eY~mrlP 129 were recryst~llice~ cce~ssiv~ly from e~yl acetate, ~et~ ;l. ;1P and ethyl acetate to obtain a sample CC.I~ ;n~ 80% of ct~preomer 2 (1.42 g), m.p. 109-111~C. lH NMR ~ (CDC13) 1.34 (4H, m), 1.55 (4H, m), 2.56 (2H, t), 2.93 (lH, dd), 3.24 (3H, m), 3.89 (lH, d), 4.09 (lH, d), 4.18 (lH, d), 4.23 (lH, d), 4.59 (lH, dd), 7.02-7.42 (7H, m). nc~ 1793 cm~
Found: C, 56.55; H, 5.65; N, 6.03%
C22H27ClN203S2 l~uiles. C, 56.58; H, 5.83; N, 6.00%
F.Y~mple 131 ~ )-N-[~(4-Chloroph~,-yllleAyl)]-4(3-ll-ie,~ ne~-y~ nyl)-2 15 oYn~q7pff~lin~l-y~r~?t~ P
The synthesis was carried out as in example 107, using N-(~(4-chlorophenyl)hex-1-yl)-4-(3-thienylmethylcl-lrhinyl)-2-oxo~7Pti-lin-l-yl~et~mi~P (0.81 g). Cyss~tli~ti~ n from ethyl acetate/pet. ether gave the title compound (0.67 g), m.p. 114- 116~C. 'H
NMR ~ (CDC13) 1.33 (4H, m), 1.55 (4H, m), 2.57 (2H, t), 3.05 (lH, dd), 3.15 (lH,dd), 3.25 (2H, m), 3.84 (lH, d), 3.94 (lH, d), 4.38 (lH, d), 4.43 (lH, d), 4.83 ~lH, dd), 5.96 (lH, m), 7.08-7.43 (7H, m). n~O 1794 cm~l Found: C, 54.62; H, 5.44; N, 5.83%
C22Hz7ClN204S2 requires: C, 54.70; H, 5.63; N, 5.80%
Examplel32 - (~ -N-[6-(4Chlorophenylhexyl)3-4(thiazol-~ U.~I~l,io) 2 25 oY,)~7P1i~in l y~ et~ P
a) (+/-)-4(2-Thi~olyl..letl.ylll~io)~7Pff~ 2-one The synthesis was carried out as in el~mplP 101a, using 2-(acety~thiomPthyl)thiazole (23 mmol) and 4-acetw~y~ in-2-one (23 mmol). Tnt~ tion with ether gave the title compound (1.48 g), m.p. 89-92~C. IEl NMR ~ (CDC13~ 2.76 (lH, m), 2.30 ~lH,m), 4.26 (2H, s), 4.85 (lH, m), 7.68 (lH, d), 7.73 (lH, d), 8.63 (lH, br s).
b) (+/-3-N-t6-(4-Chloropl-~ Il.exyl)]-4(thiazol-~yl...t~ 111.io)-2-nY~7Ptirlin.l_y~ et~mi/lP
The synthesis was calIied out as in example 101b, using (+/-)~(2-thiazolylme~yl-thio)~P-ti~ln-2-one (6.9 mmol), N-(6-(~chlorophenyl)hex-1-yl)-2-bromc~~~ P
(6.9 mmol), tetrabutylammonium bromide (0.69 mmol), and powdered KOH (6.9 mmol) in dry THF (40 ml). P~epe~t~d chromatography (silica, 2-6% MeOH in C~7Cl?; silica, t-BuOMe) gave the title co,~ d as an oil (0.04 g). IH NMR o (CDC13) 1.33 (4H, m), 1.55 (4H, m), 2.56 (2H, t), 2.99 (lH, dd), 3.23 (2H, m), 3.44 (lH,dd),3.73(1H,d),3.90(1H,d),4.12(1H,d),4.21 (lH,d),5.02(1H,dd~,6.19 (lH, m), 7.07-7.26 (4H, m), 7.31 (lH, d), 7.69 (lH, d).
F.Y~mrle 133 - (+J-)-N-~6-(4-Chlorophenylhexyl)1-1 (thiazol-2-~h...,tl~y! ~,~lrhinyl)-2~Y~7e~ in-l-y~ Pt~m;rlp (~ .,el 1) The synthesis was caIIied out as in example 102, using (+/-)-N-(6-(4-chlorophenyl)-hex-l-yl)~(2-thiazolylmethylthio)-2-oxo~7Ptitlin-l-yl~et~mi~ (1.03 g, 2.28 mmol).
45 Trituration of the crude product with ethyl acet~te gave a sample collts.;..; -g 96% of W O 97/02242 PCT~EP96/02765 diastereomer 1 (0.35 g), m.p. 15~157~C. IH NMR ~ (CDC13) 1.33 (4H, m), l.SS
(4H, m), 2.56 (2H, t), 3.02 (lH, dd), 3.23 (2H, m), 3.36 (lH, dd), 3.80 (lH, d), 4.14 (lH, d), 4.35 (lH, d), 4.42 (lH, d), 4.92 (lH, dd), 6.46 (lH, m), 7.09 (2H, m), 7.2'S
(2H, m), 7.43 (lH, d), 7.84 (lH, d). nOO 1760, 1791 cm~l S Found: C, 53.91; H, S.SS; N, 8.94%
C2lH26ClN303S2 reqnires C, 53.89; H, 5.60; N, 8.98%
FY~mrl~ (+/~)~N~t6~(4~chloro~ exyl)~4(th;~7~ yl~ p~yl~-in.l.yl ~r~ ~omer 2) The mother liquors from PY~mplP 133 were con~e~-l-; tPd and diluted with pet. ether to induce cryst~llic~tion of a sample c~ .g 94% of dias~lev~er 2 (0.49 g), m.p. 103-104~C. IH NMR ~ (CDC13) 1.33 (4H, m), 1.55 (4H, m), 2.57 (2H, t), 3.11 (lH, dd!), 3.25 (2H, m), 3.33 (lH, dd), 4.08 (lH, d), 4.29 (lH, d), 4.44 (lH, d), 4.50 (lH, d), 4.98 (lH, dd), 7.09 (2H, m), 7.24 (2H, m), 7.34 (lH, m), 7.42 (lH, d), 7.84 (lH, d).
nOO 1793 cm~l lS Found: C, 54.12; H, 5.56; N, 8.87%
C2lH26ClN3O3S2 requires: C, 53.89; H, 5.60; N, 8.98%
FY~mp'e 135 - (+/-)-N-[6-(4-Chlo~ V~~ ll.exyl)] ~ (5 ~h~ ~ I,onyl-~
ru~ ell~ylll~io)-2-oY~7eff~lin-l-ylacetamide a) Mefflyl 5-(ac~lyl~ u ~ yl)furan-5-~all~Aylalt:
20 A sollltion of pot~ccillm thio~ret~t~ (45.7 g, 0.4 mol) in dry DMF (100 ml) was added to an ice-cooled sol~lti~n of methyl S-(chloromethyl)furan-2-c~l,~"ylate (6~ g, 0.35l mol) in dry DMF (300 ml). Cooling was removed, and the u~ ulc; stirred for a fur~her 30 min, then poured into water and extracted with ether. Chromatography (silica, 0-30% ether in pet. ether) of the organic extracts gave the title compound as an oil (42.7 2~ g). IH NMR ~ (CDC13) 2.36 (3H, s), 3.88 (3H, s), 4.16 (2H, s), 6.35 (lH, d), 7.08 (lH, d).
b) ~(~-(Metho~.all,onyl)2-ru, ~ -ethylthio)~7~ffAin-2-one The synthesis was carried out as in example lOla, using methyl S-(ace~ylll.iomPthyl)furan-S-carboxylate (47 mmol), 4-aceto~Ly~7PIi~lin-2-one (47 mmol), 30 and sodium mPtllQxitle (47 mmol) in place of sodium ethoxitl~ The crude product was a~d with ether to give the title compound (8.7 g), m.p. 102-103~C. IH NMR o (CDC13) 2.85 (lH, dd), 3.43 (lH, dd), 3.88-3.92 (SH, m), 4.92 (lH, dd), 6.33 (lH, m), 6.78 (lH, br. singlet), 7.09-7.11 (lH, m).
c) (+/-)-N-t6-~4-Chlorophenylhexyl)]-1 (5-mpth~xy~~ onyl-2 35 lul~ ylll~io)-2-oYo~7~tiAin l y~ t~
The synthesis was carried out as in eY~mplP- 101b, using (+/-)-4-(S-(methoAyc~bonyl)2-furylmethylthio)~7p3~ n-2-one (21 mmol), N-(6-phenylhex-1-~yl)-2-bromo~cet~mi~le (21 mmol), tetrabutylammonium bromide (3 mmol), and powdered KOH (211 mmol) in dry THF. Chromatography (silica, EtOAc/pet. ether) gave the 40 title compound as an oil (5.0 g). IH NMR o (CDC13) 1.29-1.35 (4H, m), 1.43-1.63 (4H, m), 2.55 (2H, t), 2.94 (lH, dd), 3.19-3.27 (2H, m), 3.24 (lH, dd), 3.78 (lH, ~d), 3.88-3.90 (3H, m), 3.95-3.97 (lH, m), 4.04-4.17 (2H, m), 5.01 (lH, dd), 6.25 (lH, br triplet), 6.33-6.35 (lH, m), 7.06-7.10 (3H, m), 7.20-7.26 (3H, m).

W O 97/02242 PCT~EP96102765 Example 136- (+/-)-N-t6-(4Chloroph~l.;lh~A~ 1 (S-me~ ~l,onyl-2-~U~ ..ell~ o~ ide (~ omer l) The synthesis was carried out as in e~mrlp 102, using (+/-)-N-(6-phenylllc;A-l-yl)~
(S-meth~y.,a,l~,lyl-2-furylmethylthio)-2-oYrl~7p~ n-l-yl~r~t~m~ p (4.0 g, 8 mmol).
S Recryst~ tion of the crude product from ethyl acetate gave a sample of dia~ Gu,l,er 1 (0.8 g), m.p. 141-142~C. IH NMR o (CDC13) 1.20-1.35 (4H, m), 1.40-1.65 (4H, m), 2.55 (2H, t), 3.05 (lH, dd), 3.19-3.33 (3H, m), 3.83 (lH, d), 3.90 (3H, s), 4.09-4.16 (3H, m), 4.71 (lH, dd), 6.46 (lH, br. triplet), 6.55-6.56 (lH, m), 7.07-7.26 (SH, m). nOO 1792 cm~l Found: C, 56.65; H, 5.68; N, 5.55%
C24H29ClN206S requires: C, 56.63; H, 5.74; N, 5.50%
F-Y~P'C 137 - (+/-)-N-t6-(4Chl~,lo~llt,~ eYyl)]-4(5 ~~t~ c~l onyl-2-rul~IIllell~ ..lp~inyl)-2-o~ t~ n-l-~ de(~'~ ' .D~ner2) The mother liquors from example 136 were evaporated and recryst~ P,d from ethyl acetate to give a sample of diastereomer 2 (l.S g), m.p. 113-114~C. IH NMR ~
(CDC13) 1.29-1.40 (4H, m), 1.50-1.64 (4H, m), 2.56 (2H, t), 3.00 (lH, dd), 3.23-3.40 (3H, m), 3.90 (3H, s), 4.03 (lH, d), 4.19-4.29 (3H, m), 4.72 (lH, dd), 6.53-6.55 (lH, m), 7.00 (lH, br. triplet), 7.07-7.26 (5H, m). n~=O 1795 cm~l Found: C, 56.73; H, 5.69; N, 5.57%
C24H29ClN206S requires: C, 56.63; H, 5.74; N, 5.50%
Example 138 - (+/-)-4( 2-ful ~ Il..etl.~ io)-l-(9-~he..~lllonyl)~ 2-one A s-lspencion of sodium hydride (3.65 mmol) in dry THF (10 ml) was cooled in ice/salt, and a ~olutiorl of (+/-)-4-( 2-fulyl~ -yl~lio)azetidin-2-one (0.61 g, 3.32 mmol) in THF (10 ml) was added dropwise below 5~C. The res llting sol~ltion was further cooled to -10~C, and a sollltion of 9-phenylnonyl-1-triflate (1.17 g, 3.32 mmol) in THF (10 ml) was added gradually over 1 min. After stirring for a further S min at 0~C, the reaction Illii~Ulc~ was poured into brine and Ç~tr~t~tP~ with ether.
Chromatography of the organic extracts (silica, 10-25% EtOAc in pet. ether) gave the title compound as an oil (0.38 g). 'H NMR ~ (CDC13) 1.2-1.7 (14H, m), 2.60 (2H, t, J=8 Hz), 2.9 (2H,m), 3.3 (2H, m), 4.78 (2H, s), 4.68 (lH, m), 6.20, 6.32 (each lH, m), 7.15 - 7.3 (5H, m), 7.36 (lH, m).
Fr p!- 139 - (+/-) 1-( 2-ru,~ )-l-(9-phenylnonyl)q7~ n-2-one The synthesis was carried out as in Py~mplP 102, using (+/-)-4-(2-furylmethylthio~l-(9-phenylnonyl)q.7~ti-lin-2-one (0.37 g, 0.97 mmol). Chromatography (silica, 50-70%
EtOAc in pet. ether) gave ~Lhe title compound as an oil (0.28 g), cont~inin~ about 63%
of diastereomer 1, 37% of diastereomer 2. IH NMR ~ (CDCI3) 1.2-1.7 (14H, m), 2.55 (3H, m), 2.90, (lH~ dd, J=5, 15 Hz), 3.10 (lH, dd, J=5, 15 Hz), 3.15-3.5 (3H, m), 3.954.15 (2H, m), 4.42 (lH, m), 6.42 (2H, m), 7.1-7.3 (SH, m), 7.43 (lH, m).n~=O 1776 cm~l Found: C, 68.5; H, 7.8; N, 3.3%
C23H31NO3S requires: C, 68.8; H, 7.8; N, 3.5%
F~ 140 - (+I-) 4 ( 2-rurrlu~ yllllio~1-(9~4-flu-)lopl.~ l)nonyl)q7~ti~l;n-2-one The synthesis was carried out as in example 138, using (+/-)-4-( 2-furylmethyl-thio)azetidin-2-one (1.5 g, 8.2 mmol) and 9-(4-fluol~,phenyl)nonyl-1-triflate (2.9 g, 7.8 mmol). Chromatography (silica, 10-25% EtOAc in pet. ether) gave the title compound WO 97/02242 PCT/EP96/0276~

as an oil (0.56 g). 'H NMR ~ (CDC13) 1.2-1.7 (14H, m), 2.56 (2H, t, J=7.7Hz), 2.5l0 (2H, m), 3.29 (2H, m), 3.77 (2H, s), 4.68 (lH, m), 6.20 (lH, m), 6.31 (lH, m), 6.9'5 (2H,m),7.10(2H,m),7.36(1H,m).
Example 141 - (+/-) 1 ( 2-lu~ ~1)-1-(9-(1 5 flu~ ."' yl)nonyl)~7~t;A;n-2-one The synthesis was carried out as in ex~mrlP- 102, using (+/-)~(2-rulyl~u~ ylll~io~l-(9-(1 fluorophenyl)nonyl)~7p-tidin-2-one (0.52 g, 1.28 mmol). Chromatography (silica, 50-70% EtOAc in pet. ether) gave the title compound as an oil (0.42 g), co..~ g about 65% of diastereomer 1, 35% of ~ t~Preompr 2. 'H NMR o (CDC13) 1.2-1.7 (14H, m), 2.55 (3H, m), 2.90, (lH, dd, J=5, 15 Hz), 3.10 (lH, dd, J=5, 15 Hz), 3.1';-3.5 (2H, m) 3.95-4.15 (2H, m), 4 42 (lH, m), 6.42 (2H, m), 6.95, 7 10 (each 2H, m), 7.43 (lH, m). nOO 1776 cm~l Found: C, 65.7; H, 7.2; N, 3.2%
C23H30FNO3S requires: C, 65.8; H, 7.2; N, 3.3%
FY~nPI~ 142 - (+/-)~( 2-fUrYIm~IIJY1!~ Q~YI)-1~(9-(4 fluorophenyl)nonyl)~ ~u.l;. 2-one The synthesis was carried out as in PY~mplP 107, using (+/-~( 2-furylmethyl~ r)hinyl)-1-(9-(4-nuo.ophenyl)nonyl)~7Pti~lin-2-one (88 mg).
Chromatography (silica, EtOAc/peL ether 2:1) gave the title compound as an oil (56 mg). lH NMR ~ (CDCI3) 1.2-1.7 (14H, m), 2.56 (2H, t, J=8 Hz), 2.99 (lH, dd, J--.2, 15 Hz), 3.15 (2H, m), 3.45 (lH, m), 4.37 (2H, s), 4.57 (lH, m), 6.45, 6.55 (each lH, m),6.95,7.10(each2H,m),7.47(1H,m).
FY~mrle 143. N-[6-(4-Fluorophenyl)hex-1-yl] 3 (S-allyl~ lîur~.-2-yll~io)-2-oY- ~7eh'Ain-l-~ e~u~
A solution of 4-(5-allyloxyc~onylfuran-2-methyl)thio~pti~lin-2-one (4 g, 0.015 mol) and N-(4-fluorophenylhex-1-yl)bromo~ret~mi~lç (4.73 g, 0.015 mol) in dry tetrahyd,oru,~n (150 ml) was cooled to -30~C and a solution of pot~inm t-butoxide (1.85 g, 0.0165 mol) in dry tetrahydl.ru~ (80 ml) added dropwise over 15 min. The t~mrçr~t--re was allowed to rise to 10~C over 2 hr, then the mixture diluted with water and ç~tr~ted with ethyl acetate, filtPrin, off and discarding any in~olnbl~ solids. the extracts were dried (MgS04), evaporated, and the product purified by flash chromatography (silica, ethyl acetatelpetrol), to give the title colllp~,u..d ac a yellow oil (2.54g, 33% yield). lH NMR ~ (CDC13) 1.32 (4H, m, N(CHz)2(CH~)2), 1.~2 (4H, m, NCH2CH2 + FPhCH2CH2), 2.55 (2H, t, FPhCH2), 2.96 (lH. dd, H3a)7 3.24 (2H, m, NCH,), 3.49 (lH, dd, H3b), 3.76-4.06 (4H, CH2CO + CH2S), 4.79 (2H. m, OCH2), 5.03 (lH, dd, ~4), 5.36 (2H, m, C_2CH), 5.99 (lH, m, CHCH2), 6.30 (lH, m, NH), 6.35, 7.12 (each lH, d, furan-_), 6.92-7.12 (4H, m, FPh-_) Example 144. N-t6-(4-Fluorophenyl)hex-l-yl] 1 (5-allylo~ ln,l-~lru~--~
111~ ll~yl~ .hinyl)-2-o~ 7Ptirlin-l-yl~r~ P (D;ssl~l~omer 1) Tre~tmçnt of N-[6-(~fluorophenyl)hex-1-yl]~-(5-allylo~y~;albollylr~-2-methylthio)-2-o~co~7Pririin-1-yl~cet~millP with mCPBA in dichloromP-th~nP at low~--,pe,ature gave, after work-up and recryst~llic~tion as described for Example 102, the title compound as white crystals, m.p. 122-5~C, 16% yield. lH NMR o (CDC13) 1.32 (4H, m, N(CH2)2(C_2)2), 1.54 (4H, m, NCH2CH2 + FPhCH2CH2), 2.56 (2H, t, FPhC_2), 3.08 (lH, dd, H3a), 3.23 (2H, m, NC_2), 3.30 (lH, dd, H3b)~ 3.55~ 3.73 W O 97/02242 PCT~EP96/02765 (each lH, d, SCH~), 3.84, 4.13 (e~h lH, d, CH~CO), 4.73 (lH, dd, H4), 4.80 (2H, m, OCH7), 5.38 (2H, m, CH~CH), 5.97 (lH, m, CHCH2), 6.56, 7.18 (each lH, d, furan-H), 6.91-7.14 (4H, m, E;Ph-H) FY~mp'~ 145. N-[6-(4-~uorophenyl)hex-1-yl]~(5~allylox~ ylru~ 2-S ~ yl)-2-u~ n 1-yla~ unide (l)iastereomer2) Recryst~llic~tinn of the mother liquors from FY~mpl~ 144 gave the title co...l O...l~i (diasteresicom~r 2:1 ca 83:17) as white crystals, m.p. 79-82~C, 29% . v 00 1793 cm~
1 Found: C, 59.82; H, 5.93; N, 5.40%. C26H31FN206S requires: C, 60.22; H, 6.03;
N, 5.40%
Fy~n~rle 1~6. N-[6-(1 Fluorophenyl)hex-l-yl] 1 (~ yruldn-2-yl~ yl)-2~oq~ 1in-l~yl~ e (I)iastereomer 2) A sQllltit)n of triphenylrhosrhin~ (0.81 g, 0.31 mmol), py~rrolidine (0.027 ml, 0.31 mmol) and N-[6-(4-fluorophenyl)hex-1-yl]~(5-allyl~Ay~l,onyllu~l-2-methylc-llrhinyl)-2-oxo~7etiflin-l-yl~et~mirlP (diastereomer 2, 0.16 g, 0.31 mmol) in 15 dichloromPth~n~ ( 10 ml) wa~s treated with tetrakis triphenylphospl.;...~l,Rll~Aillm(0) (10.7 mg, 0.0093 mmol) and the mixture stirred for 2 hr. The solvent was evaporated and the residue purified by flash chromatography (silica, dichlorom~th~n.o /acetone /acetic acid). The crude product was dissolved in dichloromPth~n~q (10 ml), washed with brine, dried (MgS04), and evaporated to an oil which was treated with 20 dic-hlorom~th~np and ether to give the title compound as a solid (46mg, 31% yield), m.p.l24-7~C. lH NMR ~ (CDCl3)1.31 (4H, m, N(CH2)z(C_2)2),) 1.53 (4H, m, NCH2CH2 + FPhCH2CH2), 2.56 (2H, t, FPhCH2), 3.07 (lH, dd, H3.), 3.26 (2H, m, NC_2), 3.40 (lH, dd, H3b), 4.21-4.34 (4H, m, SCH2 + CH2CO), 4.76 (lH, dd, ~4), 6.55, 7.10 (each lH, d, furan-_), 6.92-7.16 (4H, m, FPh-H), 7.60 (lH, NH) Fy~mrle 147. N-(6-~4-Chlorophenyl}hexyl)-4(~allyloxy~ 1~o.. ~lr~l~.-2-ylll~io-2-oY0~7~h~lin l y~ e~ e Tre~tm.ont of 4-(5-allyloxyc~bonyl~ul~-2-methyl)thio~7ptirlin-2-one (2.4 g) and N-(4-chlorophenylhex-1-yl)bromo~cet~mi-le* (2.99 g) in dry te~ahydrofuran (175 ml) with a solution of potassium t-butoxide (1.03 g) in dry tetrahydrofuran (50 ml) at -40~C, followed by work-up as described for Example 143 gave the title compound as a yellow oil, 37% yield. IH NMR ~ (CDC13) 1.30-1.60 (8H, m, 4xC_2), 2.55 (2H, t, J=7.6 Hz, CH~Ph), 2.92, 2.98 (lH, dd, J=2.2, 15.4 Hz, H~), 3.24 (2H, m, NHCH~), 3.46, 3.52 (lH, dd, J=5.2, 15.4 Hz, ~3), 3.94 (4H, m, NCH~, SCH7), 4.79 (2H, m, CO2CH~), 5.02 (lH, m, ~4) 5.35 (2H, m, CH~=CH), 6.0 (lH, m, CH2=CH), 6.26 (lH, m, N_ ), 6.34 (lH, d, J=3.4Hz, furan-H), 7.06-7.26 (SH, m, furan-H, Ph-H) *obtained by treating of 6-(~chlorophenyl)hexylamine (2.0g) and Hunig's base (1.33g) in dry dichlorom~th~nP (25 ml) with bromoacetylbromide (2.07g) in dichloroln~th~nP
(10 ml) at 0-5 ~C.
FY~n~rle 148. N-(6-{4-Chlorophenyl}hexyl~1 (~allyloAy~l~uJ~ylru~
40 ~ lhyl~ iyl-~o~o~ in-l-yl)~r~ (D;a~ ~ 1).
Colourless solid, m.p. 135-136~C, 15% yield. IH NMR o (CDCl3) 1.3023-1.60 (8H, m, 4xCH7), 2.56 (2H, t, J=7.6 Hz, C_2Ph), 3.03, 3.09 (lH, dd, J=4.7, 15 Hz, ~3),3.24 (2H, m, NHCH7), 3.28, 3.34 (l~I, dd, J=5.4, 15 Hz, ~3), 3.81, 4.13 (each lH, d, J=17.2 Hz, NCH~), 4.09 (2H, s, SOCH~), 4.70 (lH, m, ~4), 4.80 (2H, d, J=5.8 Hz, CO2CH2), 5.37 (2H, m, CH2=CH), 6.0 (lH, m, CH2=CH), 6.44 (lH, m, NH), 6.56 W O 97/OZ242 PCT~EP96/0276;5 (lH, d, J=3.5 Hz, furan-H), 7.07-7.26 (5H, m, furan-H, Ph-_). v c=o 1792 cm~l.
Found: C, 58.2; H, 5.8; N, 5.3%. C26H3ICIN2O6S l~U l~S. C, 58.4; H, 5.8; N, 5..!%
Example 149. N-(6-{4Chl~,.ul~h~ hexyI)-4(5 allyluA,~I,on~Irul~,.2.
U~yl ~ yl~ ;Ain.l yl)~ 'e (Diast~ 2).
S ~'olollrl-ps~ solid, m.p. 89-92~C, 13% yield. IH NMR ~ (CDC13) 1.30-1.60 (8H, m, 4xCH~), 2.56 (2H, t, J=7.6 Hz, CH7Ph), 2.99, 3.05 (lH, dd, J=2.4, 15.4 Hz, H3), 3.24 (2H, m, NHCH~), 3.32, 3.39 (lH, dd, J=5.4, 15.4 H_, H3), 4.03, 4.25 (each lH, d,J=17.2 Hz, NCH2), 4.20 (2H, m, SOCH2), 4.72 (lH, m, ~4), 4.79 (2H, d, J=5.8 Hz, CO2C_2), 5.37 (2H, m, CH2=CH), 6.0 (lH, m, CH2=C_), 6.55 (lH, d, J=3.5 Hz, furan-_), 7.02 (lH, m, NH), 7.07-7.26 (5H,m, furan-H, Ph-H). v 00 1795 cm~l.
Found: C, 58.2; H, 5.8; N, 5.3%. C26H3ICIN2O6S requires: C, 58.4; H, 5.8; N, 5..!%
FY~mrl~P 150. N-(6-{4chlo~ l}he~y~yl) 1 (S-~b~ylu~
Ulyl~..lrl~inyl-2-oYn~7etirlin.1.yl)~ ? (D~.~~ . 2).
Tre~tment of a solution of triphenylphosphine (53.3 mg), pyrrolidine (14.3 mg) and N-[~(4-chlorophenyl)hex-l-yl]-4-(5-allylu~y~ ylfuran-2-methy~ r~ yv-2-~IY~o~7Pt~ n-l-yl~ret~mi~e (diastereûmer 2, 105 mg) in dichlûrom~th~np (4 ml) with with tetrakis triphenylphQsphinp~ m(o) (6.5 mg) and wûrk-up as ~Psrr~ fûr FY~mpl~P 146 gave the title eolllpl)u-ld as a cream sûlid, m.p. 166-167~C, 49% yield.
'H NMR ~ (DMSO) 1.26 (4H, m, 2xCH~), 1.37 (2H, m. CH7), 1.52 (2H, m, CH~), 2 50 (2H, m, CH~Ph), 2.95. 2.99 (lH. dd, ~3), 3.05 (2H. m, NHCH~), 3.83, 4.07 (each lH, d, J=17.2 Hz, NC_2), 4.29, 4.42 (each lH, d, J=14 Hz, SOCH2), 4.86 (lH, m, ~4), 6.60 (lH, d, J=3.2 Hz, furan-H), 7.15-7.32 (SH,m, furan-H, Ph-H), 8.l38 (lH, m, NH). Found: C, 54.5; H, 5.3; N, 5.6%. C23H27CIN206S l~ Uil~i. C, 55.8,;
H, 5.5; N, 5.7%
FY~r~PIe 151. N-[6-(4 F1UOr~ henYI)heX-1-YI]-4-(5 ~Pth~ ~h~ 1rU~-2 m ethyl~io) 2 o~o~ . 1 yl~C~ P
TrP~tmpnt of 4-(5-metho~yc~l~ouyl~u~n-2-methyl)thi 7Pti~in-2-one (FYZ~m[)lP 135b) and N-(4-fluorophenylhex-1-yl)bromo~et~mitlP in d~y tetralIyd~urulan with a sohltion of pot~csinm t-butoxide in dry tetrahydrofuran at -30~C, followed by work-up as ~lescri~e~i for F~c~mrl~ 143 gave the title compound as a pale yellow oil, 55% yield.
lH NMR o (CDC13) 1.32 (4H, m, N(CH2)2(CH7)2), 1.54 (4H, m, NCH2CH7 +
FphcH2cH~)~ 2.56 (2H, t, FPhCH~), 2.95 (lH, dd, H3"), 3.24 (2H, m, NCH7), 3.48 (lH, dd, H3b), 3.88 (3H, s, OC~3), 3.75-4.05 (4H, m, SCH
CH~CO), 5.02 (lH, dd, ~4), 6.30 (lH, m, NH), 6.3~, 7.12 (each lH, d, furan-H), 6.90-7.13 (4H, m, FPh-H) Tre~tmPnt of N-(6- {4-fluorophenyl }hexyI)~(~-methoAy~ onylrul~uI-2-metllyllllio-2-0~0~7Pti~lin- l-yl)~cet~mitie with mCPBA under the conditions described for FY~mpl~s 102 and 103 gave Examples 152 and 1~3 after recryst~llic~tion as ~iesrri~
for Fl~mF~lps 102 and 103.
F~ c 152. N-[6-(4-Fluorophenyl)hex-l-yl]-4-(~ ~thQ~ l,o.. ylr.. r~.-2-~ell~y~ )hinyl)~2~oy~7~ti~l;n~l~yl~r~
White crystals, m.p. 137-8~C, 16% yield. lH NMR ~ (DMSO) 1.27 (4H, m, N(CH2)2(CH2)2) 1.39 (2H, m, FPhCH2CH2), 1.53, (2H, m, NCH~CH7), 2.55 (2H, I, FPhCH2), 3.04 (4H, m, NCH, + ~3a + .~3b)~ 3.68, 4.03 (each lH, d, SCH7), 4.13, 4.39 ~9 W O 97/02242 PCT~EP96/02765 ~each lH, d, CH2CO), 4.99 (lH, m, _ 4), 6.64, 7.30 (each lH, d, furan-H), 7.04-7.24 (4H, m, FPh-H) EY~unple 1~3. N-[6-(4Fl~olv~ l)hex-l-yl]-4(~ ~rbonylfuran-2-ll~ell~tl~ l) 2 ~n~ 1 r~ le (Diastereomer 2) S White crystals, m.p. 100-2~C, 16% yield. v c~, 1795 cm~l. Found: C, 58.53; H, 5.90;
N, 5.68%. C24H29FN2O6S lc:~lui~l:s: C, 58.52; H, 5.93; N, 5.69%
E~nple201 N-~6-(Phenyl)hexyl)-(4(2-nuv~ )-2-,~ t'lin-l-yl)acetamide A sol-~tion of 4 (2-fluo~ henoxy)~7Ptitiin-2-one (O.Sg, 3 mmole), N-(6-phenylhexyl)bromo~- e~ P (0.9g, 3 mmol) and 18-crown-6 (5 mg) in dry 1~- (20 ml) was cooled to -30~C and treated with pot~ lm t-butoxide (0.3g, 3 mmol). The reS~ltin~ mixture was stirred for 90 min, warmed to 0~C, ~lnPn~hP(I with ~quPous citric acid and ethyl acetate. The organic layer was ,~Pp~tP~, washed with brine, dried(Na2SO4) and evaporated. The residue was purified by flash chromatography to give the title compound as a colourless oil (0.33g, 28%) Found: C, 59.8; H, 5.9; N, 5.5%; C23 Hz7FN203 Ø97CH2Cl2 requires: C, 59.9; H, 6. 1; N, 5.8%
The following compounds were prepared by the method ~lPsrrihed for FY~ml~lp 201 using the required ~7Pti~linonP and bromo~cet~mi~P.
FY~mpl~ 202 N-[6-(4-Chlorophenyl)hexyl]-~4-(2-fluorophenoxy2-oxo ~ ~f;~
yl) ~et~m;~l~
Colourless solid, m.p. 79-80~C, 31% yieldFound: C, 63.6; H, 6.0; N, 6.5%; C23 H26ClFN2O3 requires C, 63.8; H, 6.1; N, 6.5%
FY~mp~e 203 N-(6-(4Phenyl)heYyl)-(4-(2 metl.~ xy) 2 yl)~et~r~ide White solid, m.p. 53-4~C, 55% yield Found: C, 72.6; H, 7.5; N, 7.2% C24 H30N2O3Ø04CH2Ck requires C, 72.5: H, 7.5; N, 7.1%
FY~mp~? 204 N-(6-(4-Phenyl)heYyl)-(4-(2-bellzyloYyrh~n~Yy-2-ox~ ~;~1;~~ 1-yl) ~
White solid, m.p. 87-8~C, 38%yield Found: C, 74.0; H, 7.1; N, 5.8% C30H34N203 requires C, 74.1; H, 7.1; N, 5.8%
FY~mpl? 20~; N-(6-(4-Phenyl)heYyl)-(4-(2-m~ ylllliorh~~~oYy)-2-~
yl) ~ce~ le White solid, m.p. 79-80~C, 32% yield Found: C, 67.0; H, 7.0; N, 6.8% C24H30N203S requires C, 67.6; H, 7.1; N, 6.6%
F~ 206 N-(6-(4-phenyl)he~y-yl)-(4-(4chloroI)h~nnxy)-2-~y~7~ n-l-yl) Colo~rlP~s oil, 32.0% yield Found: C, 64.5; H, 6.4; N, 6.5%; C23H2,ClN203 0.21CH2Ck .requires: C, 64.4; H, 6.4; N, 6.5%
F.Y~m-, ' ? 207 (N-(6-(4-Phenyl)hexyl)-4-(~ -rh ~- ~Yy)-2-o~ n~
yl)~ t- -1P
Pale yellow solid, m.p. 43-45~C, 30% yield Found: C,70.3; H, 7.5; N, 7.1 %; C24H30N204 requires C, 70.2; H, 7.4; N, 6.8%

W O 97/02242 PCT~EW6/0276.5 F ,'~208 N-(-(4 PhenYI)heYYI~ (4,~ 2 yl)~~et~ide Colourless oiL 15.5% yield Found: C, 67.0; H, 6.9; N, 6.6%; C24H30N203S requires: C, 67.0; H, 7.0; N, 6.5%
FYqn~rl~ 209 N-(6-(4Chlo~ nyl)hexyl)-(4(4allyl~ ~bonyl-~lell~y~ n-y-y)-2-oy~7ptiA~ -yl)aA~t~
'H NMR ~ (CDC13) 1.37 (m, 4H), 1.53 (m, 4H), 2.55 (t, 2H,7.6Hz), 3.21 ~ (dd,lH,J=16.1Hz), 3.24 (m, 2H), 3.39 (dd, lH, J=1.6Hz), 3.59 (s,2H), 3.99, 3.94,3.99 (each lH, d, J=17.1Hz), 5.59 ~m, 2H), 5.25 (m, lH), 5.72 (m, lH), 5.86 (m, lH), 6.'34 (bm, lH), 6.81-7.26 (m, 8H) FY~~nP'e210 N-(6-(4 PhenYI)heYYI~(4 PhenOYY-2~ -1-YI)aCeb~n~de Pale yellow solid. m.p. 45-48~C, 41% yield, Found: C, 72.3; H, 7.3; N, 7.7 %; C~3 H28N203 requires: C, 72.6; H, 7.4; N, 7.4 %
F-Y~mP'C 211 N-(6-(4-Phenyl)hexy}~(~ben~yloYy-2~Y~7~ in- l-yl)acetamide Pale yellow oil, 46% yield, Found: C, 71.5; H, 7.9; N, 6.7 %; C24 H30N203 O.5GEI802 requires: C, 71.4; H, 7.7; N, 6.4 %
~Y~mp'~ 212 N-(6-(4-Phenyl)hexyl)-(4-(4JI~ell~ hi~ Yy~
()Yn~7-t~ n-l-yl)~ p Tre~tmPnt of N-(6-(4-phenyl)hexyl)-(4-(4-methylthiophenoxy)-2-o~o~7Ptillin yl)~~rPt~mitlr with meta-chloiupe~ ;oic acid (m-CPBA) (l.lequivalent) in dichloroml-th~nP at -70~C gave the title compound as a colourless oil in 92% yield after chromatography.
Found: C, 61.6; H, 6.5; N, 6.0%; C24H30N204SØ4CH2Cl2 requires: C, 61.5; H, 6.5;
N, 5.9o%F~n~ e 213 N-[6-(4phenyl)hexyl]-[4(4lm~ y~ h~
OXO ~7~t~ n-l-yl) ~CC~t,~ P
Tre~tmPnt of N-(6-(4-phenyl)hexyl)-(4-(4-methylthiophenoxy)-2-oxo~7pti~lin yl)~ret~mi-lP with meta-chloloper~ zoic acid (m-CPBA) (4 equivalents) in dichlornmPth~nP at 20~C gave the title compound as a colourless solid, m.p. 101-2~C', in 85% yield after chromatography.
Found: C, 62.3; H, 6.5; N, 6.1%; C24H30N205S requires: C, 62.8; H, 6.6; N, 6.1%
FY~mrle 214 N-(~(4-Phenyl)hexyl)-(4(2-~ -y~ henoxy)-2-~y~ 7~iAin-l-y~
Trç~tmPnt of N-(6-(4-phenyl)hexyl)-(4-(2-methylthiophenoxy)-2-oxo~7p-titlin yl)acet~mi-le with meta-chlorûp~ nzoic acid (m-CPBA) (1.2 equivalent) in dichlorometh~nP at -30~C gave the title compound as a colourless oil in 75% yield after chromatography.
Found: C, 62.9; H, 6.5; N, 6.1%; C24H30N204SØ25CH2Ck requires: C, 62.8; H, 6.6;
N, 6.0%
FY~mp'e 215 N~ 4-Phenyl)hexyl)-(4-(2 methylcl-lp~o-~y~ Yy)-2-~ ,P~ _y~ t~ Ae Tre~tmPnt of N-~6-(4-phenyl)hexyl)-(4-(2-met-h-ylthiophenoxy)-2-~xo~7pti~lin yl)~cet~miflP with meta-chlolup~;llJen~oic acid (m-CPBA) (3 equivalents) in dichloromPth~ne at 20~C gave the title compound as a colourless solid, m.p. 127- 128~C, in 82% yield after chromatography.

CA 02225627 l997-l2-23 W O 97/02242 PCT~EP96/02765 l;ound: C, 62.6; H, 6.5; N, 6.1%; C24H30N20sS requires: C, 62.8; H, 6.6; N, 6.1%F l~lt?216 N-(6-(4Phenyl)heAyl)-(4(2~ A,~ Yy)~ idin-l-yl)a~,~ide T~e~tmP,nt of N-(6-(4-phenyl)he~cyl)-(1 (2-benzyl~y~hello~cy)-2-o~ in S yl)~e~ lP with hydrogen/10% ~ Aillm on charcoal in T~ at room ~r ...
for 1 h gave the title compound as a colollrlP~ oil in 71% yield after chrQmS-to~,.~
Found: C, 64.4; H, 6.6; N, 6.4%; C23H2sN204Ø5CH2Cl2 reqllirPs C, 64.3; H, 6.7; N, 6.4%
FY~mp'e 217 N-t~(4~hlorophenyl)heAyl]-t4(4ca-boA~ henoxy~ oxo-10 ~7~ti-1in l-yl]- $~r~_"~
Tr~P~tmPnt of N-(6-(4-chlol~,phellyl)hexyl)-(4-(4-allylu)~yc~ul-yllut~ yll.l.P-~o~y~2-oxo~7pti~iin-l-yl)~cet~mitle with tetrakis(~iphellylph~srhino)r~ Aillm~
triphenylphosrhinP and pyrrolidine in dichlor~)mpth~np- at room l~ ,.I . . . e ovel---gl t and subsequent work-up followed by flash chromatography gave the title co.--pc u..d as a lS gum (38%) lH NMR ~ (CDC13) 1.13 (4H, bm), 1.53 (4H, m), 2.55 (2H, t, J=7.5Hz), 3.07 (lH, d, J=lSHz), 3.23 (2H, m), 3.39 (lH, dd, J=15,3Hz), 3.59 (2H, s), 3.91 and 4.05 (lH each, d, J=17Hz), 5.71 (m, lH), 6.36 (lH, bs), 6.83 (2H, d, J=8Hz), 7.07 (2H, d, J=8Hz), 7.24 (4H, m) FY~mrle 218 N-(~(4-Phenyl)hexyl~(~methyl-4-~ ,xy 2 ~ '' 1-yl) ~r~ rlc-3-methyl~pheno~y,.7PIi-iin-2-one was prepared ~om 3-methyl-~ac~o~y~ n-2-one as described in Prep 1 above and subsequently treated with N-(6-phenylhexyl)bromo~cet~mi-le as for F.lr~mple 201 to give the title co,llpouild as a pale yellow oil, 52.3% yield.
Found: C, 71.8; H, 7.4; N, 7.1%; C24H30N203Ø1 CH2Cl2 requires C, 71.8; H, 7.6; N, 6.9%
F.~ c 219 4-Benzyloxy-1-(~phenyl-2-ox~butyl) ~7~tiAin-~one To a solution of 4-benzyloxy~7P-ti-lin-2-one (2g, l l.Ommol), 1-bromo-2-oxo~
phenylbutane (2.9g, 12.0mmol), tetrabutyl ammonium bromide (TBAB) (0.4g, 1.2mmol) was added pott~c~ m hydroxide (0.68g,12.0mmol). The mixture was stiIredfor 2 hr. It was quenrhPd with water and extracted with ethyl acetate. The organic extract was dried and evaporated and the residue purified using flash chromatography to give the title compound a pale yellow oil (1.7g, 47% yield).
Found: C, 73.7; H, 6.6; N, 4.4%; C20H2,NO3 O.15H20 requires C, 73.7; H, 6.6; N, 4.3%
F~---l-k 220 4-Phenoxy-1-(4-phenyl-2-oxo-butyl) ~7et~lir 2-one 4-phenoxy~7Pticlin-2-one (lg ,6.2mmol), 1-bromo-2-oxo-4-phenylbutane (l.SSg, 6.7mmol), TBAB (0.2g, 0.7mmol) and potassium hydroxide (0.4g,6.7mmol) were reacted as described above to give the title compound (0.65g, 31% yield) as a pale yellow solid, m.p. 59-60~C, after flash chromatography and recryst~lli~tio~ frometherln-hexane.
Found: C, 73.0; H, 6.2; N, 4.6% ClgH,gNO3 0.2H2O requires C, 72.9; H, 6.2; N, 4.5%

W O 97/02242 P~lAhl-f/02765 F r~ 'e 301 N-l6-(naphth-l-yl)-s-hexgn-l-y~ l-yl A miAture of 4-bel~yl~-io-2-o~n~7Pti~in-l-yl acetic acid (3.4g), 6-(naphth-lyl~5-heAyn-l-ylamine (3.0g), l-hyd~ yl~ 7~'~ hydrate (1.82g) and 5 dicycloh~Aylca~l,o liimi-ie (2.77g) were stirred tC~eth~-r in dry di ~ lylr(~ P
(lOOml) overnight. The solvent was e~apo~led and the residue was taken up in ethyl acetate, filtered, and eytr~t~tpcl with water. The aqueous sol-lti~n was e~ --~d with ethyl acetate and the cQmhinPd organic sohltion~ were washed with brine, dned and t:v~ P~l Flash chrr)m~tQ~r~rhy (silica gel, ethyl acetate-heAane) afforded the title compound (4.65g) as an oil, 75% yield 1H NMR o (CDCl3) 1.66-1.82 (4H, m), 2.5~-2.63 (4H, m), 2.91 (lH, dd), 3.29-3.40 (3H, m), 3.55, 3.72 (lH each, d), 3.78 (2H, s), 4.78 (lH, dd), 6.21 (lH, br. sin~l~t) 7.22-7.85 (llH, m), 8.28-8.32 (lH, m) FY~mple 302 N-t6-(Naphth-l-yl)-5-heyyn-l-yl~-4-L~ 1-2-~
15 l-yl ~ le (~ ler~oiso --er 1) A solution of m-CPBA (1.2g) in dichloromlo-th~nP was added dropwise to a sollltic~n of N-t6-(naphth-l-yl)-S-hexyn-l-yl]~benzylthio-2-oxo~7~t~ n-l-yl ~et~mide (2.6g) indichloromethane (lOOml) cooled to -60C. The l~liA~UlC~ was stirred at this ~..~,.
for 1 hour, poured into a mixed solntion of sodium hydrogen carbonate and sodium20 s--lphitP. and the layers separated The ~qneouc solllti- n was ~ d with dichlorc-m~th~n~ and the combinpd organic solutionc washed with bnne. The solution was dried and evaporated to give an oil which gave the title compound as white crystals from ethyl aces~ase, m.p. 138-139~C, 22% yield Found: C, 70.7; H, 6.0; N, 6.0%; C28H28N203S +0.3H20 requir~c C, 70.4; H, 6.0;
N, 5.9%
FY~mple 303 N-[6-(Naphth-l-yl)-5-hexyn-1-yl~-4-b~l~y~ 1-2-.,~ ;rUn-l-yl ~~~ ~ (~li~le.~ r 2) The mother liquors were evaporated and LliLulaLed with ether to give the title compound (~ cser~omer 2) as white crystals, m.p. 95-97~C, 56% yield 30 Found: C, 70.8; H, 6.0; N, 6.0%; C28H28N203S requ res:C, 71.2; H, 6.0; N, 5.9%
The following compounds (FY~mrles 304-8) were prepared from (4-'oenzyltnio-2-n~o~7pti~1in-l-yl)acetic acid and the required amine by the method described forExample 301.
Example 304 N-t6-(3-chlorophenyl)hexyn-5-yl]-(4bel~ o-2 35 yl)~ P
Colourless oil, 67.8% yieldlH NMR ~ (CDC13) 1.34-1.67 (4H, m, 2xC_2)~ 2.44 (2H, t, J=6.51Hz, ArCCCH2), 2.94 (lH, dd, 2.43Hz, 15.34Hz, H3a), 3.31 (2H, m, NHCH2), 3.37 (lH, dd, J=5.22Hz, 15.43Hz, _3b)~ 3.63 & 3.78 (lH each, J=16.49Hz, - NC 2)~ 3.87 (2H, s, SC_2Ph), 4.80 (lH, dd, J=2.46Hz, S.llHz, H4), 6.36 (lH, m, 40 NHC=O), 7.15-7.46 (9H, m, 9xArH) FY~mple 305 N-t6-(2-Chlorophenyl)hexyn-5-yl] 1 b~ llllio-2~ox~7~1iAin-lyl e Colourless oil, 76.2% yieldlH NMR ~ (CDC13) 1.47-1.81 (4H, m, 2xCH2), 2.51 (2H, t, J=6.48Hz, ArCCC_2)~ 2.94 (lH, dd, 2.43Hz, 15.38Hz, H3a), 3.22 (2H, m, 45 NHC_2)~ 3.35 (lH, dd, J=5.13Hz,l 5.38Hz, H3b), 3.54 & 3.76 (lHeach, J=16.79Hz, W O 97/02242 PCT~EP96/02765 NCH2), 3.81 (2H, s, SCH2Ph), 4.80 (lH, dd, J=2.45Hz, 5.13Hz, 4), 6.10 (lH, m, N_C--O), 7.17-7.44 (9H, m, 9xArH) F-Y~nP'e 306 N-(6-Phenyl-3-hexynyl)-(41~ 1U-io-'~ n~ idin-l yl)acetamide ('olonrl~ss solid, m.p. 96-97~C, 78% yield lH NMR ~ (CDC13) 2.34 (2H, m, CCC_2)~ 2.46 (2H, m, CCCH2), 2.80 (2H, t, J=7.4Hz, PhCH2), 2.91, 2.95 (lH, dd, J=2.4, 15.3Hz, 3), 3.34 (3H, m, NHCH2,_3), 3.44, 3.73 (each lH, d, J=16.8Hz, NCH2), 3.80 (2H, s, SCH2), 4.83 (lH, m, H,~), 6.0 (lH, m, N_), 7.20-7.33 (lOH, m, 2Ph-H); v ~=0 1771 cm~l Found: C, 70.9; H, 6.5; N, 7.0%; C24H26N202S ,e~lu~s: C, 70.9; H, 6.5; N, 6.9%
Fy~ ple 3o7 Z-N-(6-phenyl-~hexenyl)-(4bel~yl ' '~-2-~ idin-1-yl)~r~ ~ide Colourless oil, 65% yield lH NMR o (CDC13) 2.18 (2H, m, C-CCH2), 2.35 (2H, m, C=CC_2)~ 2.66 (2H, t, J=7.6Hz, PhC_2)~ 2.89, 2.93 (lH, dd, J=2.4, 15.3Hz,_3), 3.20 (2H, m, NHCH2), lS 3.31, 3.37 (lH, dd, J=5.2, 15.3Hz, H3), 3.47, 3.65 (each lH, d, J=15.1Hz, NCH2), 3.75 (2H, s, SCH2), 4.80 (lH, m, ~4), 5.35 (lH, m, CH=), 5.51 (lH, m, CH=), 5.93(lH, m, NH), 7.16-7.41 (lOH, m, 2Ph-H) F~ e 308 E-N-(6-phenyl-3-hexenyl)-(4bel~,~ uo-2-o~
Yl)~f ' ' ~~
Colourless solid, m.p. 9~97~C, 78% yield lH NMR ~ (CDC13) 2.18 (2H, m, C=CCH2), 2.33 (2H, m, C=CCH2), 2.68 (2H, t, J=7.7Hz, PhCH2), 2.90, 2.96 (lH, dd, J=2.4, 15.3Hz, H3), 3.24 (2H, m, NHCH2), 3.33, 3.39 (lH, dd, J=5.2, 15.3Hz, H3), 3.48, 3.71 (each lH, d, J=16.8Hz, NC_ 2)~
3.81 (2H,s,SCH2),4.81 (lH,m,H1),5.34(1H,m,C_=),5.53 (lH,m,CH=),5.87 (lH, m, NH), 7.15-7.36 (lOH, m, 2Ph-_); v c=o 1771 cm~l Found: C, 70.5; H, 6.9; N, 7.0%; C24H28N2O2S requires:C, 70.6; H, 6.9; N, 6.9%
F~ 309 N~(~~Phe~OA~ y~ ~ylll~io.2 nYn~7r1iAin l yl~ ide Yellow oil, 74% yield lH NMR ~ (CDC13) 1.4-1.9 (6H, m, 3 x C_2)~ 2.93 (lH, dd, J=2, 15 Hz, H3), 3.3 (2H, m, NHC_2). 3.36 (lH, dd, J=5, 15 Hz, H3), 3.55, 3.72 (each lH, d, J=17 Hz, NC_2). 3.81 (2H, s, SCH2), 3.95 (2H, t, J=6 Hz, CH20), 4.81 (lH, m,_4), 6.13 (lH, br s, NH), 6.9 (3H, m, Ph-H), 7.3 (7H, m, Ph-F-~p'e 310 N-(2-(2-PhenoAyethoAy)ethyl)~l~ lU-.o-2-o~ r 1-..~ide 35 Yellow oil, 84% yield lH NMR ~ (CDC13) 2.89 (lH, dd, J=2, 15 Hz, H3), 3.31 (lH, dd, J=5, 15 Hz, H3), 3.50 (3H, m, NHC_2 + NCH2), 3.63 (2H, m, CH20), 3.80 (5H, m, CH20 + SC_2 +
NCH2), 4.10 (2H, m, CH20Ph), 4.82 (lH, m, H,l), 6.38 (lH, br s, NH), 6.9 (3H, m,Ph-H), 7.3 (7H, m, Ph-H) Fy~mp~e 311 N-(2-(3-Pht~ loxy)ethyl)~be-~lll-i~2-~
yl~r~t~m;~l~
Yellow oil, 77% yield lH NMR ~ (CDC13) 1.90 (2H, m, CH2), 2.68 (2H, t, J=8 Hz, C_2Ph), 2.93 (lH, dd, J=2, 15 Hz, H3), 3.36 (lH, dd, J=5, 15 Hz, H3), 3.45 (7H, m, NHC_2 + C_2~ +

W O 97/02242 PCT~EP96/02765 NCH2), 3.80 (3H, m, SCH2 + NCH2), 4.85 (lH, m, ~4), 6.25 (lH, br s, NH), 7.3 (lOH, m, Ph-_) The following snlfo~ e~ (FY~mrl~s 312 - 327) were prepared in the same way as (l~scnhe~l for Fy~mrl~s 2 and 3.
Example 312 N-[6-(3-Chlorophenyl)hexyn-S-yl~ 1 be~ I-2-oxo-q7PtiA;n.l_yl ace~amide Whi{e solid, m.p. 133-134~C, 15.5% yieldFound: C, 62.8; H, 5.4; N, 6.13%;
C24H2sClN203S requires: C, 63.1; H, S.S; N, 6.1%
Example 313 N-[6-(3-Chlo.~ e"~l)hexyn-~-yl] 1 ~ b-,l~hinyl-2 ox~
~7~tiA;r~ l-yl ~
White solid, m.p. 68-70~C, 18.0% yieldFound: C, 62.8; H, 5.5; N, 6.2%;
C24H2sClN203S requires: C, 63.1; H, 5.5; N, 6.1%
FY~mple 314 N-[6-(2-Chlorophenyl)hexyn-5-yl~-4-~e ~ 2-oxo-~7~tillin.l.yl ~ret~",~
lS White solid, m.p. 132-134~C, 48.1% yieldFound: C, 62.8; H, 5.5; N, 6.1%;
C24H25ClN203S requires: C, 63.1; H, 5.5; N, 6.1 %
F ~ 31~ N-t6-(2-chlorophenyl)hexyn-~-yl~e~ p~:nyl-2 ~7~tiA;n-l-yl ~
White solid, m.p. 91-92~C, 48.1% yieldFound: C, 62.9; H, 5.6; N, 6.2%;
C24H25ClN203S requires:C, 63.1; H, 5.5; N, 6.1 %
Example316 N-(6-Phenyl-3-hexynyl)-(4 bt~ lsulphinyl-2-o~
yl)~ret~nide(~lia~ ;eo~.~. 1) Colourless solid, m.p. 186~C, 14% yield lH NMR ~ (CDC13) 2.34 (2H, m, CCCH2), 2.46 (2H, m, CCCH2), 2.80 (2H, t, J=7.4Hz, PhC_2)~ 2.91, 2.95 (lH, dd, J=4.4, 14.8Hz, 3), 3.31 (2H, m, NHCH2), 3.41, 3.44 (lH, dd, J=2.0, 14.8Hz, _3), 3.78-4.01 (4H, m, NCH2, SOCH2), 4.59 (IH, m, H4), 6.38 (lH, m, NH), 7.20-7.40 (lOH, m, 2Ph-H); v c=o 1791 cm~l Found: C, 68.0; H, 6.1; N, 6.6%; C24H26N203S requires: C, 68.2; H, 6.2; N, 6.6C~o FY~mple 317 N-(6-Phenyl-3-hexynyl)~(4~b~ yl~ k~ lir 1-yl)~et~rnill~ (diastereoisomer2) Colourless solid, m.p. 127-128~C, 48% yield lH NMR ~ (CDC13) 2.34 (2H, m, CCCH2), 2.46 (2H, m, CCCH2), 2.72-2.81 (3H, m, PhCH2, H3), 3.09, 3.13 (lH, dd, J=5.6, 15.2Hz, _3), 3.34 (2H, m, NHC_2)~ 3-93~
4.19 (4H, m, NC_2~ SOC_2)~ 4.65 (lH, m, H4), 6.74 (lH, m, N_), 7.20-7.40 (lOH, m, 2Ph-H) Example 318 Z-N-(6-Phenyl-3-hexenyl)-(4-~e~ o~ lin-1-yl)~ *~ (diastereQieom~
Colourless soild, m.p. 145-146~C, 19% yield lH NMR ~ (CDC13) 2.21 (2H, m, C=CCH2), 2.35 (2H, m, C=CCH2), 2.66 (2H, t, J=7.6Hz, PhC_2)~ 2.91, 2.95 (lH, dd, J=4.8, 14.8Hz,_3), 3.19 (2H, m, NHC_2)~
3.42, 3.45 (lH, dd, J=2.0, 14.8Hz,_3), 3.73, 4.02 (each lH, d, J=17.6Hz, NCH2), 3.87, 4.01 (each lH, d, J= 13.2Hz, SOC_2)~ 4.53 (lH, m, H1), 6.47 (lH, m, N_), 7.16-7.41 (lOH, m, 2Ph-_); v ~=o 1791 cm~l Found: C, 67.6; H, 6.6; N, 6.7%; C24H28N203S requires: C, 67.9; H. 6.7; N, 6.6%

W O 97/02242 PCT~EP96/02765 E~nple319 Z-N-(6-phenyl-3 '~ 1)-(4-1~ l 2-~ idin-1-yl)A~ de(~ t .~ - 2) Colourless solid, m.p. 104 105~C, 14% yield lH NMR ~ (CDC13) 2.21 (2H, m, C=CCH2), 2.37 (2H, m, C=CCH2), 2.67 (2H, t, S J=7.6Hz, PhCH2), 2.79, 2.83 (lH, dd, J=2.4, 15.6Hz, H3), 3.12, 3.16 (lH, dd, J=5.6, 15.6Hz, H3), 3.22 (2H, m, NHC_2)~ 3.90, 4.18 (each lH, d, J=16.8Hz, NCH2), 3.97,4.16 (each lH, d, J= 12.8Hz, SOC_2), 4.61 (lH, m, H"), 5.35 (lH, m, C_=), 5.51 (lH, m, CH=), 6.95 (lH, m, N_), 7.16-7.41 (lOH, m, 2Ph-_); v ~=0 1793 cm~l Found: C, 67.4; H, 6.6; N, 6.7%; C24H28N203S ~ es. C, 67.9; H, 6.7; N, 6.6%
F~ c 320 E-N-(6-Phenyl-3-lltAt:JIyl)-(4 b~y~ idin-1-yl)~~~ de (Ji:~l~.~. ~.-~-- 1) Colourless soild, m.p.l82-183~C, 18% yield lH NMR ~ (CDCl3) 2.19 (2H, m, C=CCH2), 2.31 (2H, m, C=CC_2)~ 2.67 (2H, t, J=7.7Hz, PhCH2), 2.91, 2.96 (lH, dd, J=4.7, 14.8Hz,_3), 3.24 (2H, m, NHCH2), 3.41, 3.47 (lH, dd, J=2.2, 14.8Hz, H3), 3.73, 4.02 (each lH, d, J=17.3Hz, NCH2),3.88, 4.01 (each lH, d, J= 13.1Hz, SOCH2), 4.55 (lH. m, H1), 6.44 (lH. m, N~), 7.16-7.40 (lOH, m, 2Ph-H); v 00 1790cm~l Found: C, 67.5; H, 6.6; N, 6.6%; C24H28N203S requires: C, 67.9; H, 6.7; N, 6.6%
Example 321 E-N-(6-phenyl-3-l~A~ l)-(4 yl)~e~ ide (~lia~ ~ieom~r2) rlp~ solid, m.p.l l l-112~C, 13% yield lH NMR o (CDC13) 2.21 (2H, m, C=CC_2)~ 2.34 (2H, m, C=CC_2)~ 2.67 (2H, t, J=7.6Hz, PhCH2), 2.78, 2.84 (lH, dd, J=2.5, 15.3Hz, H3), 3.11, 3.17 (lH, dd, J=5.3, 15.3Hz, H3), 3.28 (2H, m, NHC_2)~ 3-90, 4.18 (each lH, d, J=17.1Hz, NC_2)~ 3-97 4.16 (each IH, d, J= 12.9Hz, SOCH2), 4.62 (lH, m, H1), 5.38 (lH, m, =C_), 5.53 (lH, m, =C_), 6.86 (lH, m, N ), 7.16-7.42 (lOH, m, 2Ph-_); v ~=0 1793cm~l Found: C, 67.8; H, 6.6; N, 6.6%; C24H28N203S requires: C, 67.9; H, 6.7; N, 6.6%
FY~nnrle322 N (S ph~noxypentyl~(4_be.~l~u~finyl2 yl)acetamide White solid, 18% yield, m.p. 132-135 C
lH nmr ~ (CDC13) 1.17-1.54 (6H, m, CH2CH2CH2), 2.94 (lH,dd, J=15.0, 4.75Hz, H3b), 3.25 (2H, m, NH-C_2)~ 2.44 (lH, dd, J=15.0, 2.25Hz7 _3a)~ 3.68-4.16 (6H, m, C_2-OPh, N-CH2, SOC_2Ph), 4.52 (lH, m, H4), 6.74 (lH, m, NH), 6.86-6.95, 7.22-7.35, 7.37-7.40 (3H, 4H, 3H, m, O-Ph-_, SOCH2Ph-H).
FY~mp~e 323 N-(~-ph~no~y~llLyl)-(4-~ ulr~ o~ ;n-l-yl)~e~ ~de Whitesolid,21%yield,m.p. 116-118 C
lH nmr ~ (CDC13) 1.46-1.86 (6H, m, C_2C_2CH2), 2.87 (lH, dd, J=15.5, 2.0Hz, --3a)~ 3.17 (lH, dd, J=15.5, S.OHz, H3b), 3.26-3.39 (2H, m, NH-C_2)~ 3.85-4.29 (6H, m, N-C_2~ C_2-OPh, SOC_2Ph), 4.60 (lH, m, _4), 6.86-6.94,7.22-7.43 (3H, 8H, m, CH2Ph-H, O-Ph- , N_).
Found: C, 64.2; H, 6.4; N, 6.5%; C23H2gN204S requires: C, 64.5; H, 6.6; N, 6.5%
FY~mrle 324 N-(2-(2-Phenoxyethoxy)ethyl)-(4-bt:l~y~ .hinyl 2 o...~,-~1;.l;,- 1-yl)~e~ ~iso~
Colourless solid, m.p. 133-5~C, 40% yield CA 0222;i627 1997-12-23 W O 97/02242 PCT~EP96/0276!;

lH NMR ~ (CDC13) 2.89 (lH, dd, J=S, lS H~, H3), 3.39 (lH, dd, J=2, lS Hz, H3) 3.45 (2H, m, ~NCH2), 3.64 (2H, m,OCH2), 3.80 (2H, m, OCH2), 3.90 (4H, m, NCH2 + SOC_2)~ 4.12 (2H, m, CH20Ph), 4.60 (lH, m, H4), 6.65 (lH, br s, NH), 6.95 (3H,m, Ph-H), 7.3 (7H, m, Ph-H); v ~=0 1789 cm~l S Found: C, 61.1; H, 6.0; N, 6.6%; C22H26N20sS requires: C, 61.4; H, 6.1; N, 6.5%
F -- 'C 325 N~ ..uA~ u~)ethyl)~ hinyl-2-~ idin.l.
yl)acetamide (Diasl~ e~ 2) Colourless solid, m.p. 109-12~C, 47% yield lH NMR o (CDC13) 2.67 (lH, dd, J=2, 15 Hz,_3), 3.06 (lH, dd. J=S. lS Hz, _3) 3.5 (2H, m, NCH2), 3.65 (2H, m,OCH2), 3.82 (2H, m, OC_2)~ 4.0 (6H, m, NCH2 t SOCH2 + CH20Ph), 4.65 (lH, m, H,l), 7.06 (lH, br s, N~, 6.9 (3H, m, Ph-H), 7.3 (7H, m, Ph-H); v ,~0 1790 cm~l Found: C, 61.0; H, 6.0; N, 6.5%; C22H26N20sS requires: C, 61.4; H, 6.1; N, 6.5~Yo FY~n~P'~ 326 N-2-(3-Phel.yl~ loYy)ethyl~ h~yl~ulphinyl-2 yl)acetamide (Dia~.k~ omPr 1) (~olonrl~ solid, m.p. 124-5~C, 27% yield lH NMR ~ (CDC13) 1.90 (2H, m, CH2), 2.68 (2H, t, J=8 Hz, CH2Ar), 2.91 (lH, d,~, J=S, lS Hz, H3), 3.4 (7H, m, NCH2 + H3 + 2 x OCH2), 3.85 - 4.0 (4H, m, SOCH2 +
NCH2), 4.62 (lH, m, H4), 6.61 (lH, br s, NH), 7.15 - 7.45 (lOH, m, 2 x Ph-H); v ~=O
1789 cm~l Found: C, 64.2; H, 6.5; N, 6.6%; C23H2gN204S requires: C, 64.5; H, 6.6; N, 6.5~7FY~mr'e327 N-2-(3-Pht~ v~yloxy)ethyl-(4-l~e~l~y~ lrhinyl-2~ e~ ]I-yl)~et~niAP (Di~l~:.~isoll.er2) Colourless solid, m.p. 82-4~C, 24% yield lH NMR ~ (CDC13) 1.85 ~2H, m, CH2), 2 7 (3H, m, C_2Ar + H3), 3.09 (lH, dd, J=S, lS Hz, H3), 3.45 (6H, m, NC_2 + 2 x OCH2), 3.9 - 4.2 (4H, m, SOCH2 +
NCH2), 4.67 (lH, m, ~4), 6.97 (lH, br s, N_), 7.15 - 7.4 (10H, m, 2 x Ph-_); v c~o 1790 cm~l Found: C, 64.3; H, 6.5; N, 6.6%; C23H2gN204S requires: C, 64.5; H, 6.6; N, 6.5~7FY~mrl-P 328 N-[6-(2-chlorophenyl)he~y~yn~5-yl]~b~ , ~7Pti~ yl ~'el*~ P
Treatment of N-[6-(2-chlorophenyl)hexyn-S-yl]~ben_yl~nlrhinyl-2-oxo-~7Pti-lin-l-yl ~cet~mi~le (diastereoisomer 1) with mCPBA (1 equivalent) in dichlorom.o~h~n~ at room telllper~tL~l~ gave the title compound as a white solid, m.p. 114- 117~C, 86.7% yield;
Found:C, 60.4; H, 5.4; N, 5.8%; C24H2sClN204S requires:C, 60.9; H, 5.3; N, 5.8'~O
The following sulfones (FY~mI-1eS 329-331) were prepared in an analogous way, orwere isolated from the mixture formed when the corresponding sulfides were treated with mCPBA.
F~~ ,IC 329 N t6_(3 ChlOrOPhenYI)heXYn-5-YI]-4b~ 1.OnYI-2-OXo-~7~ti~1;n_l_yl ~et~miA~
White solid, m.p. 122-124~C, 5.6% yield Found: C, 60.7; H, 5.3; N, 6.0%; C24H2sClN203S requires: C, 60.9; H, 5.3; N, 5.9%
FY~nnr1e 330 N-(6-PhenYI-3-heXYnYI)-(4-beI~ nYI-2-~A~ ;r 1-Yl)~t~,n;~

W O 97102242 PCT~EP96/02765 Colourless solid, m.p. 135-136~C, 88% yield lH NMR o (CDCl3) 2.33 (2H, m, CCCH2), 2.47 (2H, m, CCCH2), 2.81 (2H, t, J=7.4Hz, PhCH2), 2.94, 3.00 (lH, dd, J=2.4, 15.3Hz,_3), 3.07. 3.13 (lH, dd, J=5.1, 15.3Hz, _3), 3.30 (2H, m, NHCH2), 3.6g, 3.97 (each lH, d, J=18.9Hz, NCH2), 4.30,S 4.37 (each lH, d, J=14.2Hz, S02C_2)~ 4.89 (lH, m, H1), 5.77 (lH, m, N_), 7.20-7.40 (lOH, m, 2Ph-H); v c=o 1792 cm~l Found: C, 65.4; H, 6.0; N, 6.4%; C24H26N204S requires: C, 65.7; H, 6.0; N, 6.4%
Example331 E-N-(6-phenyl-3 "-YPnyl)-(~ be,.-~yl Irhonyl-2-; e'~
y~ t~ de Colourless solid, m.p. 115-116~C, 39% yield lH NMR ~ (CDC13) 2.17 (2H, m, C=CCH2), 2.35 (2H, m, CCCH2), 2.69 (2H, t, J=7.6Hz, PhC_2)~ 2.94, 3.00 (lH, dd, J=2.4, 15.4Hz,_3), 3.07, 3.13 (lH, dd, J=S.l, 15.4Hz, H3), 3.24 (2H, m, NHC_2)~ 3.74. 3.95 (each lH, d, J=16.9Hz, NC 2)~ 4-30-4.37 (each lH, d, J=14.2Hz, S02C_2)~ 4.87 (lH. m, H4), 5.33 (lH, m, =CH), 5.53 (lH, m, -C_), 5.70 ( lH, m, NH), 7.16-7.44 (lOH. m. 2Ph-H); v ~=0 1794 cm~l Found: C, 65.1; H, 6.3; N, 6.4%; C24H28N204S requires: C, 65.4 H, 6.4; N, 6.4%
Example332 1-(2-(6-Phenylhexyloxy)ethyl-4-Le,~lll io-2~ idine A 60% ~licpPrciQn of sodium hydride in mineral oil (0.30 g, 7.5mmoles) was ~ Pd in dry THF (lS ml) at -10~C under nitrogen and a solution of 4-('~ll~yl~uo)-2-~7Pt~ nonP (1.35g) in THF (10 ml) was added over 10 mins k~epin~ temp <0~C. The was stirred at 0~C for 15 mins, cooled to -10~C and 2-(6-phenylhexyloxy)ethyl triflate(3.54g,) in THF(10 ml) was added over 3 mins keeping temp <0~C. The mixture was stirred at RT for 30mins then poured into brine (50 ml), separated and the aqueous extrAetP~l with ether. The combined organics were dried over MgS04 and evaporated to a red oil. This was purified by ch~ atography on silica gel (40-60petroleum ether/ethyl acetate) to give 1-(2-(6-phenylhexyloxy)ethyl~bel~yllllio-2 oXo~7Ptirlin~ as a colourless oil (1.71g, 62%) lH NMR o (CDC13) 1.3-1.7 (8H, m, 4 x C_2)~ 2.59 (2H, t, J=8 Hz, CH2Ph), 2.88 (lH, dd, J=2, lS Hz, _3), 3.0 (lH, m, NCH2), 3.27 (lH, dd, J=5, 15 Hz, _3), 3.4 (5H, m, NCH2 + C_20CH2), 3.81 (2H, s. SCH2), 4.75 (lH, m, _4), 7.15-7.35 (lOH, m, Ph-H ).
The following F.x~mpl.-s (333-336) were prepared from 4-bell~yllllio-~7Pti-iin-2-one and the corresponding triflate in an analogous manner to FY~mrl~ 332.
FY~mrl~P 333 1-(~(6-(4-Chlorophenyl)hexyloxy)ethyl)~bt~ lU.io-2-~,Y~ ;,,P
Colo~lrl~s oil, 62% yield lH NMR o (CDC13) 1.2- 1.7 (8H, m, 4 x C_2). 2.55 (2H, t, J=8 Hz, CH2Ph), 2.88 (lH, dd, J=2, 15 Hz, H3), 3.0 (lH, m, NCH2), 3.28 (lH, dd, J=5, 15 Hz, H3), 3.4 (5H, m, NCH2 + C_20CH2), 3.81 (2H, s, SCH2), 4.75 (lH, m, H4), 7.07 (2H, m, ClPh-H), 7.35 (7H, m, Ph-H + ClPh-H) F~y~rnple 334. 1-(2-(6-(4-~luo,o,~he~ l)hexyloxy)ethyl) 1 a~ lll.io-~
O~f~~l7el ;AinP
Colourless oil, 22% yield lH NMR o (CDC13) 1.2-1.7 (8H, m, 4 x C_2)~ 2.55 (2H, t, J=8 Hz, C_2Ph). 2.88 (lH, dd, J=2, 15 Hz, H3), 3.05 (lH, m, NC_2)~ 3.27 (lH, dd, J=5, 15 Hz,_3), 3.4 (SH~ m~ NCH2 + CH20CH2), 3-81 (2H, s, SC_ 2)~ 4.75 (IH, m, H4), 6.95, 7.10 (ea~:h 2H, m, Fph-H), 7.25 (SH, m, Ph-_) Example 33~ N-3-(Ph~-uA~ 31)-4b~ 1lluo~ e Yellow oil, 82% yield lH NMR ~i (CDCl3) 2.0 (2H, m, CH2), 2.89 (lH, dd, J=2, 15 Hz, _3), 3.08, 3.41 (each lH, m, NCH2), 3.26 (lH, dd, J=5, lS Hz, H3), 3.78 (2H, s, SCH2), 3.95 (2H,m, CH20Ph), 4.63 (lH, m, _ 4), 6.9 (3H, m, Ph-H), 7.3 (7H, m, Ph-H) F~ C 336 1-(2-Benzyl~ lu~io-azetidin-2-one Colourless oil, 74% yield lH NMR o (CDC13) 2.7 (lH, dd, J=2, 15 Hz, H3), 3.0 (lH, m, NC_ 2)~ 3.26 (lH, dd,J=5, lS Hz, H3), 3.5 (3H, m, NCH2 + CH2C_ 2~)~ 3.76 (2H, m, SC_2Ph), 4.50 (2H, m, OCH2Ph), 4.7 (lH, m, H4), 7.2-7.4 (lOH, m, 2xPh-_).
The following sulfoxides (FY~mr1~ 337-345) were prep~d by treating the corresponding sulfides with mCPBA, as described in FY:ImI)1PS 302 & 303.
Example 337 1-(2-(6-Phenylhexyloxy)ethyl-4be~ line (80% Dia~ o-~-~. 2) Colourless solid, m.p. 47-9~C. 37% yield lH NMR ~; (CDC13) 1.2-1.7 (8H, m, 4 x CH2), 2.6 (3H, m C_2Ph + H3), 2.98 (lH, dd, J=5, lS Hz, H3), 3.3-3.8 (6H, m, NCH2 + CH20CH2), 4.05 (2H, d, J=13 Hz, SCH2), 4.52 (lH, m, _ 4), 7.14-7.4 (lOH, m, Ph-_ ); v ~=0 1776 cm~l Found: C, 69.7; H, 7.4; N, 3.5%; C24H31N03S requires: C, 69.7; H, 7.6; N, 3.4%
FY~nrl~P 338 1-(2-(6-(4-chlorophenyl)he~y-ylo~y~y)ethyl)~4-~ h.~nyl-2 1inP (Dia~,~.~J.
Colourless oil, 27% yield lH NMR ~ (CDC13) 1.2-1.65 (8H, m, 4 x CH2), 2.58 (2H, t, J=8Hz, C_2Ph), 2.87 ~lH, dd, J=S, lS Hz, H3), 3.25 - 3.7 (7H, m, NCH2 + CH20CH2 + H3), 3.84,3.98 (2H, 2 x d, J=13Hz, SOC_2)~ 4.51 (lH, m, H4), 7.09 (2H, m, ClPh-_), 7.3 (7H, m, Ph-_ + ClPh-_); v c=o 1777 cm~l Found: C, 64.1; H, 6.6; N, 3.1%; C24H30CIN03S requires:C, 64.3; H, 6.8; N, 3.1~~7 Example 339 1-(2-(6-(4-Chlorophenyl)hexyloxy)ethyl) 4be,~ 1-2-n~ 7f ~ inP (Diastere~)ico~l~r2) Colourless solid. m.p. 86-8~C, 37% yield lH NMR ~ (CDC13) 1.2-1.7 (8H, m, 4 x C_2)~ 2.55 (3H, m, CH2Ph + _ 3), 2.99 (lH, dd, J=S, lS Hz, H3), 3.3 - 3.8 (6H, m~ NC_2 + CH20CH2), 4.01,4.09 (2H, 2 x d, J=13Hz, SOCH2), 4.52 (lH, m, H4), 7.09 (2H, m, ClPh-H), 7.3 (7H, m, Ph-H + ClPh-H); v 00 1777 cm~l Found: C, 64.2; H, 6.6; N, 3.3%; C24H30ClN03S requires: C, 64.3; H, 6.7; N, 3.1~3~o Example 340 1-(2-(6-(4FluulolJhenyl)hexyloxy)ethyl)-4h~l~L~ ph;nyl-2-~J.~ ine (Diastere--icom~r 1) Colourless oil, 12% yield lH NMR ~i (CDC13) 1.25-1.65 (8H, m, 4 x C_2)~ 2.58 (2H, t, C_2Ph), 2.87 (lH, dd,J=5, lS Hz, H3), 3.25 - 3.7 (7H, m, NC_ 2 + CH20C_2 +_3), 3.84,3.98 (2H, 2 x d, J=13Hz, SOC_2)~ 4.52 (lH, m, H~l), 6.95, 7.10 (each 2H, m, FPh-_), 7.3 (5H, m, Ph-H); v ~=0 1777 cm~l - 6g -W O 97/02242 PCTfEP96/02765 ~:xample 341 1-(2~ (4Fluu .~nyl)hex~lo~y)ethyl)~ ,hinyl 2 A, ~;-7;~r (Di~~ 2) Colourless solid, m.p. 77-8~C. 37% yield lH NMR ~ (CDCl3) 1.25- 1.65 (8H, m, 4 ~c C 2)~ 2.55 (3H, m, CH2Ph + H3), 2.98 S (lH, dd, J=S, lS Hz, H3), 3.4 - 3.75 (6H, m, NC 2 + CH2OC_2)~ 4.02,4.09 (2H, 2 x d, J=13Hz, SOCH2), 4.52 (lH, m, _4), 6.95, 7.10 (each 2H, m, FPh-_), 7.3 (SH, m,Ph- ); v c=o 1777 cm~l Found: C, 66.5; H, 6.9; N, 3.2%; C24H30FNO3S ,eyu~es: C, 66.8; H, 7.0; N, 3.3%
FY~mp~ 342 4-B~l~y~ hinyl-l-(3-phL.~oAy~ one (Di~S~ n~ ~Pr 1) Colourless solid, m.p. 93-97~C
lH nmr ~ (CDC13) 2.05-2.17 (2H, m, CH2C_2CH2), 2.78(1H, dd, J=14.75, 4.75Hz, H3b), 3.34-3.57 (3H, m,_3a~ N-CH2), 3.82, 3.92 (2H, dd, J=13.00, 13.00Hz, SOC_2Ph), 3.95-4.06 (2H, m, C_2-OPh), 4.37 (lHt m,_4), 6.83-6.98 (SH, m, OPh-lS _), 7.19-7.37 (5H, m, CH2Ph-H).
Found: C, 66.5; H, 6.2; N, 4.1%; ClgH21NO3S requires: C, 66.3; H, 6.2; N, 4.4%
F~ 343 4Benzylclllrllinyl-l-(3-rh - y~-ù~ e~ ~one (D - ~isol..e. 2) - Colourless solid, m.p. 62-65~C
lH nmr ~ (CDC13) 2.12-2.19 (2H, m, CH2C_2CH2), 2.47 (lH, dd, J=15.0, 2.25Hz, H3a)~ 2.91 (lH, dd, J=15.0, 5.0Hz, 3b)~ 3.51-3.67 (2H, m, N-C_2)~ 3.95-4.07 (4H,m, C 2~~ SOCH2Ph), 4.42 (lH, m,_4), 6.83-6.97 (5H, m, OPh-H), 7.22-7.39 (5H, m, SOCH2Ph-_).
Found: C, 66,5; H, 6.2; N, 4.1%; ClgH21NO3S requires: C, 66.4; H, 6.3; N, 4.4%
FY~mp~ 344 1-(2-Benzylc~xy~ yl)-4-b~ h;nyl-~7~ -2 one(57%
Diastereoiso...~
Colourless oil, 49% yield lH NMR ~ (CDCl3~ 2.78 (lH, dd, J=S, lS Hz, _3), 3.35 (lH, d, J=13 Hz, _3), 3.
3.8 (4H, m, NC_2C_2)~ 3.95, 4.07 (each lH, d, J=lS Hz, SOCH2), 4.5 (3H, m, OCH2Ph +_4), 7.2-7.4 (lOH, m, Ph-_); v c=o 1777 cm~l F~Y~mrle 345 1-(2-Benzylo~yt:ll.yl)-4-b~.~y~ 7~ti ~ n-2~ne (80%
D~~ . 2) ~olol~rlPcc oil, 26% yield lH NMR ~ (CDCl3) 2.49 (lH, d, J=lS Hz, _3), 2.93 (lH, dd, J=S, lS Hz, _3), 3.4-3.8 (4H, m, NC_2CH2), 3.95, 4.07 (each lH, d; J=13 Hz, SOC_2)~ 4.4-4.6 (3H, m, OCH2Ph + H4), 7.2-7.4 (lOH, m, Ph-_); v ~=0 1777 cm~l Found: C, 66.4; H, 6.2; N, 4.3%; ClgH21NO3S requires: C. 66.5; H, 6.2; N, 4.1%
F.Y~mrl~ 346 4-Methylthio-l-(3-phenoxyl~lu~u~ 7~t~ n-~ûne A solution of 4-methy]thio~7~ti~in-2-one (0.7g, S.g7mmol) in dry THF (lOml) was added dropwise over 10 min~ltes to a s~lcpen.cio l of NaH (0.24g, 6.07mmol) in dry THF (Sml) at -20~C under a N2 at nosphere. A solution of 3-iodo-1-phenox~ p~e (1.56g, 5.97mmol) in dry THF (lOml) was added dropwise over 10 ..~i..u~s at-55~C.
This ~ u,~ was stirred for 18 hours overnight then poured onto ice/water (50g), filtered and partially evaporated. The residue was dtreated with ethyl acetate and the 45 organic layer was washed with brine (x2), dried (MgSO4) and evaporated under reduced pl~Lue tO a yellow oil. The oil was purified by fiach chrom~togr~phy on silica gel to give 4-methylthio-l-(3-phenu~y~ yl)~7Pt~ n-2-one a cclonrlPcs solid (0.64g, 42%), m.p. 41-2~C.
lH NMR ~ (CDC13) 2.04 (3H, s, SC 3), 2.10 (2H, m, CH2), 2.95 (lH, dd, J=2, 15 Hz, H3), 3.25 (2H, m, H3 +NC_2)~ 3.56 (lH, m, NCH2), 4.02 (2H, m, CH2OPh), 4.66 (lH, m, H4), 6.9 (3H, m, Ph-H), 7.3 (2H, m, Ph-F - A ? 347 4Mell.~ "vA~ )~7~ ;n 2-one Tre~tmPnt of 4-methylthio-1-(3-phenoxy~l~yl)~7P,ti~lin-2-one (0.59g,2.34mmol) ~qth mCPBA as in FY~mplP 302 gave 4-Methylclllphinyl-l-(3-phenuAy~ yl)~7~ptitiin-2 one as a waxy white solid (0.39g, 62%).
lH nmr ~ (CDC13) 2.12-2.23 (4H, m, 2xCH2CH2CH2), 2.43(3H, s, SOCH3), 2.5l5 (3H, s, SOCH3), 2.78 (lH, dd, J=15.00, 2.50Hz,_3a)~ 3-07 (lH, dd, J=14.5, 4.75Hz, H3b), 3.24 (lH, dd, J=15.00, 5.25Hz,_3b)~ 3.47-3.71 (5H, m, 2xN-CH2, H3a)~ 4.()5-4.20 (4H, m, 2xCH2O), 4.40 (lH, m, _4), 4.50 (lH, m, H4), 6.8-7.0, 7.2-7.33 (6H,4H, m, 2xAr-_).
Found: C, 58.4; H, 6.4; N, 5.2%; C13H17NO3S requires: C, 58.1; H, 6.5; N, 5.3~7 F.Y~mplr 348 1-(2-(6-(~Fluv.vlJhenyl)heAyloAy)ethyl)-4-(4 ethvAy.srl~v.,yll>e~ o)-2-vx~
A sollltion of 4 (4-(etho,~yc~L,onyl)benzyllhio)~7Pti~1in-2-one (1.85g, 0.00697 moles), 2-(6-(1 Fluorophenyl)hexyloxy)ethyl triflate (2.62g, 0.00704 moles), terabutylammonium bromide (0.22g, 0.00068 moles) in dry tetrahyd.~,ru,dll (40ml), cooled to iooc, was treated with powdered po!~ .Ci~ hydroxide (0.47g, 0.00838 moles). The cooling bath was removed and the reaction was stirred at room for 2 hours, partitioned be~weell brine (70rnl) and ethyl acetate (75ml).
The organic layer was dried (MgSO4) and t;va~ al~d to an oil (3.7g). Purified byflash column chromatography on silica gel eluted with 2:1 P.E. 40-60~C:ethyl acetate to give 1-(2-(6-F-luorophenyl)hexyloxy)ethyl) 1 (4-ethoxy~ lJollylbel~ylll~io)-2-oXo~7Pti~linP as a colourless oil (1.15g, 34%).
1H nmr ~ (CDC13) 1.42 (1 lH, m, CH2x4, CH3), 2.55 (2H, t, J=7.6Hz, CH2Ph), 2.84,2.90 (lH, dd, J=l.9, 15.2Hz, H3), 3.03 (lH, m, 1 of NCH2), 3.26, 3.32 (lH, dd, J= 5, 15.2Hz, H3), 3.40 (5H, m, CH20CH2,1 of NC_2)~ 3.85 (2H, s, C_2S), 4.36 (2H, q, CH2O), 4.75 (lH, m, _4), 6.91-7.11 (4H, m, p-F-Ar-_), 7.39, 8.01 (4H, 2xd, J=8.3Hz, Ar-H) F~ c 349 1-(2-(6-(4-Fluorophenyl)hexyloxy)ethyl)-4(4 ~ x~ u~lbe~,yl~ulphinyl)-2-v~
Tr~tmPnt of 1-(2-(6-fluorophenyl)hexyloxy)ethyl)~(4-etho~y-;~L,onylbenzyl-sulphinyl)-2-oxo~7Pti~linP (1.05g) with mCPBA (0.67g) following the method of FY~mplP 302 gave, after chromatography and re-cryst~lli.c~tior-c, the title colllpou--d as a g6:4 ratio of diastereoicomers 2: 1 as a colourless solid, m.p. 75-75~C, 25% yield lH nmr ~ (CDC13) 1.42 (1 lH, m, CH2x4, C_3), 2.56 (2H, t, J=7.7Hz, CH2Ph), 2.63,2.69 (lH, dd, J=2.2, l5.1Hz, H3), 3.05, 3.10 (lH, dd, J= 5, 15.1Hz,_3), 3.37-3.73 ( 6H, m, CH2OCH2, NCH2), 4.08 (2H, s, C_2SO), 4.36 (2H, q, CH2O), 4.54 (lH~
m, _4), 6.91-7.11 (4H, m, p-F-Ar-H), 7.38, 8.05 (4H, 2xd, J=8.3Hz, Ar-H) W O 97/02242 PCT~EP96/02765 F~y~mple35o 1-(2~(6~(4El~ el,~l)hexyloxy)ethyl~4L~4 1) The recryst~llic~tio~c of FY~mplP 349 also gave the title colll?oul,d as a 68:32 r~t;
of diastereoi.comP-rs as a colollrl~ss solid, m.p. 53-55~C, 12.5%yield lH nmr (diastereoicrmpr 1)~ (CDC13) 1.42 (1 lH, m, C_2x4, C_3), 2.56 (2H, t, J=7.7Hz, C_2Ph), 2.85, 2.90 (lH, dd, J=4.6, 14.6Hz, H3), 3.30-3.7 (7H, m, H3, C_2OCH2, NCH2), 3.93 (2H, m, C_2SO), 4.36 (2H, q, CH2O), 4.53 (lH, m, H4), 6.91-7.11 (4H, m, p-F-Ar-H), 7.33, 8.05 (4H, 2xd, J=8.2Hz, Ar-_) W O 97/02242 PCT~EP96/0276.5 R:ol~,;r~l Data 1. Screen for Lp-PLA2ir~ihi~
Enzyme activity was ~Iç~ d by m~cllring the rate of turnover of the artificial substr~tç (A) at 37 ~C in SOmM HEPES (N-2-hy~ yt:~yll il~.,.i;..~-N'-2 lphonir acid) buffer co.~ g 1~0mM NaCl, pH 7.4.

~ ~ _O(CH2)9CH3 N~2~--~o_ O
--O ~o(cH2)2NMQ3 (A) Assays were ~l~",~ed in 96 well titre plates.
Lp-PLA2 was partially purified by density gra~liPnt centrifugation of human plasma. Active fractions were pooled and used as the source of Lp-PLA2. The enzyme was pre-inc~lb~tP-d at 37 ~C with vehicle or test compound for 10 min in a total volume of 180 ~11. The reaction was then initi~tçd by the a(l~ition of 20 ~Ll lOx s~bstrat~ (A) to give a final snbstr~tP conrçntrati~n of 20 ~IM. The reaction was followed at 40~ nm for 20 mimlt~s using a plate reader with -~lltom~tir mixing. The rate of reaction was measured as the rate of change of abso,l,ance.
20 RPe~
The compounds according to the present invention are found to have IC~;o values in the range 0.7-100.000 nM.

Claims (32)

Claims

1. A compound of formula (I):

in which:
R1 and R2, which may be the same or different, is each selected from hydrogen, halogen or C(1-8)alkyl;
R4 and R5 which may be the same or different is each selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, aryl, aryl(C1-4)alkyl and heteroaryl(C1-4)alkyl eachof which may be optionally substituted or R4 and R5 may be linked together to form the remainder of a (C3-7)cycloalkyl ring;
X is direct bond; a group X1(CH2)m in which X1 is CO, CONR6,COO, CONR6CO, or CONR6O in which R6 is hydrogen or C(1-6)alkyl and m is 0 or an integer from 1 to 12;
a group (X1)aX2 in which a is 0 or 1 and X2 is a C(1-12)alkylene chain interupted and/or terminated at the end adjacent to Y by one or more groups X3 selected from O,S(O)x,NR6, alkene or alkyne, in which x is 0,1 or 2; or a C(1-12)alkylene chain optionally interupted by X1;
Y is an optionally substituted aryl group;
Z is oxygen an R3 is C(1-8)alkyl, C(3-8)cycloalkyl, C(3-8)cycloalkylC(1-6)alkyl, heteroaryl, heteroaryl(C1-4)alkyl, aryl, or aryl(C1-4)alkyl, each of which may be optionally substituted or Z is S(O)n in which n is 0,1 or 2 and R3 is heteroaryl, or heteroaryl(C1-4)alkyl, each of which may be optionally substituted.

2. A compound as claimed in claim 1 in which R4 and R5 is each hydrogen or one is hydrogen and the other is methyl.

3. A compound as claimed in claim 1 or 2 in which Z is oxygen and R3 is optionally substituted aryl; or S(O)n in which n is 0,1 or 2 and R3 is optionally substituted heteroaryl(C1-4)alkyl.

4. A compound as claimed in claim 3 in which Z is oxygen and R3 is optionally substituted phenyl.

5. A compound as claimed in claim 3 in which Z is S(O)n and R3 is optionally substituted heteroarylmethyl.

6. A compound as claimed in claim 5 in which which ZR3 is optionally substitued fur-2-ylmethylsulphinyl.

7. A compound as claimed in claim 6 in which which ZR3 is 5-carboxyfur-2-ylmethylsulphinyl.

8. A compound of formula (I):

in which:
R1 and R2, which may be the same or different, is each selected from hydrogen, halogen or C(1-8)alkyl;
R4 and R5 which may be the same or different is each selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, aryl, aryl(C1-4)alkyl and heteroaryl(C1-4)alkyl eachof which may be optionally substituted or R4 and R5 may be linked together to form the remainder of a (C3-7)cycloalkyl ring, with the proviso that R4 and R5 are not both hydrogen;
X is a direct bond; a group X1(CH2)m as defined in claim 1; a group (X1)aX2 as defined in claim l; or a C(1-12)alkylene chain optionally interupted by X1;
Z is S(O)n in which n is 0,1 or 2 and R3 is C(1-8)alkyl, C(3-8)cycloalkyl, C(3-8)cycloalkylC(1-6)alkyl, aryl or aryl(C1-4)alkyl, each of which may be optionally substituted;
Y is an optionally substituted aryl group;
Z is S(O)n in which n is 0,1 or 2 and R3 is C(1-8)alkyl, C(3-8)cycloalkyl, C(3-8)cycloalkylC(1-6)alkyl, aryl, aryl(C1-4)alkyl, heteroaryl, or heteroaryl(C1-4)alkyl, each of which may be optionally substituted.

9. A compound as claimed in claim 8 in which one of R4 and R5 is hydrogen and the other is methyl.

10. A compound as claimed in any one of the preceding claims in which, when one of one of R4 and R5 is hydrogen and the other is methyl, the absolute configuration at the carbon to which R4 and R5 are attached is S.

11. A compound as claimed in any one of claims 1 to 11 in which X is CONH(CH2)6, CONR6(CH2)4C=C or (CH2)O(CH2)6.

12. A compound of formula (I):

in which:
R1 and R2, which may be the same or different, is each selected from hydrogen, halogen or C(1-8)alkyl;
R4 and R5 is each hydrogen;
X is a group (X1)aX2 as defined in claim 1; or a C(1-12)alkylene chain optionally interupted by X1;
Z is S(O)n in which n is 0,1 or 2 and R3 is C(1-8)alkyl, C(3-8)cycloalkyl, C(3-8)cycloalkylC(1-6)alkyl, aryl or aryl(C1-4)alkyl, each of which may be optionally substituted;
Y is an optionally substituted aryl group;
Z is S(O)n in which n is 0,1 or 2 and R3 is C(1-8)alkyl, C(3-8)cycloalkyl, C(3-8)cycloalkylC(1-6)alkyl, aryl, aryl(C1-4)alkyl, heteroaryl, or heteroaryl(C1-4)alkyl, each of which may be optionally substituted.

13. A compound as claimed in claim 12 in which X is CONR6(CH2)4C=C or (CH2)O(CH2)6.

14. A compound as claimed in any one of claims 8 to 13 in which ZR3 is optionally substituted benzylsulfinyl.

15. A compound as claimed in claim 15 in which ZR3 is 4-carboxybenzylsulfinyl or aC(1-6)alkyl or C(2-6)alkenylester thereof.

16. A compound as claimed in any one of claims 1 to 3 and 5 to 15 in which, when Z is S(O)n, n is 1.

17. A compound as claimed in claim l6 in which the absolute configurations a:
C-4 and the SO moiety are R and S respectively.

18. A compound as claimed in any one of the preceding claims in which Y is benzene ring, optionally substituted by up to three further substituents.

19. A compound as claimed in claim 19 in which Y is phenyl optionally substituted by halo.

20. A compound of formula (I) selected from:
N-[6-(4-chlorophenylhexyl)]-2-[4-benzylthio-2-oxoazetidin-1-yl]propionamide (diastereoisomer b);
N-[6-(4-chlorophenylhexyl)]-2-[4-benzylthio-2-oxoazetidin-1-yl]propionamide (diastereoisomer a);
N-[6-(4-chlorophenylhexyl)]-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]
propionamide (diastereoisomers b1 &b2);
N-[6-(4-chlorophenylhexyl)-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]
propionamide (isomer(-)b2);
N-[6-(4-chlorophenylhexyl)]-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]
propionamide (isomer(+)b2);
N-[6-(4-chlorophenylhexyl)]-2-[4 benzylsulphinyl-2-oxoazetidin-1-yl]
propioramide(isomer(+)b1);
N-[6-(4-chlorophenylhexyl)]-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]
propionamide (isomer(-)b1);
N-[6-(4-chlorophenylhexyl)]-2-[4-benzylsulfinyl-2-oxoazetidin-1-yl]
propionamide (diastereoisomer a1);
N-[6-(4-chlorophenylhexyl)]-2-[4-benzylsulfinyl-2-oxoazetidin-1-yl]
propionamide (diastereoisomer a2);

N-[6-(4-fluorophenylhexyl)]-2-[4-benzylthio-2-oxoazetidin-1-yl]propionamide (diastereoisomer b);
N-[6-(4-fluorophenylhexyl)]-2-[4-benzylthio-2-oxoazetidin-1-yl]propionamide (diastereoisomer a);
N-[6-(4-fluorophenylhexyl)]-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]propionamide (diastereoisomers b1+b2);
N-[6-(4-fluorophenylhexyl)]-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]propionamide (diastereoisomer(-)b2);
N-[6-(4-fluorophenylhexyl)]-2-[4-benzylsulphinyl-2-oxoazetidin-1-y1]propionamide (diastereoisomer (+)b2);
N-[6-(4-fluorophenylhexyl)]-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]propionamide (diastereoisomer a1);
N-[6-(4-fluorophenylhexyl)]-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]propionamide (diastereoisomer a2);
N-[6-(4-fluorophenylhexyl)]-2-[4-benzylsulphonyl-2-oxoazetidin-1-yl]propionamide (diastereoisomer a);
N-[6-(4-Fluorophenylhexyl)]-2-[4-benzylsulphonyl-2-oxoazetidin-1-yl]propionamide (diastereoisomer b);
N-(Benzyl)-2-[4-benzylthio-2-oxoaxetidin-1-yl]propionamide (diastereoisomer a);
N-(Benzyl)-2-[4-benzylthio-2-oxoazetidin-1-yl]propionamide (diastereoisomer b);
N-[6-(4-Fluorophenylhexyl)]-2-[4-(allyloxycarbonylbenzylthio)-2-oxoazetidin-1-yl]propionamide (diastereoisomer a);
(+/-)-N-[6-(4-Fluorophenylhexyl)]-2-[4-(allyloxycarbonyl-benzylthio)-2-oxoazetidin-1-yl]propionamide (diastereoisomer b);
(+/-)-N-[6-(4-Fluorophenylhexyl)]-2-[4-(4-allyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-1-yl]propionamide (diastereoisomers b2+b1);
(+/-)-N-[6-(4-Fluorophenylhexyl)]-2-[4-(4-allyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-1-yl]propionamide (diastereoisomer b2);
(+/-)-N-[6-(4-Fluorophenylhexyl)]-2-[4-(4-allyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-1-yl]propionamide (diastereoisomer b1);
(+/-)-N-[6-(4-fluorophenylhexyl)]-2-[4-(4-(allyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-1-yl]propionamide (diastereoisomer a1);
(+/-)-N-[6-(4-fluorophenylhexyl)]-2-[4-(4-(allyloxycarbonyl)benzylsulphinyl)-2-oxoazetidin-1-yl]propionamide (diastereoisomer a2);
(+/-)-N-[6-(4-fluorophenylhexyl)]-2-[4-(4-(carboxy)benzylsulphinyl)-2-oxoazetidin-1-yl]propionamide (diastereoisomers b2+b1);
(+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylthio)-2-oxoazetidin-1-yl-3-(3-furyl)propionamide (diastereoisomers a and b);
(+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylsulphinyl)-2-oxoazetidin-1-yl-3-(3-furyl)propionamide;

N-[6-(4-Fluorophenyl)hexyl]-2-(4-benylsulphinyl)-2-oxoazetidin-1-yl-3-(3-furyl)propionamide (diastereoisomer a2);
(+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylthio)-2-oxoazetidin-1-yl-3-phenyl)propionamide (diastereoisomer a);
(+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylthio)-2-oxoazetidin 1-yl-3-phenyl)propionamide (diastereoisomer b);
N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylsulphinyl)-2-oxoazetidin-1-yl-3-phenyl)propionamide (diastereoisomer a2);
N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylsulphinyl)-2-oxoazetidin-1-yl-3-phenyl)propionamide (diastereoisomer a1);
(+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylsulphinyl)-2-oxoazetidin-1-yl-3-phenylpropionamide (diastereoisomer b1);
(+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylsulphinyl)-2-oxoazetidin-l-yl-3-phenylpropionamide (diastereoisomer b2);
(+)-N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylsulphinyl)-2-oxoazetidin-1-yl-3-phenylpropionamide (diastereoisomer (+)-b2);
(-)-N-[6-4-Fluorophenyl)hexyl]-2-(4-benzylsulphinyl)-2-oxoazetidin-1-yl-3-phenylpropionamide (diastereoisomer (-)-b2);
(+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylthio)-2-oxoazetidin-1-yl-2-allylacetamide (diastereoisomer a);
(+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylthio)-2-oxoazetidin-1-yl-2-allylacetamide (diastereoisomer b);
(+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylsulphinyl)-2-oxoazetidin-1-yl-2-allylacetamide (diastereoisomers a2+a1);
(+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-(4-benzylsulphinyl)-2-oxoazetidin-1-yl-2-allylacetamide;
(+/-)-N-[6-(4-Fluorophenylhexyl)]-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]
butyramide;
N-[6-(4-Fluorophenyl)hexyl]-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]
butanamide;
(+/-)-N-[6-(4-Fluorophenyl)hexyl]-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]
butanamide (Isomer a1);
(+/-)-N-[6-(4-Fluorophenylhexyl)]-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]
butanamide (isomer b1 and b2);
N-[6-(4-FLuorophenyl)hexyl]-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]
butanamide (isomer a2);
(+/-)-N-[6-(4-Fluorophenylhexyl)]-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]
pentanamide;
(+/-)-N-[6-(4-chlorophenylhexyl)]-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]
propanamide;

N-(Benzyl)-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]propionamide (diastereoisomer b1&b2);
N-(Benzyl)-2-[4-benzylsulphinyl-2-oxoaxetidin-1-yl]propionamide (diastereoisomer a1);
N-(Benzyl)-2-[4-benzylsulphinyl-2-oxoazetidin-1-yl]propionamide (diastereoisomer a2);
(.alpha.-S,4-R,SS)-N-[6-(4-Fluorophenyl)hexyl]-2-[4-carboxybenzylsulphinyl]-2-oxoazetidin-1-ylpropionamide;
(.alpha.-S,4-R,SS)-N-[6-(4-Fluorophenyl)hexyl]-2-[4-allyloxybenzylsulphinyl]-2-oxoazetidin-1-ylpropionamide;
(+/-)-4-(Pyrid-2-ylmethylthio)-1-(4-phenyl-2-oxobutyl)azetidin-2-one;
(+/-)-4-(Pyrid-2-ylmethylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one (diastereomer 1);
(+/-)-4-(Pyrid-2-ylmethylsulphinyl)-1-(4-phenyl-2-oxobutyl)azetidin-2-one (diastereomer 2);
(+/-)-N-(6-Phenylhex-1-yl)-4-(pyrid-4-ylmethylthio)-2-oxoazetidin-1-ylacetamide;
(+/-)-N-(6-Phenylhex-1-yl)-4-(pyrid-4-ylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 1);
(+/-)-N-(6-Phenylhex-1-yl)-4-(pyrid-4-ylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 2);
(+/-)-N-(6-Phenylhex-1-yl)-4-(1-oxopyrid-4-ylmethylsulphonyl)-2-oxoazetidin-1-ylacetamide;
(+/-)-N-(6-Phenylhex-1-yl)-4-(2-furylmethylthio)-2-oxoazetidin-1-ylacetamide;
(+/-)-N-(6-Phenylhex-1-yl)-4-(2-furylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 1);
(+/-)-N-(6-Phenylhex-1-yl)-4-(2-furylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 2);
(+/-)-N-(6-Phenylhex-1-yl)-4-(2-furylmethylsulphonyl)-2-oxoazetidin-1-ylacetamide;
(+/-)-N-(6-[4-Fluorophenyl]hex-1-yl)-4-(2-furylmethylthio)-2-oxoazetidin-1-ylacetamide;
(+/-)-N-(6-[4-Fluorophenyl]hex-1-yl)-4-(2-furylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 1);
(+/-)-N-[6-(4-Fluorophenyl)hexyl-4-(2-furylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 2);
(+/-)-N-(6-[4-Fluorophenyl]hex-1-yl)-4-(2-furylmethylsulphonyl)-2-oxoazetidin-1-ylacetamide;
(+/-)-N-(6-[4-Chlorophenyl]hex-1-yl)-4-(2-furylmethylthio)-2-oxoazetidin-1-ylacetamide;

(+/-)-N-(6-[4-Chlorophenyl]hex-1-yl)-4-(2-furylmetthylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 1);
(+/-)-N-(6-[4-Chlorophenyl]hex-1-yl)-4-(2-furylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 2);
(+/-)-N-(6-[4-Chlorophenyl)hex-1-yl)-4-(2-furylmethylsulphonyl)-2-oxoazetidin-1-ylacetamide;
(+/-)-N-(6-[4-Chlorophenyl]hex-1-yl)-4-(3-furylmethylthio)-2-oxoazetidin-1-ylacetamide;
(+/-)-N-(6-[4-Chlorophenyl]hex-1-yl)-4-(3-furylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 1);
(+/-)-N-(6-[4-Chlorophenyl]hex-1-yl)-4-(3-furylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 2);
(+/-)-N-(6-[4-Chlorophenyl]hex-1-yl)-4-(3-furylmethylsulphonyl)-2-oxoazetidin-1-ylacetamide;
(+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(2-thienylmethylthio)-2-oxoazetidin-1-ylacetamide;
(+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(2-thienylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 1);
(+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(2-thienylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 2);
(+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(2-thienylmethylsulphonyl)-2-oxoazetidin-1-ylacetamide;
(+/-)-N-[6-(4-Chlorophenylhexyl)-4-(3 -thienylmethylthio)-2-oxoazetidin-1-ylacetamide;
(+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(3-thienylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 1);
(+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(3-thienylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 2);
(+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(3-thienylmethylsulphonyl)-2-oxoazetidin-1-ylacetamide;
(+/-)-N-[6-(4-Chlorophenylhexyl)-4-(thiazol-2-ylmethylthio)-2-oxoazetidin-1-yl-acetamide;
(+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(thiazol-2-ylmethylsulphinyl)-2-oxo-acetidin-1-ylacetamide (diastereomer 1);
(+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(thiazol-2-ylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 2);
(+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(5-methoxycarbonyl-2-furylmethylthio)-2-oxoazetidin-1-ylacetamide;
(+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(5-methoxycarbonyl-2-furylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 1);

(+/-)-N-[6-(4-Chlorophenylhexyl)]-4-(5-methoxycarbonyl-2-furylmethylsulphinyl)-2-oxoazetidin-1-ylacetamide (diastereomer 2);
(+/-)-4-(2-furylmethylthio)-1-(9-phenylnonyl)azetidin-2-one;
(+/-)-4-(2-furylmethylsulphinyl)-1-(9-phenylnonyl)azetidin-2-one;
(+/-)-4-(2-furylmethylthio)-1-(9-(4-fluorophenylnonyl)azetidin-2-one;
(+/-)-4-(2-furylmethylsulphinyl)-1-(9-(4-fluorophenyl)nonyl)azetidin-2-one;
(+/-)-4-(2-furylmethylsulphonyl)-l-(9-(4-fluorophenyl)nonyl)azetidin-2-one;
N-[6-(4-Fluorophenyl)hex-1-yl]-4-(5-allyloxycarbonylfuran-2-methylthio)-2-oxoazetidin-1-ylacetamide;
N-[6-(4-Fluorophenyl)hex-1-yl]-4(5-allyloxycarbonylfuran-2-methylsulphinyl)-2-oxoazetidin-1-ylacetamide (Diastereomer 1);
N-[6-(4-Fluorophenyl)hex-1-yl]-4-(5-allyloxycarbonylfuran-2-methylsulphinyl)-2-oxoazetidin-1-ylacetamide(Diastereomer2)N-[6-(4-Fluorophenyl)hex-1-yl]-4-(5-carboxyfuran-2-methylsulphinyl)-2-oxoazetidin-1-ylacetamide (Diastereomer 2)N-(6-{4-Chlorophenyl}hexyl)-4-(5-allyloxycarbonylfuran-2-methylthio-2-oxoazetidin-1-yl)acetamide;
N-(6-{4-Chlorophenyl}hexyl)-4-(5-allyloxycarbonylfuran-2-methylsulphinyl-2-oxoazetidin-1-yl)acetamide (Diastereomer 1);
N-(6-{4-Chlorophenyl}hexyl)-4-{5-allyloxycarbonylfuran-2-methylsulphinyl-2-oxoazetidin-1-yl)acetamide (Diastereomer 2);
N-(6-{4-Chlorophenyl}hexyl)-4-(5-carboxyfuran-2-methylsulphinyl-2-oxoazetidin-1-yl)acetamide (Diastereomer 2);
N-[6-(4-Fluorophenyl)hex-1-yl]-4-{5-methoxycarbonylfuran-2-methylthio)-2-oxoazetidin-1-ylacetamide;
N-[6-(4-Fluorophenyl)hex-1-yl]-4-(5-methoxycarbonylfuran-2-methylsulphinyl)-2-oxoazetidin-1-ylacetamide (Diastereomer 1)N-[6-(4-Fluorophenyl)hex-1-yl)-4-(5-methoxycarbonylfuran-2-methylsulphinyl)-2-oxoazetidin-1-ylacetamide (Diastercomer 2)N-[6-(4-Chlorophenyl)hexyl]-[4-(2-fluorophenoxy 2-oxo azetidin-1 yl)acetamide;
N-(6-(4-Phenyl)hexyl)-(4-(2-methylphenoxy)-2-oxoazetidin-1--yl)acetamide;
N-(6-(4-Phenyl)hexyl)-(4-(2-benzyloxyphenoxy-2-oxoazetidin-1-yl)acetamide;
N-(6-(4-Phenyl)hexyl)-(4-(2-methylthiophenoxy)-2-oxoazetidin-1-yl) acetamide;
N-(6-(4-Phenyl)hexyl)-(4-(4-chlorophenoxy)-2-oxoazetidin-1-yl)acetamide;
(N-(6-(4-Phenyl)hexyl)-4-(4-methoxy-phenoxy)-2-oxoazetidin-1-yl)acetamide;
N-(-(4-Phenyl)hexyl)(-(4-methylthiophenoxy)-2-oxoazetidin-1-yl)acetamide;
N-(6-(4-Chlorophenyl)hexyl)-(4-(4-allyloxycarbonyl-methylphenoxy)-2-oxoazetidin-1-yl)acetamide;
N-(6-(4-Phenyl)hexyl)-(4-phenoxy-2-oxoazetidin-1-yl)acetamide;
N-(6-(4-Phenyl)hexyl)-(4-benzyloxy-2-oxoazetidin-1-yl)acetamide;

N-(6-(4-Phenyl)hexyl)-(4-(4-methysulphinylphenoxy)-2-oxoazetidin-1-yl)acetamide; N-[6-(4-Phenyl)hexyl]-[4-(4-methylsulphonylphenoxy-2-oxo azetidin-1-yl) acetamide;
N-(6-(4-Phenyl)hexyl)-(4-(2-methylsulphinylphenoxy)-2-oxoazetidin-1-yl)acetamide N-(6-(4-Phenyl)hexyl)-(4-(2-methylsulphonylphenoxy)-2-oxoazetidin-1-yl)acetamide; N-(6-(4-Phenyl)hexyl)-(4(2-hydroxyphenoxy)-2-oxoazetidin-1-yl)acetamide, N-[6-(4-chlorophenyl)hexyl]-[4-(4-carboxymethylphenoxy)-2-oxo-axeridin-1-yl]-acetamide;
N-(6-(4-Phenyl)hexyl)-(3-methyl-4-phenoxy-2-oxoazetidin-1-yl) acetamide;
4-Benzyloxy-1-(4-phenyl-2-oxo-butyl)-azetidin-2-one;
4-Phenoxy-1-(4-phenyl-2-oxo-butyl)-azetidin-2-one;
N-[6-(naphth-1-yl)-5-hexyn-1-yl]-4-benzylthio-2-oxoazetidin-1-yl acetamide;
N-[6-(Naphth-1-yl)-5-hexyn-1-yl]-4-benzylsulphinyl-2-oxoazetidin-1-yl acetamide (diastereoisomer 1);
N-[6-(Naphth-1-yl)-5-hexyn-1-yl]-4-benzylsulphinyl-2-oxoazetidin-1-yl acetamide (diastereoisomer 2);
N-[6-(3-Chlorophenyl)hexyn-5-yl]-(4-benzylthio-2-oxo-azetidin-1-yl)acetamide;
N-[6-(2-Chlorophenyljhexyn-5-yl]-4-benzylthio-2-oxo-acetidin-1yl acetamide;
N-(6-Phenyl-3-hexynyl)-(4-benzylthio-2-oxozetidin-1-yl)acetamide;
Z-N-(6-phenyl-3-hexenyl)-(4-benzylthio-2-oxoazetidin-1-yl)acetamide;
E-N-(6-phenyl-3-hexenyl)-(4-benzylthio-2-oxoazetidin-1-yl]acetamide;
N-(5-Phenoxypentyl)-4-benzylthio-2-oxoazetidin-1-ylacetamide;
N-(2-(2-Phenoxyethoxy)ethyl)-4-benzylthio-2-oxoazetidin-1-ylacetamide;
N-(2-(3-Phenylpropyloxy)ethyl)-4-benzylthio-2-oxoazetidin-1-ylacetamide;
N-[6-(3-Chlorophenyl)hexyn-5-yl]-4-benzylsulphinyl-2-oxo-azetidin-1-yl acetamide;
N-[6-(3-Chlorophenyl)hexyn-5-yl]-4-benzylsulphinyl-2-oxo-azetidin-1-yl acetamide;
N-[6-(2-Chlorophenyl)hexyn-5-yl]-4-benzylsulpbinyl-2-oxo-azetidin-1-yl acetamide;
N-[6-(2-Chlorophenyl)hexyn-5-yl]-4-benzylsulphinyl-2-oxo-acetidin-1-yl acetamide;
N-(6-Phenyl-3-hexynyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide (diastereoisomer 1);
N-(6-Phenyl-3-hexynyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide (diastereoisomer 2);
Z-N-(6-Phenyl-3-hexenyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide (diastereoisomer 1);

Z-N-(6-phenyl-3-hexenyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide (diastereoisomer 2);
E-N-(6-Phenyl-3-hexenyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide (diastereoisomer 1);
E-N-(6-phenyl-3-hexenyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide (diastereoisomer 2);
N-(5-phenoxypentyl)-(4-benzylsulfinyl-2-oxoazetidin-1-yl)acetamide;
N-(5-phenoxypentyl)-(4-benzylsulfinyl-2-oxoazetidin-1-yl)acetamide;
N-(2-(2-Phenoxyethoxy)ethyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide (Diastereoisomer 1);
N-(2-(2-Phenoxyethoxy)ethyl)-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide (Diastereoisomer 2);
N-2-(3-Phenylpropyloxy)ethyl-(4-benzylsulphinyl-2-oxoazetidin-1-yl)acetamide (Diastereoisomer 1);
N-2-(3-Phenylpropyloxy)ethyl-(4-benzylsuphinyl-2-oxoazetidin-1-yl)acetamide (Diastereoisomer 2);
N-[6-(2-Chlorophenyl)hexyn-5-yl]-4-benzylsulphonyl-2-oxo-azetidin-1-yl acetamide;
N-[6-(3-Chlorophenyl)hexyn-5-yl]-4-benzylsulphonyl-2-oxo-azetidin-1-yl acetamide;
N-(6-Phenyl-3-hexynyl)-(4-benzylsulphonyl-2-oxoazetidin-1-yl)acetamide;
E-N-(6-phenyl-3-hexenyl)-(4-benzylsulphonyl-2-oxoacetidin-1-yl)acetamide;
1-(2-(6-Phenylhexyloxy)ethyl-4-benzylthio-2-oxoazetidine;
1-(2-(6-(4-Chlorophenyl)hexyloxy)ethyl)-4-benzylthio-2-oxoazetidine;
1-(2-(6-(4-Fluorophenyl)hexyloxy)ethyl)-4-benzylthio-2-oxoazetidine;
N-3-(Phenoxypropyl)-4-benzylthio-2-oxoazetidine; 1-(2-Benzyloxyethy])-4-benzylthio-azetidin-2-one;
1-(2-(6-Phenylhexyloxy)ethyl-4-benzylsulphinyl-2-oxoazetidine (Diastereoisomer 2);
1-(2-(6-(4-Chlorophenyl)hexyloxy)ethyl)-4-benzylsulphiny1-2-oxoazetidine (Diastereoisomer 1);
1-(2-(6-(4-Chlorophenyl)hexyloxy)ethyl)-4-benzylsulphinyl-2-oxoazetidine (Diastereoisomer 2);
1-(2-(6-(4-Fluorophenyl)hexyloxy)ethyl)-4-benzylsulphinyl-2-oxoazetidine (Diastereoisomer 1);
1-(2-(6-(4-Fluorophenyl)hexyloxy)ethyl)-4-benzylsulphinyl-2-oxoazetidine (Diastereoisomer 2);
4-Benzylsulphinyl-1-(3-phenoxypropyl)azetidin-2-one (Diastereoisomer 1);
4-Benzylsulphinyl-1-(3-phenoxypropyl)azetidin-2-one (Diastereoisomer 2);
1-(2-Benzyloxyethyl)-4-benzylsulphinyl-azetidin-2-one (Diastereoisomer 1);

1-(2-Benzyloxyethyl)-4-benzylsulphinyl-azetidin-2-one (Diastereoisomer 2);
4-Methylthio-1-(3-phenoxypropyl)azeridin-2-one;
4-Methylsulphinyl-1-(3-phenoxypropyl)azetidin-2-one;
1-(2-(6-(4-Fluorophenyl)hexyloxy)ethyl)-4-(4-ethoxycarbonylbenzylthio)-2-oxoazetidine;
1-(2-(6-(4-Fluorophenyl)hexyloxy)ethyl)-4-(4-ethoxycarbonylbenzylsulphinyl)-2-oxoazetidine (Diastereoisomer 1); and 1-(2-(6-(4-Fluorophenyl)hexyloxy)ethyl)-4-(4-ethoxycarbonylbenzylsulphinyl)-2-oxoazetidine (Diastereoisomer 2).

21. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1,8 or 12 and a pharmaceutically acceptable carrier.

22. A compound of formula (I) as defined in claim 1,8 or 12 for use in therapy.

23. The use of a compound of formula (I) as defined in claim l,8 or 12 in the manufacture of a medicament for treating atherosclerosis.

24. The use of a compound of formula (I) as defined in claim l,8 or 12 in the manufacture of a medicament for treating diabetes, hypertension, angina pectoris, after ischaemia, reperfusion, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury, sepsis, and acute and chronic inflammation, inflammatory conditions of the brain such as Alzheimer's Disease, neuropsychiatric disorders such as schizophrenia, and psoriasis.

25. A method of treating a disease state associated with activity of the enzyme Lp - PLA2 which method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor of the enzyme.

26. A method as claimed in claim 25 in which the disease state is associated with the increased involvement of monocytes, macrophages or lymphocytes.

27. A method as claimed in claim 25 in which the disease state is associated with the formation of Iysophosphatidylcholine and oxidised free fatty acids.

28. A method as claimed in claim 25 in which the disease state is associated with lipid peroxidation in conjunction with Lp PLA2 activity.

29. A method as claimed in claim 25 in which the disease state is associated with endothelial dysfunction.

30. A compound of formula (I) as defined in claim 1, 8 or 12 in combination witha further therapeutically active agent selected from an anti-byperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-anginal, anti-inflammatory or anti-hypertension.
agents for use in therapy.

31. A process for preparing a compound of formula (I) as defined in claim 1, 8 or 12 which process comprises:
(A) treating an azetidone of formula (II):

in which:
n, R1, R2 and R3 are as hereinbefore defined;
with an alkylating agent of the formula (III):

L1Cr4R5XY
in which Z is a suitable leaving group such as halogen;
one of R4 and R5 is hydrogen; and X and Y are as hereinbefore defined;
in the presence of a suitable base such as sodium hydride or potassium hydroxide, a suitable alkylating solvent such as tetrahydrofuran (THF), and at a temperature in the range -10 to 0°C;

(B) treating a compound of formula (VIII):

in which R1, R2, R3, R4 and R5 are as hereinbefore defined;
with an alkylating agent of the formula (IX);

in which R3 and Z are as hereinbefore defined;
under suitable alkylating conditions, at a temperature in the region 25°C;
(C) when X denotes a group CONR6(CH2)m, CONR6X2, CONR6O(CH2)m or CONR6OX2, treating an acid of the formula (IV):

in which:
Z, R1, R2, R3, R4 and R5 are as hereinbefore defined;
with an amine of the formula (V):

or a hydroxylamine of the formula (VI):

in which X5 is (CH2)m or X2 and m, R6, Y and X2 are as hereinbefore defined, in the presence of an activating agent such as ethyl chloroformate or dicyclohexylcarbodiimide (DCC), in a suitable solvent such as chloroform or dimethyl formamide, at a temperature in the range -10 to 20°C;

(D) when X denotes a group COO(CH2)m or COOX2, effecting a transesterification reaction with the methyl ester of formula (VII):

in which:
Z, R1, R2, R3, R4 and R5 are R5 hereinbefore defined;
using conditions well known in the art for such reactions, for instance heating in toluene in the presence of a catalytic amount of sodium methoxide and an alcohol.

(E) when X denotes a group COO(CH2)m or COOX2, treating a compound of formula (IV) with an alcohol YX5OH or an activated derivative thereof, for instance a tosylate; and (F) when the linker group X contains an ether function, treating a compound of formula (VIII):

in which Z, R1, R2, R3, R4, R5 and X2 are as hereinbefore defined;
with a compound of formula (IX):

in which:

one of L2 and L3 is a halogen or other suitable leaving group such as triflate or tosylate and the other is OH or a suitable salt therof, and p and q are as hereinbefore defined;
under standard ether forming conditions.

32. A compound of formula (I) substantially as herein before described in any one of Examples t to 350.