CA2114007C - Substituted beta-lactam compounds useful as hypocholesterolemic agents and processes for the preparation thereof - Google Patents

Abstract

Novel compounds of formula (I) wherein A is -CH = CH-B; -C .ident. C-B; -(CH2)p-X-B, wherein p is 0-2 and X is a bond, -NH- or -S(O)0-2-; optionally substituted heteroaryl or benzofused heteroaryl;
-C(O)-B; or (Ia), wherein k is 1-2; D is B'-(CH2)m C(O)-, wherein m is 1-5; B'-(CH2)q-, wherein q is 2-6; B'-(CH2)e-Z-(CH2)r-, wherein Z is -O-, -C(O)-, phenylene, -NR8- or -S(O)0-2-, e is 0-5 and r is 1-5, provided that the sum of e and r is 1-6; B'-(alkenylene)-; B'-(alkadienylene)-;
B'-(CH2)t-Z-(alkenylene), wherein t is 0-3, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2-6; B'-(CH2)f-V-(CH2)g-, wherein V is cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
B'-(CH2)t-V-(alkenylene) or B'-(alkenylene)-V-(CH2)t-, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2-6; B'-(CH2)a-Z-(CH2)b-V-(CH2)d-, wherein a, b and d are 0-6, provided that the sum of a, b and d is 0-6; T-(CH2)s-, wherein T is cycloalkyl and s is 1-6; naphthylmethyl or optionally substituted heteroarylmethyl; B is optionally substituted phenyl; B' is naphthyl, optionally substituted heteroaryl or optionally substituted phenyl; R is hydrogen, fluoro, alkyl, alkenyl, alkynyl, or B-(CH2)h-, wherein h is 0-3; R4 is optionally substituted phenyl, indanyl, benzofuranyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl or quinolyl; are disclosed, as well as their use as hypocholesterolemic agents; the method of using compounds of formula (II), wherein R20 is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heteroaryl, or optionally substituted benzofused heteroaryl, R21, R22 and R23 are independently selected from H or R20; E, F and G are independently a bond; cycloalkylene;
alkylene; alkenylene; alkynylene; a substituted alkylene, alkenylene or alkynylene chain; an interrupted alkylene, alkenylene or alkynylene chain; or an interrupted alkylene, alkenylene or alkynylene chain substituted by one or more substituents; or one of R21-E and R22-F is selected from the group consisting of halogeno, OH, alkoxy, -OC(O)R5, -NR10R11, -SH or -S(alkyl); R5 is alkyl, phenyl, R14-phenyl, benzyl or R14-benzyl; R10 and R11 are independently selected from H and lower alkyl, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier as hypocholesterolemic agents is also disclosed.

Description

Wf.~ 93t02~48 PG'I'/~1~9~10597Z
3'~.~:~~~
,_ s 1 ~ 'i"he p~'a~snt inv~ntion relates to substituted ~-lactarrts us~fui as hypochefastarol~mic agents in the treatment and prevention of ath~r~sciarosis end td procasssas for preparing ~-iactams.

Atharosciarotic coronary heart diseb~~ represents the major cau~a for depth and cardiov~scuiar morbidity in the v~restarn 1 ~ ,~~rid: Risk factory far ath~rosclerotic coronary heart disease include -hypertension; diabetes rnaliitus, family history, male sex, cigar~tt~

smoking and ~anam ch~i~st~rol. A total choldstar~i level in excess of - 225p~~~ mg/dl is ass~c~ated with signit:rcant. elevation of risk.

~h~i~st~ryl esters are a major compon~nt of 2p dth~ro~cier~tic iesi~hs and the major storage f~rm of chot~estaroi in . ~da~iai grail cdiis> Forrr'ation of choiast~ryi esters i~ also a key st~p in the intas~tiriat abs~rpti~n of dietary cholas~aroi. "i'ha intracellular astar~fication of ~cholastergl is catalysed by the an~yma acyi .. ~~~a~hot~~~eroi acyi transferasa (~A~AT; ~~ 2.3~1.26~. 'Thus,.
inhibition 2~ df AC~1 i~ likely t~ inhibit th~ progression of atharosciarotic lesion .. f~~ati~n; de~raas~ ~h~ accumulation of dhol~steryi asters in the arterial ~aii; and buck the intestinal absorption of dietary cholesterol.

~ fad ~lactam compounds havb bean reported as being useful in i~vuadng cholesterol and/or in inhibiting the formation of ~~ ch~last~roi-~ntaining lasio~s ih mammalianvarteriai ~aiis.
l~.S.

~;g33 ~g~ disdio~~s t~-sulfonyi-2-azatidindrtas as anticholast~roiamic , ager~fis and i~am, at ai., in ~~~~ae'n.. ~e~t: t3. ~ ~~~,12 ~'i g9~D~, p.

1134-~', disclose ~thy! 4-~2-~xoa~at~dirt-4-yi~ph~nc~~y-atkanoatas as hypolipidamic agae~ts. ~caropaan Ratan~ P'ubiipati~n ~~4,~31 discloses S~~ '3°~°T~i ~, ..19~5~2048 PC.T/~1~921~DS972 ;' 1-substituted-4-phenyl-3-(~-oxoalkylidene)-2-azetidinones as blood platelet aggregation inhibitors.
~1 ~t~An~~RY ~F THE INVEfaf~i~N
Novel hypocholest~rolemic compounds of the present invention are represented by the f~rmula i wherein i a A is -Ctrl=CH-~;
:CSC-~p ~~CH~)p-?C-B, wherein p is 0, 1 or 2 and X is a bond, -~lb~-~r _~~~)0-2-1 hbteroaryi, benzofus~d fleteroaryi, Vll-substituted heteroaryi or VII-~~bstituted benzof~~ed heteroaryl, ~nrf~erein heteroaryi is seteed from ~~e gr~up c~nsisting of pyrrolyt, pyridinyi, pyrimidinyi, pyrazinyl, friazinyt, imidazolyi; thiaz~lyi; PYrazblyl, thi~nyi, ~xa~oiyi and furanyi, and for nitrogen~containing heteroaryis, the f~-oxid~s thereof, and wherein ily is 1~:3 substitudnt~ ors the ring Garb~n atoms selected from the group ~0 cos~~isting of lower alkyl, hydroxy lower alkyl; lowbr aikoxy, aikoxyalkyi, atko~yaikoxy, aikoxyc~rbonylatkoxy, dower aikoxy-irnind)lower alkyl, tc~wec atkanedi~yi; i~uver alkyl lower alk~tttedioylailyipxy, -Ct=a, -~CF~, ben~yt, ~~~ bbn~i; b~r~~ytoxy, IRaa-ben~yloxy; phertt~~cy; R~~-Phenoxy, diox~iar~yi, t~C)2, rNRjOF~~i. ~1~~~~9~Ciower aik~l)-, ~R~pRl~~i~v~er ~~ aikoxy) , ~H, halogen~, -t~NC ~)~Fi~, -Nt'°0BC , -.
~ s~~~)~~-, a~C~)~~~x9 °~~~)0-2~~0, t~~-~'utyidin~athy~silytoxyrnethyl, C~°Ig~' f ~~13 -C{~)~.~~ a,rrd , and vuh~rasn the substituents on the substTtutbd heteroaryi ring nitrogen at~rns, m~h~n pr~sant, art aetect~l from the group consisting of tower alkyl, lower aikoxy, °C~~)~~5, ;..' _.: .;'.., ,.., .~.° , ~~~~,_. ,y~ ~~ ~ , ~,.. a.. ~- ' . : : .' J'!,s, , ~.;' . ,... . .. ;: . j ,, - ,. ,.. ..... ;. . .:~ ..~.: . . . ......
W~ 93/~20s88 - PG'I'/US92/~059°72 a~~.~~v~
~(~3)Rs, OH, ~IR~ pR1 i Gower alkyl)-, 1VR~ pR~ ~ (lower aikoxy)-, -S(O)~NH~
and 2-(trimethylsiiyi)ethoxymethyl; .
-C(O)-B; or -(Ct~ 2)k~ ~ X13 - ...
wherein k is 1 or ~;
D is B'-(~ti2)m~(O)-s wherein m is 'I , 2, 3, 4 or 5;
Be-(~R2)~-, wherein ~ is 2, 3; 4, 5 dr 6;
B'-(~i"i2)~-Z-(~R2~~-, wherein Z is -~-~ -~~~)-9 phenyiene, r~~~~ ~r -B(~~~~°, ~ is 0,1, 2, 3, 4 or 5 and r is 1, 2, 3; 4 or 5, provided that the gum of a and r is 1, ~, 3, 4, 5 or 6;
B'-(~~-Gs aiicenylene)-; B'-(C~-~s ~Ikadi~nylen~a)-B°-~C~~)t°~-~~~-~s alkenylene)~; ~rhbr~ir~ Z is as defined ....
above, end vuh~reih t is 0,1, 2 or 3, provided that the suns ~f t and the nurr~t~er ~rf carbon att~rtts in the alkenyiene chain is ~, B, ~, 5 ar 6;
~'-(~H~)t-V-(~1H2)g-, wherein V is-C3-Ge oycioalkyi~n~, f is ~ 5 1 ~ 2, 3, 4 or 5 end g is 01 y 2~, 3, 4 or 5, provided that the sum of f end g is t ,, 1~1 ~ or~) B'-(~H2)t-~'°(~~-~6 aikenyfen~e)- tar B'-(~2-!~s aik~nyiene)_ -~~R~)ta~ w~~rein V and t aye as dbfined above; provided that the sum of t and the number of oarbon ator~ns in the ~tkenylene chain is 2, 3, 4., 5'.
~..ol; ~, ~'-(~~2~a-~°~~H~~b°~°~~~z)d°e i~h~~'~i~1 ~ and ~/
ark as d~fined above and a ;b end d are independently d; ~ , 2, B, 4, ~ br 6, providbd.that the seam ~f a, b arid d ls~ 0, ~, 2, 3;: ~, ~ pr ~;
T-(~H2)~-, wherein °T is cyol~aikyi of 3-6 o~rbon atoms and 25 sis't2;3~;5orFa; ~r nap~thylrrtethyi, het~r~arylme~hyi, ~r ~V-substituted heteroaryimethyf; wherein heteroary6 and UU are ~s defined above;
B is .
~8 , BO B' is n~phthyl, heteroaryi or ~V-substituted heter~aryi, wherein hetaroaryi is a~ defined above, or e~~ 9~lO~Oa~ 3P('T/US92/~972 'o R i~ hydrogen, fluoro, Ci-C~~ alkyl, Ct-C15 alkenyl, C1°C15 alkynyl, or ~-(CH2)~ -, wherein h is 0,1, 2, or 3;
R~ , ~~ and F~3 are independently selected from the group ~ d~n~i~ting of f~°t, lo~or alkyl, hydroxy lower alkyl, lower alkoxy, aikoxyalkyf, elk~xyalkoxy, elk~xycarbonylaikoxy, (Bower alkoxyimino)-cower alkyl, lower alicanedioyl, lower alkyl lower alkanedioyl, aliyloxy, AC~~, -CCF3, benzyl, Rj~:benzyl, benzyloxy; R~4-benzyloxy, phenoxy, ~~~-ph~noxy, dioxdlanyi, 1VC?~, -N~~aR1l. N~~o~l9(iower alkyl)-, ~IR~pR~~(low~r aikoxy)-; CH, o-haiogen~, m-halogeno, -B~HC(C))~R5, a~HG(C~~~, ~sc~~SNI~-° ~~s~zs)~~-, °~(C)~~~~. -S(~)o-~~~o, t~rt-C~r2 ~~~3 and butyidimefhyl~iiy6~xyn,ethyi; -C(~)1~9~.
"' C~ ~D ~93 ~r R~ is hydrogen and R2 and F33, together with adjacgn:
carbon atoms to which they are attached, ~~rm a dioxsalanyl ring;
~ 5 t~l °~ ~2" ~d ~~' are independently ~~tected from the group eonsi~ting of H, I~wer a4kyi, hydroxy 1~wdr alkyl; lower alkoxy, ~tkox~aikyl; elk~xyalko~cy, alkoxycarbonylaikoxy; (lower alkoxyimino,-I~wer ~lkyi; iow~r aikanedi~yl, lower alkyl ~ik~nedsoyt, allyloxy, -C~~, ~~C~~; ben~yi, Rig-benzyl; benzyloxy; Rid-behxyloxy, phenoxy, R~
phcnoxy, dioxolar~yl, l~C~, ~NFt'p~~l, l~~tpRtl(hwer alkyl)-, 1~~~~R' f(1~wer alko~y)-; O~, halogeno; -l~~lC(~}~t~~, -~tC(~)R~a ~s~~~NH-, (R~CzS)~~-. -~(~)2~~2. -~(~)o-~~~os tart-butyldimethyl-R93 " ~°.. ~ X93 ~iiyloxym~thyi, ~~(~)R12, and . or F~i~ is hydrpgen and R~e arid R3°, together with adjacent carbon atoms to which 2~ they are atta~phed; form a dioxotanyi rang;

~V~ 93!~2~4~ p~'IIJS~21i35972 -Fis , wherein n is 0,1, 2 or 3, indanyl, .
benzofurenyl, benzodioxolyl, tetrahydronaphthyl, pYridyl, pyrazinYl, pyrimidinyl or quinolyt;
~s is lo~rer alkyl, phenyl, ~~~-phenyl, benzyl or Ft~~-benzyl;
Rs is ~H, lower alkyl, phenyl, benzyl, R~~-phenyl or ~~~-benzyl;
_H, is lower alkyl, lower aikoxy, OH, h~log~no, ~NRtQR~I, -~IHC(~)C~RS, -~1H~~~)R5, N~~, -~N, -hls, -SH, -S(a)o-2-(lovrrer aikyl)~
~~~~~Ig, -~C~hIF~iQRy 1. -~~~12~ Ph~noxy, ber~Yloxy, -~~~~, or t~rt-butyldirnethylsilytoxy, end where n is 2 or 3, th~ Ry groups can b~ th8 1 ~ same or different;
Hs is H, lower alkyl, phenyl lo~rer alkyl, or -~(Q)~i9;
H~ is H~ lower alkyl, phenyl or phenyl lower alkyl;
Rip and X11 are independently ~~lected from H and lower alkyl, 1 ~ Ftt2 is H~H, ~IkoxY, phenoxy; benzylbxy, , -IVFii~R~19 ~o~rer alkyl, phehyl or R~~-pher~ylm R'3 is -O-, -MHz-, -~IH- or -IV(lo~rer ~Ikyl)-; and ~9~ is ~I°3 9r~u~ps independently selected from the group ~on~isting of lower alkyl, lower alkoxy, -~OCJH, N~~, -~lR~ p~t~ ~, C?H or ~~ halogeno;
b~' a pharrnaceuticaliy accep~abfe salt thereof.
preferred aye caornpounds ~f formula l wherein R is H.
pn~ther gr~u~ of preferred compounds ~f formula 9 is that wh~rein I3 is ~~ ~rsc~H~)~~s, ~~-(~~~9~-~°(~Hz)r-~ ~'-(C2°Gs alk~nylene)-, ~r ~'-(~i'I2)t-'~-(~~z)g°, wherein B', ~, V; q, e, r; fp arid ~ are as defined abov~s ~ third' group of preferred compo~~ds bf formula I is that wherein l~ is phenyl, ~9-substituted phenyl or ~nd~nyl. Sti91 another group of pretprr~d compounds of formula I is that wherein A is -~CH~ )p-X-~, w~~rein ?C, ~ and p are as defined abave:
~speciailY preferred are c~mpou~ads of fiorrnula I wherein ~
is: B'~(~H~)q-, wherein ~' is phenyl and q Is.3 or 4; Et'-(~H~)~°~-(~H~)r , ~7)~

a...:.:.. '.. , . : ~~.1' , ...::.. . ';', ; . ~.~, . ~'., . :.~~. . ..,.,'. .
., ' ~~:~. . . ~ ~;.'. ., ,.';', , ' .:. ~ ,:' f ' ~.~.:. ~..:., , ,,,,.:.. ~.
. , ~ , -, .: ,..':.
::::: '.a:.: .~::- ,..~ '... "~'~':y , :.:'.: . ...;'..,a; . ~.~.. ,.~,;::...
.,...
~_ "~ ~~/~~~~ P~.TlL~S92/OS972 wherein R° is p-fluorophenyl or p-methoxyphenyl, a is zero, Z is -~-, and r is 2; R°-(C~-Cs aBkenyler~e)- is 3-phenyl-1-propenyl; or ~°-(CH~)~-V_ (CH2)~-, wherein ~' is phenyl, f is 1, V is cyclopropylene, and g is zero.
Also especially preferred are compounds of formula 1 wherein P~ is -(CHI )p-X-~ wherein p is zero and X is a bond. Preferably R~, R2 and Rs are selected from H, OH, -NO~, lower alkoxy, alkoxyalk~xy, lower alkyl lower alkandioyl; m-hatogeno, NR'pR~~(iower alkoxy)-, allylo~cy, phpnoxy, atkoxycarbonylalkoxy and -C(O)R~2. Compounds wherein R~
and R~ are each H and R2 is in the pare-position are more preferred.
R~ is preferably selected from lower alkyl, tower alkoxy, halogeno, -C'?CF3; lower alkylthi~, -NRIpRI~; -CN, OH, and -COFt~2.
tvlore preferred are compopnds wherein n is 1 and R~ is in the pare-position.
especially preferred compounds of formula i, wherein R is hydrogen, are shown in the following Table .~
C A ~
C6Hs°(~H~)s- p-CHsO-CsH4- -p~CR30~CsH~_ . ~s~5-CCH2)~- p-CH3~-CsH~- p-CHsO-CsH~_ CgHS-(CH2)~' p-CHgO-CgH4- C6H5-~sHs-(CH~)s- p-OH-CsH~- p-C~fsO-CsH4-C~H~_~GH~)~- p~CH3~-CsH~- p-Ct-CsH~_ C~H~-(~H~)~- p-CHsCH2-O°CsH~- p-CHI~-CsH~-Cs~IS-(CH~~3- P-~H~~-'Cs~~- ~-~HSC~a~o-cs-p-F-CsH~-Q-(CH2)2- p-CHsO-CsH~- p-CH30-CsH4-C~las-(CH2)~- p-CH30-CsH~- p-F-CsH~_ GsH~-(CH~)s- p~CHsO-CsH,~- m-CHs~-CsH~_ CsH~-(CH~)~~ p-CH~O-CsHa- p-CFsO-CsH~_ -CHI-CsH~-CsH~-(CH~)3- p-CH30-CsH~- p CsHs_C~2-CHvCH- p-CH~O-Cs~~° P°CHs~-CsH~
GsH~-(CH~)s- p-(CH3(CH2)3)-~-CsH~- p-CH~O-CsH~
_CH~S_C6H4_ CsH~-(CH2)s- P-~HsO-CsH4- P
~~H~-(~H~)3° P-tCH~C~t-CH2-O~-C6id~- p°CH3O-C~H4-CsH~-(C~9~)s- P-(CsHs-O)'CsN~~ p-CH~O-CsH~_ . . . :... :. . .. : ..:::
."r,. ,:...~.. , ~ ";.., .. .:;~.:,,' .-:,.~: . .....:. ~ . ~ :~.~... ...,:.;;
...:. .. . :~.::~. . ,.e..... w.:a, ....:-: ...~.-.... .: ;~:..,. . . . .. . .
~~ 93/02~8~ P~'I°/~3592/(159'?2 C~H~-(CH2)~° p-CH,~~-CsH~_ ~s~~-(~~2)s° p-(GH~~~2CH2-O)-Cst~~- p-CH3~-~~1~~_ CsH~-(CH2)5° P°~H~~°CsH4° p-CNJ~~°C~H~_ C~~~_(~;~2)~° p-CH30-C~H~- p°((C~~CH~)~N)°
C6~4_ C~H~a(CH~)~° p°(C~3C~-12O)-C~H,~- CsH~~ .
~~HZ.~ p_CH~~_C~H~_ p_CH~~_C~~,~_ ~~~ ,~H~° Cy~'°' cH-CsHS"(~M2)~° p-((CM3)2CH°'C)"C6H~° p°~H~C3-CShB~_ .. .. P°F-~sH4°~-~CH~)z°
P°~~°'~3~°~6H~' . C~HS_ _ C6~g~~(CH~)s- P-C~sQ-Cs~~° ~t ~ ~ o ~6~5-(c~2)~' ~ P'(~H3~'2~)°~6~4' ~,~~5_ C6~~°~C~2)3° p°t'H~~'CgH~' 1 ~6H~P(CI-~2)~° ! ~ ~C~~ p°C~-l~C;~-C~H~°
~~~p C~~fi~~(CH~)~° P°CM3C°CsHa~ p~cN~ccca~~°cs~~_ C~HS-(~H2)3- 0 ~ OCH3 p°CH3C~-CsH,~°
Cfi~S"~~~2)s' p-(CH3C~CH2C~~'~6H~° C6H~_ H~o-C~~~.-o-~C~~12- p~CH~~_C6H~,- C~~~°
C~H~_~CH~)~r p-(CH3CH2~~(~)Ci~~~)- P~CI~,~C)-Cs~l~_ C~H~-C~N~-(C&i2)~° p-(CN30C(~)-(CH~)2- p°CH~C)-Cshi4_.
~(~~_~'_~&~~_ C~~~-(C~z)3° P°((C~3)~~-(~H~)s°~)- p-C~1~~°C~~B~_ ~s~a°
C~~~-(C~2)3° P°~iC?°C~H~- p-~i~-CsH~-( ~- p-CH3~°C6~i~- CsE'1~°

r , .i: , s S.. ...4, r1" :'.': ...., ... m i .' ,. , ~ , ., .." . . ~' . ~ , ~.~, . , .,:.:. .
~'.;. . . .: . 'v. . : ~' , . ~ . .:',.. .. ~ : :~., .., ..
t?.SS..: s..,:. .,. -.,~.,~.....: . ... .:.....: ,.,.. ~;.~.. ; :.~ ..
.~.:...~,. .,, , ..:- ; r~.: '.':: 1 ::.~,. . .,;~:.: ~. .. ..~.,: ,.. ~~.~ .
,. ... ., ~.:. ,...
~~°r/vs9z<os9a~
~- ~ 93/02~~
_g_ The first-listed compound in the above table having the (~I~~~~~ absolute °
st~reochemistry is rr~ore preferred.
This invention also relates to the use of a novs! compound of formula I of the present invention as a hypocholesterolemic agent in a mammal in ns~d of such trsatmer~t.
In another aspect, the invention relates to a pharmaceutical composition connprisin~ a novel ~-lactam of formula t of the present invention in a pharmaceutically acceptable carrier.
In still another aspect, the present invention relates to a ~ pharmaceutical c~mposition comprising a cholesterol-lo~rsring eff~ctiv~
amount ef a compound having the structural formula 11 t ~~aa~
~~ o R~ l1 v~herein Rip i~ phenyl, l~l-substituted phenyl, naphth~l, VV-1 ~ substituted naphthyi, benzodioxoiyl, heteroaryl, VV-substitute heteroaryi; bent~fusec~ hsteroaryl and ~l-substituted b~nzofussd hstsro~ryl; v~hsrgirt hst~roary! is sei~c~ted from the group consisting of pyrrblyl, pyridinyi; pyrirnidinyl, pyrazinyl, triiny6, imidazoiyl, thiazoiyl, pyca~~lyi, thesnyB, o~xez~ly! and turany~, and for nitrogen-containing ~0 heterd~ryis, the ~t-oxides there~f;
~~9 ~ ~~ and ~~3 are independently selected froc~n H or Rya:
lllf is 1 to ~ substituents independently selected frog the group consisting oaf i~wer alkyl, hydr~xy lo~rer ~tkyi, lower alkoxy, 25 ~Iko~ralkyl; aikoxya~koxy, alkoxyrcarbonyialkoxy, (lower alk~xyirr~in~i-lower alkyl, lowed alkbnedioyl, lower alkyl lower alkanedioyl, ~ilyloxy, -~~~. -~~~~, b~r~yl, R~~ bsnzyl, bsnzyi~xy,1~~~-ben~ylo~yy, phenoxy, ~'~~ pheno~y9 ~aoxolanyl, I~t~~, '~~~Q~,~9 ~~~~~~~(to~~r ~lkyl~-, N~~p~.~.~(lo~rer aikoxy)-, ~1~, halogeno, -iVl-i~(~ C~R~, -N~~(~~~5a w~ 9~roz~as Pc~rru~9zr~~~~z -R6o~Sl~H-, (l~so~s)2~-, -S(~)z~H2, -s(~)o-zRio, lark-butytdimethyt-r'~ r-~ .

~~a N ~m - ~~- N R~3 w ~
~

and ;
sityl~xyr~aethyt, -C(o)~i12, . E, F and ~ are independently a bond; ~3-C6 cyctoalkytene; C1-C10 alkylene; C1-C10 aikenytene; G1-C10 atkynyien~; an alkylene, alkenylene or aikynytene chain as defiined substituted by one or more substituents independently selected fr~m the group consisting of phenyl; yll-substituted phenyl, heteroaryt and V1I-substituted hetaroaryl, wherein heteroaryt is as defined above; an atkylen~, alkenytene or alkynylene chain as defined interrupted by one 0 or more groups ihdepend~ntty selected fr~m the group consisting of -o-, -S-, -~~-, -~C3~-, ~~B~s, -C(o)-, C3-Cs cycloa(kylene, phenylene,1~'-..

~ubstitufed phenylerve, heteroarylene and 1!~-substituted heteroaryiene;

~r an interrupted atkytene; alkenylene br atkynylene chain as defiined s~abstitut~d by one or more substituents independently selected from the g~~up c~r~~isting ofi phenyt, ~Vsubstituted phenyl, heteroaryt and iiV-~ubstituted hetbr~aryt; ~r ~ne of R~$-E and Ft~-~ is selected from the group consisting ~fi hatogeno, OH, tower atk~xy, -~C~o)Rs, -tVFi~pRl~, -SH Or -S(Iower alkyl);

~~ ;s louver alkyl, phenyl, F31~-Phenyl, benzyt or 1~~~-benzyt;

p ~~ is 4Htbwer alkyl, ph~nyt; benzyt, Rya-phenyl or R1a-bart~yi; v ~~ i~ ~; lower alkyl, phenyl t~er alkyl pr -C(o)Rea ~e is H; lower alkyl, phenyl or phenyl i~wer btkyt;

. ~~ and 'Ft~ ~ are ind~penden8ty selected from H and tower .25 a9k~t;

~ X13 Ft~2 is i~, ~M, atkoxy, phenoxy, benzytoxy, ~' , -I~RtpR~l; t~v~er alkyl; phenyl or Fi~q.-phe~yi; ._ ..

~~~ is ~-~ -Cfi-i2-, -~t~!- or -tV~to~ver alkyl)-;

y Rig is i-3 groups independently ~et~~ed~ firom th~ group.

~0 consisting ~fi lower ~ikyt, tov~er alko~y, -COO~i, hlC~~, NF~~pi~~', off or halt~gano;

i~"~'m 93/02i~1~ ~G'~'/1U~92/05972 -1~~
provided that when G is a bond, R~3 is not H, and provided ' that when E~~~ is W-substituted phenyl, VII is not p-halogeno~ .
or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.
It is noted that nova( compounds of formula I are included within the sc~pe of formula It.
preferred compounds of formula It are those wherein Rz~ is ~ and ~ is a bond or lower alky~ene, end those rwherein F%~1 is phenyl ~ and ~ is tower alkylene. Also preferred are compounds pf formula It ,herein R~ is ~6 and, F is a bond. Another group of preferred compounds of formula It is that wherein G is a bond and I~~ is phenyl ubstituted by O~I; -~IG~, lo~rer alkoxy, alkoxyatkpxy, m-hatogeno, tower alkyl lower alkandi~yl, NR~ pf3y 1 dower alk~xy)-, allyidxy, phenoxy, ,t ~ atkoxyc~rbonylalko~cy; and -C~~)R~2. Stilt another group of preferred .
comp~unds of forput~ tt ~s that wherein Rip is phenyl or phenyl substituted by fo~nre~ alkyl; l~wer alkoxy, haiogeno, -~GFs; lower alkytthio; -~IR~aRi~: -G~, ~H or acetyl.
C~~air~ compounds not within the scope of formula t but ~0 ' within he scope of formula ll are novel compounds. Examples of such 'fhe present invention also relates to tie method of tovuering serum cholesterol in a mamma( in need of such treatment ~Y~ 93/02448 ~ PL°y'/CI892105972 comprising administering a pharmaceutical composition comprising a compound of formula ii in a pharmaceutically acceptable carrier.
The present tpvention also relates to the use of a compound of formula I or II as an ACAT inhibitor.
The present inventi~n also relates to a stereosetective process for producing (i-lactams of formula i, wher~in F~ is hydr~g~n ,and and A have tans relative stereochemistry, from a hydroxyamtde of the formdia ..
~~
o wherdsn ~, A and ~~ a~r~ a~ defined above, by cyciizing the hydroxyarr~ide, and wherein th~ ~ydroxyamide is prepared from a carboxylic acid ~~C9H2C~O~t, an aldehyde A-CNC~ arid an amine R4~IH2, ~ 5 wherein ~, A and R~ ire as defined above, in a process utilizing as a chifat auxiliary an Oxa~~lidinone of the formula ~ ~ C.
~ ~ C:~
R'~$ BVh.t ~18 1~9i'i ~$8~'is° i°'i ~~8's~a s ~ '. ~ r ~1~ ~~g i~~~ X99 v~herein Ris and f~l~ are independee~tiy ei~cted from the group ~' consisting of: hydrogen; ~~-Ce alkyl, p9~enyi~, naphthyt, s~abstitufied ph~r~yl, substittated naphthyl, and benzyt, wherein said chirat auxiliary is preferably ~~(f)-4-beh~yi-oxazotidinone.
°fhis pr~cessr designated Method I~, for producing .. ~~~b~~ds of form~ia ~, wh~r~i.n ~ is hydrogdn, and i3 and A have tans ~5 r~tative stereoch~~s~try; bomprises th~ ~tepS:
(a~ reactsn~ a carboxylic acid of the formula ~-~~2~p~~, wherein ~ is as defined' above, with a ...
chlorinating agents 'tvn 93f02048 12_ PGTf1J~92f~D59'32 (b) deprotonating a chiral oxazolidinone, as described ' above, preferably !~-(+)-4-benzyloxazolidinone, with a strong base or a tertiary amine base and treating the resulting anion with the product of ' step (a);
(c) enolizing the product of step (b) with eitherv (i) a dialkylboron triflate and a tertiary amine base;
or (ii) ~'i~h and tetramethylethylenediamine (1'~1~~A) or ~ mixture of °TI~IEL~A and tri~thyiarrtlnap then c~ndensing with an aldehyde caf the formula A-CHI, wherein ~4 is as de~r~ed above;
(d) hydrolyzing the product of step (c) with a base and hydrogen per~xide;
_. (e) cohdensing the product ~~ step (d) with an amine of ~ 5 the fomnula E~~N~~x, whdrein Ft~ is as defined above, by treating with a dehydr~tier~ doup$ing agent; optionally adding an activating agent;
- (f) cyclizirig the product of step (e) by reacting the product of step (e) with:
Vii) a dialkyiazodicarboxylata and a ~ trialkylphosphine; or (ii) a di- or tri-chlor~benzoyl chloride, an aqueous sblutibn of a base and a phase transfer catalyst, th~n treating the resultsng di- or $ri-chlorob~nzoate kith bn aqueaus s~luti~n of ~ base and a phase 25 transfer datalyst; or (iii) a dialkylchlorophosphate, an aqueous solution of a base and a phase transfer catalyst; or (iv) a di- or tri-chlor~benzoyi chloride and a metal hydride.
~p In ~noth~r embodiment, the process of this invention provides the steps of pr~ducing a ~i-lact~m ~f formula I, wherein ~ is hydrogen, and ~ end ~ have traps relative stereochemistry, fr~rr~ a ~°
arninoamide derivative ~f the formula w~ 93r~2~s ~crms~zr~sg°rz - ~ '~ -..
m ~~ ~ HM,~
.
by cy~lizing the ~-aminoamide; wherein the ~-aminoamide~is prepared frorh a carboxyiid ~~id t~irt~i~C~~H, and an imina ACH=~J-R~, wherein ~ D, A and R4 are a~ defined above, in a process utilising as a chirat auxiliary ~n ~xa~~lidino~e of the formula (~ ~ ~ ~ ~
RIB $~91~'1' Rye iilt°i ~~8,m 6~it~f R'~p~r' ~Bi-f or 4 ~rher~in R1~ and R~9 ire as defined above, and wherein said chiral ~~axiliary is preferably t°t-(+j-4-benzyl-ox~olidinone.
i'his pr~cess, designated ~~thbd F, for pr~ducing compounds of formula l, wherein R is hydrogbn; and ~ and A have trans _ relative stereoch~rnist~y; comprises the sups:
15 (a) e~ofizing the product ~f tUieth~d ~, step (b) v~rith ~~I~ end tetramethyiethyfengdiamine ~'t~~~A)9 h~n condensing with an ~~reine of the formula ~°C~1=i~-R~, wherein A and are as defrned ab~~~';
fib) ' ~ycii~ing the produi~t ~f step Via} by treating with a st~c~~g non-nucleopholic base, preferably sodium bistrim~thylsiiylarnid~. .
~ y .~,~~I~~i:
~~ used herein, the terns "i~~ver aticyi" rn~ans straight car e~~~cn~d ~i~ys ~nai~s ~$ ~ t~ s curb~~ ~t~~,s ~r~~ ~i~w~r ~t~y~xyp ~5 ~imiia~i~ r~~e~ t~ ~i~~xy gr~~ps na~ar~~ ~ t~ syc~rb~n atoms.
~pAik~nyi" means straight or bran~~ed ri~on chains having one or more d~uble bonds in the dhain; conjugated or unco~jugated, '~~ "~ 93/02048 p~'/~JS92/059?2 2:~~t~~i'~
and alkadienyl refers to chains having two double bonds in the chain.
Similarly, '"alkynyl" means straight or branched carbon chains having s one or more triple bonds in the chain.
111Jhere an alkyl, alkenyl or all<ynyl chain joins two other variables and is therefore bivalent, by~ terms alkylene, alkenyiene and alkynylene are used.
'~Cycloalkyl" means a saturated carbon ring ofi 3 to fi carbon atbms, while "cycloalkylsne" refers to a corresponding bivalen$ ring, wherein the paints of attachment to other groups include all positional is~tn~rs.
~~~~logeno" refers to fluorine, chlorine, bromine or iodine radicals.
"HBtcroaryl" includes all positional isomers for a given heteroaryl group as defined above, for example 2-PYridYl, 3-pyridyl and . 15 4-py~idyl. ~enzofusad tieteroaryi refers to radicals formed by the bonding of a benzene radical to adjacent carbon atoms on a heteroary!
ring; examples are i~doiyl, quinplyl, quinaxolinyl, quinoxaiinyl, benzotriaz~lyl, ic~~lazolyt, b~nz~xazolyl, benzbthienyl and Benz~furanyl.
"phanylene" tate~ps a bivalent phenyl group, including 2~ ortho, mete and pare-substitution and '°heteroarylene~ ~imifarlY
means a bivbi~~at het~roaryl gr~up, concluding ill positibr~al isomers.
"(L~wer aikoxyirr~inojlowe~ alkyl" refers to the group (~1°~s l~wer alk~xy~-1V.=~~!-(C1-~~ lower clkyl): '"Lower alkanedioyf° rn~ans :radicals of he formula -~~(~j(~~~y~-~~(~j~H, while "lower alkyl low~r 25 alkar~~droyl" means radicals of the fc~rrraula -~C(Q)(~il~~~.~~(~)~-(lower alkyl,.
~.~~-benzyi and t~i~-benzyioxy refer to benzyl and benzyloxy radicals which are substituted on the phenyl ring.
"T~r~iary amine base" means a tri~Bicylarnine, such as ~0 triefihyiarnine ~r d~ic~propylethyian~ines or a n~trogcn ccantaining .
heterocy~le, such a~ pyridine.
"~ase~ jeans a mete! hydr~xida bade such as iithiur~, sodium or p~tassium hydroxide ~.d , S ,... .':. .., "... ,~.,:',... ,. . _ , .'... .,- ., , :. ~. r.:.' . .
.;~;'y. . ..:;:.':. ~.~,'.., : ~ ~.; : ._.:' :::'.~ .., '.~.:,: .. ,,... . : , Pl~r, ~ , ~ '.' ,.~ . .:. :;, ..',".' ... ,~. : . ",,. :. :. ...:;:.,. ,:. ; .
. . . . .~.. . :': ' ;". , ,.':.,,; . ..~.
~fva. 4,:~~:~".', ',:'..~ ,.... :.,..~: ~:.,...., ,_,. . .,~; . .,~. , . . , .." ... .,~.' . ...,.. .. ".. . , ,. .;:..... . ;.
rwc~ ~~/ozo~s p~rivs~z~os~'z ' .. "Strong base" means a non-aqueous base such as a metal hydride or an alkyllithium.

"Metal hydride" means a commercially available metal hydride such as lithium, sodium or potassium hydrid~

"~ikyllithium" means a alkyllithium reagent such as n-butyl-lithium, s-butyllithium, t-butyllithium or methyllithium.

""~ehydrative coupling agent" means a carbodiimide such a~ 'l~(3'-dim~thylamirtopropyl)-3-ethylcarbodiimide hydrochloride (D~~G) d icyclohexylcarbodiimide (~CG). . ..
or 1 ~D "Activating agent"'means an agent used to facilitate the formati~n of amide bonds s~rch as 1-hydroxybanzotriazole (~t~JS~) or ~N-hydrdxysuccinimide.

'I-laude salt" means a metal salt of a halogen such as sodium, lithium or Qotaasium bromide.

~ ~ The carbon chains as defined in ~, F, and ~, when substituted by ~ptibnally subststuted phenyl or heteroaryl gri~ups, may irtolude independent substitution on different carbon atoms, di substitutibn on one carbon atom, or both. C)ne skilled in the art will recbgniz~ that the number of double or triple b~nds present, the 2o replacement of carbon atoms in the chain and the presence of substitutents ors ~ha carbon moms in the char are all dependent on the length bf the chain: shorter carbon chairs cannot accommodate as ' marry double or triple bonds, carbon replacements or substitu~nts as Ibager carbon chains fan. In general, u~sat~arated carbon chains ~5 main I t~'4 double gar triple b~nds, cpnjugated yr non-conjugated.

there carbon atoms are replaced, ! t~ 4 rapf~dament groups can be .

.... present. Similarly, when carbon atoms in the chain are substituted, 1 to ~ substituents can ba present.

. ~~amples of alkyl chains are methyl, ethyl, propyl, butyl ~~ and decyl, ~xar~nples of unsaturated ~~ F and C~ groups era ethylanv and acetylene: ._..

Examples of ~, ~ and groups v~rherein the carbon atoms ~n' the. chain are replaced ar~ '~'I'-I~~'1-IQ , - II'Z II2-, '~.~~~-a W(~ 93/020~~ PGT/US92/~i597~

°CF~I~Ct-l~~t-I°Z~-, -Ct-~2"~'~t-12°, -CH2Ct-I2_Q°CI-i2, -Ct-I°~C 2° ..' _ -CI~~C~i2-N(Cl-l3)- and -Q-CH2C(C)~Nt-I-.
Compounds of the invention have at least one asymmetrical carbon atom and therefore all isomers, including diastereomers and rotational isomers are contemplated as being part of this invention. The invention includes d and t isomers in both pure form and in admixture, including racemic mixtures. isomers can be prepared using conventional techniques, either by reacting enantiomeric starting materials or by separating isomers of a compound of formula 1 or 11.
f 0 - Isomers may include geometric isomers, e.g. when I~, F or G contains a double bond. Alt such isbmers are c~ntemplated for this invention.
Thane slotted in the art will appreciate that for some compounds of f~rmulae l and 11, one isomer will show greater pharrr~acoiogical activity than another isomer.
Compounds o~ the invention with an amino group can form phamn~ceutic~lly acceptable salty with organic and inorganic acids.
~xamptes of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric; acetic, citric, oxalic, malonic, salicyt'sc,' vatic, fumaric, ~0 ~ucuir~ic, ascorbic, r~~teic, me~hanesulf~nic and other minerat~and carb~xytic acids welt known to those in the art. The gait is prepared by c~ntacting the free base fbrm with a sufficient amount of the desired acid to produce a salt. The free base f~rrn rhay be regenerated by treating tho salt with a suitabto dilute aqueous base sc~lutior~ such as dilute ~b ague~us a~dium bicarbonate. The free base form differs from its respective salt form somctnrf~at in certain physical p~pperties, such as solubility in polar solvents, but the salt is oti~es~rise equivalent to its re~p~ctiva free taase forms for purposes of the invention.
Certain compounds of the inventioh are acidic ~e.g., those ~0 compounds which p~s~ess a carboxyl group). "These compounds f~rrr~
pharmaceutically acceptable salts with inorganic and organic bases.
Examples bf such salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyallcylamines, N-methylglucamine and the like.
Compounds of formulae 1 and Il can be prepared by several known methods, and in particular compounds having traps stereochemistry can be prepared by a novel method D, as disclosed in U. S. Patents 5,306,81'l; 5,561,277; and 6,093,812 or novel method F.
' A R D . 4.,, ~ ,, ~A
R
+ ~ I
N
~ ~R15 O ~~
IV V Ia ~A
.~
D I
N~
O Ra Ib Compounds of formula la and Ib, wherein A, D, R and R4 are as defined above, can be prepared by treatment of an ester of formula V, wherein R~5 is lower alkyl such as ethyl or a chiral moiety such as menthyl or 10-(diisopropylsulfonamido)-isobornyl, with a strong base such as lithium diisopropylamide in a suitable solvent such as tetrahydrofuran (THF) at -78°C. Hexamethylphosphoric triamide (HMPA) may optionally be added as a cosolvent. An imine of formula IV is added and the reaction mixture is warmed to room temperature and the product isolated using conventional purification techniques. When a chiral ester of formula V is used, the resulting compound of formula la or Ib is not racemic.

i~"'' 93/~204~ P~'/US92/0~37~
_18_ ~:
A
°°, base ~ ati~ng agcI a o~ a~cylating agent Ic (lt~l"lf) ~ ~
~~' base ~ Ib ~ alkylating agent ~ ~~ ~ ar acylating agent (R ~ ~) Id (R=I~) Compounds of formula is dr td can be converted to compounds of b formula la or ib by treatment with a strong base such as lithium ~tiisoprop~larr~i~i~ in a suitabi~ solvent such as :T~l~ in the presence or absence of H~F'A at ~78~C; followed by the addition of an aikylati~g agent ~-~1~, dr an acylatir~g agent such as Fi-C(~)~-alley! or ~~~(~)~i, wherein ~ is as defisted above, except that R is not hydrogen, and R~? is a iaavin~ grouQ such a~ bromo or iodo.
~.4~.;
?'rar~s compounds of for~muta ld can be converted tb the corresponding cis compounds of formula lc by~ using Method ~; above; but using a proton source such as aCetiC acrd in place of the alkylating agent.
~ ~.
°frans cor~pourids of formula id, wherein R is hydrogen and A, D and t are as defined above ban be prepared by traatir~g cis compounds of ~ormuta Ic with a. str~ng base uch as lithium ~tiisopropyBamid~ ~r pot~~s~um °t-but~xide sn a suitable soi~rent arch as THE'. 'th~se skilled in the art en~~ll aepreciet~ that since the reabtion cordite~ns of Method ~ can b~ sirrdiidr to tt~tas~ gf 6lAethod A, th~ conversion ~f cis t~ traps sornetimas occurs in situ under th~ conditions of Method A. .

~~ 9~'~zo4s ~ ~~-a~o~~~zio~~~z _;9~.~:1'~
- chlorinating agent ia~ ~~i~1 ~'~ ~~~i Step ~9 3t!!!~ ~lV
Ph 1) . strong base or tertiary amine base '' P1H
~ z ) ~~ COCI ~
~~ ?C~i ~CIW ~'V!
Step ph ~ ._. ~H
~-~~
?LV!! ~
~!!
(allcyl)Z1~S43~F3.
tertiary amine base; Q
or ~'.\/!!!
'~iGl4, TN~D~A (or °t'N1EDA ~-S~~p C)3 triethylamine ..
~2~z1 4 ~~
,!!! ' base Step D~4 X!X
~2 ~ ~
xlx ~ ~n~~
c~uplin~ ~~~t~t . .
acti~~ting ~ge~at Step ~5 ~~°~ ~~r~a~s PG'1'/t3~~~f~59~2 co ~ca~o3 ~- ~.~,.
diadl~ylazodicarboxylate; or J
t _ .a (ii) di- or tri-chlorobcnzoyl ~ ~ ~a chloridc, aqueous base, phase transfer rcagcnt; or (iii dialkylchlorophosphatc, aqueous base. phase transfer reagent; or (ivy di- or tri-cholorobenzoyl step ~6 chloride + all~ali metal hydride In step ~l of tUiethod ~, the carboxylic acid XI11 is treated ~rith a cht~rinating agent, e.g., thionyl chloride or oxatyl ch1~ride, under ~ ~ d~ atmosphere, neat or in a suitable inert organic s~Ivent, e.g., totuerie, at ?0°C t~ pr~duce comp~und XIV.
_ In step D2; pompound ~I i~ converted to compound ~!1 in ~ fro step reaction, fret by deprbtonating rwi~h a strong base, such as an alkylii~hium, e.g., n-butyllithium; or tn~tal hydride, e:g., sodium hydride, ~ p or a tertiary amine base; such triethytamine, an a suitable anhydrous organic solvent, e:g:; dry THE, under a dry; inert atmosphere, e.g., nitragen; of about 0°C to about -~5°C, preferably abbot -78°~, over a Pariod df about 30 t~ ab~~st 90 minutes; preferably about fi0 minutes, and second by reacting the resulting ~r~ion, ~~thout isolation; with 1 ~ cor~pourid XIV in ~: suitable anhydr~us ~rganic ~~Ivent, e.g., dry ~'H~, under ~ dry, inert a~sn~~phere, e.g., rt~trog~r~; at abput -50°~ to about ~~~~; prefardbfy about-~8°G, over a p~ribd of ~b~ut 30 to about FO
minutes, preferably about ~~ minutes; foltov~~d by continbed reaction at about -10°~ to ab~~at 10°~; preferably'ab~~ut 0°~, for a period of about 2~ 30 t~ about 90 ~i~utes, preferably about 60 minutes, then isolating the product, compound Wit, by extractioh.
lr~ step ~~, compound ~C~ll is rested ~rith a dialkylboron triflat~, e.g., din-bo~tylboron~riflate (~u~~S~3C~o~y in a suitable inert .
organic sol~rent, e.g: CHZCt~, under a dcy; mart atmosphere, ~.g., ~~ nitr~~en, at about -~~°~ to about ~ 0°~; preferably about -10°~ tp about p°~, for a period ~f about 10 minutas. I~ tertiary amine base, e.g., diisopropylethytaminb, is added at about -10°~ to about 0°C, preferably WD 93102Q4~ PC.'I'l~lSg2/0~~'72 -21-?~~~~'~
about -6C to about-3C, for about 20 to about 40 minutes; prafarabiy about 30 minutes. Tha mixture is stirred at about -50C t~ about -85C,.

pref~rably about -78C, for about 20 to about ~0 minutes, preferably about 30 minutes, than treated ~rith compound XViI, at about -50~ to about -85C, pr~farab6y about -78G, for about 20 to about ~0 rninutas, pr~farabty about 30 minutes. The mixture is stirred at about -10C to abau~ 5C; pr~ferabl~r about 0C for about 30 to about 90 rninutas;

preferably about 60 minutes, than quenched vuith an aqueous pH 7 buffer solution, e.g., ~n aqubous solution of iCN~P~~ and iVa~~d, and ~ ...

traatbd with matharaot, end hydrogen peroxide; pr~farably 30d hy~r~gen psroxlde; at about -5C to about 5~Gr pr~fer~bly about 0G, for about 1 hour. Th~ product is isolated by extraction and crystallized from a suit~bl~ solvent; ~.g.; haxanalathyl acetat~, to obtain compound ~CVlli.

Aftamativaly, stop D3 compreses treating compound XVi 'I S with titanlur~ tgtrdchlorida (TiCI,~~; in a sul~~bla inert organic oivant, a.g.

~ttzCl~, at about -60C to about 0C, preferably about -~5C to about -i r~C' dnd most p~dforobly at about -20G; for a peri~d of about ml~tutes. ~'~tramothylothyienediamine (T~itEDi~~ ~r ~ cb~'~tbirtatl~n of T~~GA and triatl~ylamine is added slovsoly ~ver d pa~iod of about 10 ~0 s; srtrhile main~ainir~g the temperature at about about -25G
~ to ...
,~inut about -10~. The mixtur~ is. stirred at about -2aC to about -1 ~C, pr~farably ab~ut -1~G to about ~l0G; for .a period ~f 3p to 90 minutes, preferably about fi0 minutes, than traatod ~rith a ppmpound of the fbrmula ~Vl~: ~ Tha rnixi~r~ is stirred at about =~5~ tp about -10G, 25 preferably about -~ 6C to about -10C; for a peri~d of 30 to 9~ nnirautas, preferably about 6a minbtes; then stirred for 30 td 6~ minutes;
pr~~~r~bly bout 4.0 minutes; while warming to about QC to about t 0C, preferably about 9 dC: The .mixture is quenched with an aqueous solution of ta~~~c-~cpd; pra~ordbty a solution of ab~ut '10% tartaric acid sn v~ratar. .

~4 Tha product is than isolated by extracti~n v~ith a: suitable solvent, a.g.

ath~r( acatat~; 2nd recrystallized frbm. a suitabi~ ~olva~nt;
such as athyi a~'t~tatelhaxan~f tb obtain c~mpound iiid . .

in step D4; compound XVt~i i~ troatad with hydrogen peroxide, praferablyv30% hydrogen pproxido, in d ihadC organio solvent, ~d'° 93/0z0~8 P~L~"7C/LJ~~~Jd159~2 e.g., T~FI water, at about -5°C to about 5°C, preferably about 0°G, fior about 10 t~ about 2a minutes, preferably about 9 5 minutes, then treated with ~ base, e.g:, lithium hydroxide, at about -5°C to about 5°C, preferably about 0°C, until no starting material remains, as determined by thin lay$r chromatography (TLG), in about 2 hours to about 4 hours, preferably about 3 hours. Th~ excess peracid is reduced by slowly adding a solution ~f podium sulfite in water to the mixture over a period of about 30 to about 90 minutes, preferably about 70 minutes. The bulk of the s~Ivent is removed under vacuum and the residue dihated vtith 10~ water. Compound 1V is repovered fram the mixture by extraction ~nrith a suitable inert organic solvent, e.g., toluene. The remaining aqueous solution is acidif~~d tb a pl~i of about 2.0 to about ~.0, preferably pH of abotat ~.4, using hydrochloric acid. The pr~duct is isolated by extraction using a ~uitabt~ inert organic solvent, e.g., ethyl acetate, to provide 1 ~ cot~~bund %I%~
1n step t~5, c~mp~und %1% is reacted with compound %%, a d~hydrative coupling agent, e:g., dicyclohexylcarbodiimide (~GC), and an activating agent, ~.g., 1-hydroxybenzotriazole t~iG~T), in a suitable inert organic sotvent9 e:g., dirxtetl~ylf~rmamide or abetonitrile, at about 20 25"C to abort 50~°C, preferbbly about 40°C. 'The reaction is continued until-the St~rtlflg 1'~lat~rlal i5 ConSUmed, as d0teft~llrt~d by T~.~r, in ~,boLf$ 4~
h~t~rs. The pr~duct is isohted by extractipn to obtain corr~pound %%1.
In step ~6, compound %.)C! is cyclized by treating with triph~rlylphasphine or prefierably a t~ialkylp~osphine, e.g., tri-n-b~ttyl~
~5 phbsphine, aid a diolkyfazodicarboxylato, e.g:, diethylazodicarboxyfate ~CEA~); in a suitable anhydrotas organic solvent, e.g., dry T'~iF, under a dry, inert atmosphere; e.g: nitrogen, at about -50°G to about -55°G, preøerabiy about -70°G; for ab~ut ~I to about 3 hours; preferably about hourso The reaction is then continued at abbot room t~rnperature for ~0 bout '~ 2 td about 24 hdurs. The product is purified by preparative high p~rformari~e liquid chromatography ~~IhLC) to obtain a compound of forrg~t~ia i, having traits relative stereochemistry: ~Th~ use of tributyiphosphine in this step gives reaction yields ~ignifscantly higher than the yields ~btained using triphenylphasphine.

'WO 93/02~4~ PCT/Y.1S92/~5972 -~3r Alternatively, step ~6 comprises combining compound i and a suitable phase transfer catalyst; ~:g. tetra-n-butylammonium hydrogen sulfate, in a suitable solvent, such as methylene chlorid~. The mikture is stirred while tooting to about 0°C to 20°C, pr~ferably about 10°C to about ~0°C, then treated with an aqu~ous base, such as an alkali m~tai hydroxide, preferably 50°I° aqueous sodium hydroxide. A
di- or tri-chlorobenzbyi chloride, preferably 2,6-dichiorob~n~oyl chloride or 2,4,x-tribhlorobenzoy9 chloride, is slowly added over a period of 20 to 60 minutes, preferably about 30 minutes. 'The mi~ure Is stirred at about 0°C to about 25°Cpreferably about i 5°C to about 20°C, for a period of 2 to 4 hours, preferably about 3 hours, then poured into cold water. The organic layer is separated and washed with water to neutral pH. 'The di-~r tri~hlorobenzoate pr~duct is isolated by cryst~ilization from metPaylene chlorid~/hsptane. The di- or tri-chlorobenzbate product is ..
1 ~ combined with a suitabtp phase transfer catalyst, e.g benzyitriethyi-arram~inlum chtorid~; in a suitable solvent, such as a rr~lxture rrwthyiene chloride and ~~ethyt -butyl ether. The mixture is stirred at about' O~C t~
about ~~°C; prefierabiy about 15°C to ab~ut 20°C, and treated with an aqueous base, e.g. ~n qlkaii metal hydr~xide; preferably 50% aqueous ~p so~diurn hydroxide: After stirring fir a periodof ~ to 6 hours, preferably abbut 4 hors, the rr~ixture is poured into ice water. The organic layer is washed with wqter ~ neutral pi-I. The prodbct is isolated by ~ernovong the solvent; thin purified by chr~matograph~ and recrystallization from a scaitabie solvent td give'a compound of f~rmt~ia l; having traps reiativ~
25 stereaehemistry.
A third alternative for step L~C bomprisbs treating compound f in a suitable solvent, such as CI-t2Ciz, with a dialkytchioroph~sphate; preferably diethylchlorppl~osphate, and an aqueous base; such as a~ ~Ikafi metal hydroxide, preferably 50°A~
30 aqueous sodium hydrbxide, in the presence bf phase transfer dataiyst, y such as tetra-n-but~larnmonium h~dr~gen sulfate or benzyitriethyt-am~nertium chi~rids:
Anath~r atternativ~ for step D6 corhprise~ treating compoundrXXi ~nrith ~ di- or tri-chiorobenzoyi chloride, ~referabty ~,6-~ ~ ' 93802048 PG'I'1U~92105972 )~~.~ ~'~
dichtorober~zoyt chloride or x,4,6-trichforobenzoyl chloride, and a suitable base, such as sodium hydride in a suitable solvent, such as ~CH2Ct~, dimethylformamide, or a combination thereof. The product is isolated and purified by chromatography fotto~red by crystallization from a suotable solvent, ~.g. ether/hexane.
Starting c~mpounds 3f111, XV, XVtI, and ?tX are all either commer~ciatly available or well known in the art and can be prepared via known methods.
.bQS:
~ ~ 4,'m ~~~~
.f. ~,. I
~' ~ Q ~ O ~ ~a '9 ~ ~ ~ v ~~~x I a Cbmpour~ds o~f forrmuta to can also b~ prepared by treatment of an imine at tbrmuia 1V with an activatbd carboxylic acid derivative of formula Xtt in the pr~~ence df a b~sE such as tri~thyiam~ne, tributytamine or diett~ylisopropytamir~e i~ an inert solvent such as Ct~2Clz, heptane or 15 toluene. Examples of activated carboxylin acid derivatives of formula ~Clt include acid chtorid~s (l~=CI), mixed anhydrides formed with phenyl pho~phbrodichiorid~te ~t:=~P(o)(CI)OPh), and IV~methylpyridinium esters firmed from the reac~~on of an acid pith tJ-methyl-~-chl~r~apyridinium iodide ~L~=2-~xy-~-methylpyridinium iodide).
~0 starting materials of forrhutae tl~ and V bre known or can b~ prepared by methods welt known in the ~r'f.
step Pf ~,~~~~~~t-~
~ ~ TiC1 ~
~ N ~
O !~
~7 p ~t7 931~204~ Pt.'TIUS921d~5972 - 2~ -. ~Si(CH3l~
N~ ~ .
~~i~~~~~~ ~~l~w~
R~ O HN~ ~ R~
Ia tap F2 In step F1, compound XVl (from I~athod l~, step 2) is dissoiered in a suitable s~lvent, e.g. methyiene chloride, then treated . weth titanium tetrachloride at about -6~°C t~ about 0°C, preferably about -25°~ to about r~'5~~, under a dry, inert atmosphere, preferably nitrogen; for ~ p~ri~d of about 5 min. TD~tE~A is added and the rrti~ture stirred at about -64°~ to about -~ 0°C; preferdbBy about -25~~
to about - .
20°C, for a period bf abbot 1 h~ur. The irnin~ (A-Chi~N-R4) is siowly ~ 0 over a period of 2o to ~ttJ yin., prefarabiy.,about 30 rain., ant~~the rnixtura i~ stirred at about -60°~ to about 0°C, preferably about -25°~ to~about - .
15°~, fior 20 to 40 min>; pr~ferably. ~bbut 3fl nnin. The mixture is then yyarrried tm about 0°C and the reaction m~rv6tor~d by high pressure liquid chromatography (l-IPLC) until complete. The tt~ixture is then poured into ~ 5' a soiuti~n of ta~t~ric abid in water, preferably 10°/m tartaric acid. Tha produdt is isc~tated by ~xtraction with a suitaf~le solvent, e.g. athyi ~.
~b~t~te, then purafied by crystallizati~r~. .
in slap F2, the product of step F1 is treated ~rith a strong non~nudieophific~ base,. such as sodium or lithium bistrimethyisilyl~mide, 2p in ~ suitable inert organic sole~nt, e:g: ~H2~1~, at about -2~°~ ~o about _.
°ip~~, preferably about 0°~. The mi~:urs is stirred while gra~~~lly ~. _ warming to abort 2~° to about.25°C, then monitored by t-iD~D..C.
until the starting materi~i is gone, typically after a periad ~f i to 2 hours. The reactian mixture is p~ured 'ento aqueous tartaric acid, preferably 1 ~Qf~
~5 ~ddric acid, ahd th~..prpduct isolated $rom the ~rganic layer. .
Imine~ of the fornnbla ~4-~i°D~I~-R~ can be prepargd~ fronn ._ . ald~ahyde~ of the formula ~-~M~ and arrtinas ~f the for~aufa ~f~-Nl°D2 by proc~dures weli~ known in the art. ~Idehydes of formula A-~~D~ and .
amines of forrnuia R~-~1H2 are commercially av~iiabfd or can bw 30 prepared via known procedures.

w~ ~ 93ioxoas P~TI~TS92/oSg~x -~s-Compounds of formula it can be prepared by methods similar to those described for compounds of formula I.
it will also b~ apparent to those skilled in the art, and by .
reference to the examples which follow, that compounds of formuiag i and ii ~n be converted into different compounds of formula B or ti by w~li known methods. for example, a compound of formula I wherein ~
comprises a doubt~ or triple bond, or a compound of formula it wherein ~ comprises a d~ubie or triple bond can be converted to the ~rresp~ryding saturated compound by treatment with hydrogen gas in -i ~ the presence of 'catalyst such as palladium or platindm on carbon.
~e~ive gr~up~ dot involved in the dbov~ processes can be protected during the reactions with conventional protecting groups whidia can b~ remgved by standard procbdur~s aftea° the reaction. The f~liowidg Table 3 shops some typical protecting groups:
Table 3 Gr~up t~ be Group to be Protected and ~rdtectecl Protecting tar~up ~O~H ~C3~alkyf, -~~Ob~nzyi, ~~~pheny!
~ ~~ ~ ~~~alkyl ~ i~G~ber~zyt, ~ NCC,~phonyi, "o-~ / - ~
HIV C I°~t~~i-i2C t°°l2Si (C i~)~~~8~~~)~~(CH3)s, ~~ben~yl; ~NSi(Cfas)s; t~Si-~t~H)s CHs v~H2 m ~
~ ~~~s ~'.~H3~ "°' ~3~.tt~'r~'1~~9~ ~ ~-~'~~''~I)3 ~I~~

'!~~ 9~/0~t1~8 PCI'/~JS92/OS972 ' ~Ve have found that the compounds ~f this invention lov~ar serum lipid levels; in particular serum cholesterol levels.
Compounds of this invention have been found to inhibit the intestinal absorbtton of cholesterol end to significantly reduce the formation of fiver cholasteryt esters in animal models. Some compounds also inhibit ACAT
1n~1'tro.

~'hus, compounds ~f this invention are hypochol~sterotemic agents by virtue of their ability to inhibit the esterification andlor intestinal absorption of chole~terot; they are then~fore useful in th~
treatm~nt and prevention of atheroscl~rpsis in mammals,. in parttcuiar in humans.

~ 0 !r~ addition to~ the compound aspect, the present invention ... .. therefore stab relates to a method of towering serum cholesterol levels.

which method comprises administering to a mammal in need of such treatmb~t ~ hypbch~le~terolemlc ~ffective amount of a compound of fiouta 6 or tt gfi thl~ invention. The cornpour~d is~ preferably _ 'i 5 administered in a pharmaceutically acceptable carrier suitable for oral admihistr~tior~: .

The.' and ' ~ activity of the compounds of farmulae t ~r'It c~r~ be determined by the foltouving procedures.
o!

~0 ~ AT ~l~n vii This assay measures the activity of A~A'f' by measuring th~

~~AT-mediated tr~:nsfer of tritiated oleic acid from acyl-CoA
to choiester~I to give labellsd cholesteryf oteate. Rat fiver microsomes are used as the source ~f ~4GAT. Assays are performed...;h r~und bottom r~tlcrotiterplates using ~ total incubation ~~l~sme of 50 p.L: each 25 incubation yell receives. l 0 ~L assay buffer (Q:51~
tCt~F'~,~.
1 ~ pM

dithiothreitol, p~Ev x'04}, ?.5 pL of 40 mglmL SS~1' (~cwine ~erurn ~lbe~min}

and 12.5 pg of microsomal protein. Tha test. compound (in suffix!~nt amount to bring the final xoncentration to from 0:1 to 25 paili}, ~~ferenxe compound, or v~hlcte c~ntrot is added and the final volume brought t~

~0 47 pL. The trticr~titcrptate is then floated on the surfaxe of a 37G water bath for fifteen mlntJtes. Incubations era started by the additiop of 3 pL

s~l~~~rt ~oA (~p.~ilv~retl, fine! concentrati~n ~f i~ p.~cyi Co~C}. '~hh~

ptate is then returhed to the water bath for ~ 5 minutes.
The incubations are then terminated by application of i5 p.L from each incubatipn to a . 93/020~9~ Pg.'I°/~.1592/05972 '~ :~. :1 ~ t~'~
_2g_ individual lanes on a thin layer plate (Silica Get GF 20 x 20 cm).
Standards are applied to several lanes so that the cholesteryl ester band can be identified. After drying, the plates are eluted with 80:10:1 petroleum ether:diethyl ether:acetic acid. 'The standards are visualized via iodine vapor, and the regions corresponding to cholesteryl ester are scraped into ? mL scintillation vials. 4 mL of scintillant are added to eaoh vial, end the radioactivity quantified. Background count is determined by the boiled contrpis. Full activity is determined by activity in the presence of vehicle. The percent inhibition is calculated by subtracting ~h~ background frorh both control and test samples, and the test value 6s c~atc~rlated as a percentage of the c~ntrol. For IC~a deternyinati~ns, the inhibition is plotted against drug does on a log scale and the conc~ntrati~n at v~hich 50°/~ inhibition is obtained is d~termined.
~#a~~tdr~ are separated into groups of sia~ and given a ~ntrc~tted cho6esterot diet (~'urina Chow #~500i containing 0.5°!~
dhof~sterot~ fir seven days: ~iet consumption is monit~red to determine ~0 dietary chote~ter~! exposure in the face of test compounds. The animals are dosed ~nrith the test corr~pou~d ~nce deify beginning with the ini~iatir~n of diet. Dosing i~ by oral gavage of 0.2rnL of corn oil alone (cbntrol graup) or sotc~ion (or suspension) ~f best compound in com oil.
~tt enirnals moribund ~r in paor physical c~ndition ark euthanized.
~a ~l~ter s~~een days; the a~timats and anesthetized by IIVI injection ~f ketar~tine and sacrifined ~y decapitation. Blood is collected into vacutainer tubes cr~ntaining B~TA for plasma lipid analysis and the liver excised f~rti~sde lipid analysis. Cats is rep~rt~d-~s percent reduction ~f lipid v~r~us cor~tr~l. . .
The present invention also relates to a pharmaceutics! .
comp~siti~n cc~i~prising a compound of ~~rrnuta i ~r ll o~ this invention and a pharmace~tticatly acceptable carrier: The campounds of formula t or II n be administered in any conventions! oral dosage dorm such as '~~ 931020~t lPGT/lUS~2f OS97~
_Zg_ capsules, tablets, powders, cachets, suspensions or solutions. The _ formulations and pharmaceutical compositions 'can be prepared using conventional pharmaceutically acceptable excipients and additives and conventional techniques. Such pharmaceutically acceptable excipients and additives include n~n-toxin compatible fill~rs, binders, disint~grants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like.
The daily hypocholesteremic dose of a compound of formula l or II is abbot 7 to about' 30 mglkg of body weight per day. For $ p ~n average body weight of ~'Okg, the dosage level is therefore from about 500 t~ abouf 2000 mg of drug per day; given in a single dose or 2-4 divided doses . The exact dose, ho~rev~r, is determined by the attendihg clinician and is dependent on the p~tency of the corr~pound adoministered, the age, weight, condition arid response of the patient.
~ 5 F~llovring are examples Qf preparing comp~unds~of forrnula~ I and I!: The"stereochemistry listed is relative star~ocheomistry unless othennrise noted: The t~rms cis/traras refer to the relative _._ orient~tir~ns at the b~ta-lectarrt 3- and 4- positions when each is mono-substituted (i:e.. ~3=H).
AlulPl ~CH~
ph(CI-12)~~ ,,~'°
~Ci-~la ~~ Freshly prepare lithium diiso~aropyl amide ~L~~) by dissohoing 23.~6mL (~~.3gg, ~72mmol) diisopropylamine in 230mL dry 25 . TIiF at -Z6°~ uhder nitrogen. Add i 03.~mL (i 66 mmcl l .6tt~ In hexanes) of r~-bc~tyl lithium and stir at -76°C fag ~ h. To this cold solution add 32.558 ~'9 ~~mmol) of 5-phenyl val~rid acid ethyl ester in ~ 95mL dry THF over ~~ h; keeping the reaction femparatura belo~r -65aC. Stir for 1 h at -7~°C, thin add 3~.i 3g ~155mrr~~I) ~f 4-reiethoxybenzylidine ~°%~ 9~/020~~ PdCI'/iJS92/~972 anisidine in 350mL dry CH2Cl2. Allow the reaction to slowly come to ' room temperature and the precipitate that forms viii begin to go into solution. stir the reaction mixture for 16h at room temperature. Partition ' the mixture between i .2liter of 9 hI aqueous hydrochloric acid ~HCI) and i liter of ether. ~t'ash the ether iay~r with 300 mL 1 I~ HCI. Combine th~
acid layers and extract with °l liter of ether Combine the ether extracts, dry over NtgSiJ~ and concentrate in vacuo. Crystallize the residue (35:038, 55%~ from °~200mL. ethyl acetate-he~cane (9 :1 ) to give 32.058 of the title racemic compound as an off white crysta9, mp = 90-93°C.
Using a similar procedure, the foifovt~ing compounds shown in 'fables 4 and 4A cap also be prepared:

~~~ ~3rox~c.-rr~s9a~os9~z -32_ r ~ ~ ~ o ~ U O r V '~r rt9 A v Of !~
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!_~ ~ ~ ~ f~V ~ idi PC~9 I ~. ~ r"G t~ ~ Q;
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~~ ~~1~2~~ PC'I'lU592l05972 - 4't -OcH3 Ph(cH~~
_.
o I
~'" OcH~
~T~~ 1 a Add 39.1 mL (1 ~17.~ mmol) of ethyl magnesium bromide to a p°~ sot~tion of 31.~Og (97.6 mmol) of ~-)-10-(diisopropylsutfanamido)-is~borneot (~e~ ~pP~I~er, et at, 'let Lett.. 25 (1964), p. 5665) in S7~mL
dr~r TIFF. Stir the mixture for Q.Sh at 9°~, then at room temp~rature for 0.5h. Add 37.'~~4rn~ (39.678; 117.2mmol) of 5-phenyhaleric acid . anhydride to thin mi~rfure at 0°G and stir overnight at room temperature.
Pour the rnixtur~ into 116ter of hail-saturated NaHC~~ and. ~~ctract with ... ;t ~ too-600mL portions ef hexane. ~ry the bombined hexan~ layers with ~a~~(~~ end conc~ntrat~ in vacuo. ~hrom~tograph the residue {57o35g) in thr~~ portions over ~600g Sii7~ eluting with 2% ethyl d~etate-~H~~t~ to ~btain the. desired. ester (42.078, 90.~°/a), t=~AS
!V!S :
(~li+1 ) 479.
15 STEM 2: lJsing a pr~cedure similar to Example 9 , treat the ester of Step 1, washing the ~th~r layer with 200mL 1 t~ aqueous Hit, drying with tVtgS~~ and ~or~centrating irt ~ac~o. ~hromatograph the residue direr 1kg Si~~, eluting ~iih 2Q% ethyl acetate-hexane to give 24,198 ("T9°l°) of th~ rec~vered atcot~ot and ~5.fi6 (66°/a) of the tit4~
~~ ~h,~ntiornerically enriched ~-tact~m. This-tactarri can be further enriched by chromatography ~~er a ~Chiratcel'r~ ~D column ~~aicet Ghemicat v tnd~stries, Ltd., Fbrt Lei, X1,9), eluting with 10°/a isoprop~not-heacanee.
~rryst~ttize the r~~uiting enantion~~rically pure (3,45) compound from ~~ ~ -~~.~°
ether-hexane td obtain a white solid, mp = 64 - a5°~~
~5 (!~e~t°i). , losing a similar procedure; the f~tt~wtng ensrntiomedcatly lure ~3F~;4R) connpound ~~XA~IPL~ 2A) can ~t~o be prepared: .

1'G°I'/'~3592/~5~72 ~v°' ~83/0~04~
_42_ ~ ~
h (C!"~2}3ss "~ ~CH3 .2. [a]o = +98.0° (~eO~l)).
(m.p. ~ 8485~C; CAB f~S: (P~+'! ) 402 , ~x~~LF~L~ 3 F'h(CHZ)3~ ,~~~ ~h r ~~i-!s ~reshty prepare a so9utidr~ of tithiurn isopropytcyclohexyl ~rsaid~ (C.lCA) by ~isspfvirag 0.68rn'L (0.5~g, 4.11 rnmol) 6sopr~pyicycDo-hexyD canine in 20mL THE at -78°~ under nitrogen. Add ~.58rnL
~4.08r~nmol) rt-butyl lithiurrs (1.6DUi, from Aidrich, t~ii~aukee, HIV!) and stir at -~8~~ 'fbr 1 h: Add 1.U~g (2.61 mmot) ~f the cdrnpound ofi Example 1 Dt in a~,L dry T~~ to tl~e solution. After 2h at ~~8°~, add 2.8rnL (2.89g, i 6rnrnol} of he~c~methylphospho~ic t~iam~de ~oilowed by 0.33anL (641 ~ng, 4:11 mmo!) of ethyl io~9de at -~8°~s stir the rni~tur$ overnight ~t room ternperatur~. C~u~nch thg reaction wit~a 40mL 1 ~1 aqueous H~l and ~ 5 extract with tw~-50m~: portions o~ OH2~tz. Oombine the O~~OI~ layers and vrash sequentially with 50mL 1 ~I aqueous HO! and 50rnL Na~~O3.
dry wbr ~lg~~~ dnd c~ncentrate in vacuo. ~hr~rnatograph the residue over 40g ~!'0~~ ~i~ting with 20~/~ ethyl acetate-hexane to give 0.958 (83%) ~# fhb title c~rnpound as a colorless bil, ~A~ ~I~ : (~~ ) ~~fi.4 ~0 l9~ing a similar procedure, th~ foll~vuihg cornppunds , shbwn in T~bDe~ 5 and SAcan also be prepared:
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...... , ... ..,. .....,. .,.... ::.:.. .i; .,..I.n'i" . ...~ . . . . ..

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' 93/02048 PCTlLJ~92105972 ~ / ~_"_ ~Ct-is Add 100rng (0.30mmol) of the traps ~-lactam of Example 1 V in-2c~L dry T'NF o a solution of 1:~2mL (0:32mmot) LEA (1.5M, from ~4td~ichn Nfiiwaukee~ t~U'I) in 0:5m~. dry 'UHF at -76°~ under r~itr~gen. Stir f~r 5min at -76°C, then quench at iow t~mp~rature with ~°0:3mL acetic acid. Partition the mixture between ~rntr. ethyl ac~t~t~ and 20mL water. flash the organic layer with ,20 mL
10°/a aq0e~us N~t~~4~ solutlop, dry ~ver tVlg~O~ and concentrate in 1 ~ vacuo t~ give 03rng of an oily white s~lid. Chromatograph the residua over ~i~z, eluting' with 20°/~ ethyl acetate-hexane to obtain ~6 mg of th~
~tle cis ~-lactam' as a-v~rhite solid; tnP --14'1.3 -142.3°~.
FXAN6PL~ 5 ~C~t3 ~~(c3 '~~
~ ~ °~.
~ C~~Hs t~issot~e 32.058 (79.6mm~t) of the racemic cis ~-hcftam of %~mple l in 500~r"tt~ of 'i°!-iF. add R .768 (16.Omm~t) of p~t~s~iur~ ~
.
but~xide end stir at 0°C for ~ .5h. ~a~titiora the reaction mixture betvvean 600mL 1 ~d ~que~us HCt and 1.2iiters of ether. extract the aqpeoua 20 tay~r v4rit~ 4G0mL df ether: ~pr~'~bine the ~thee layers, dry ~~er t~g~~~
and conc~ntrdt~ in vacuo to give 32.08 ~f a mixttare of cis end trdns iaciams (~:7:1 ). Isolate the pure traps ~-tactam via silica get ~~'1;~

W~ 9310204 ~GTltJS92/~~972 -47_ chromatography, eiuting with 10% ethyl acetate-hexane. Crystallize tr~m ethyl acetate-hexane to give white crystals, rnp = 9fi.0 - 97.5°.
i.lsing a procedure similar to that of Example 5, the fail~wing compounds sh~wn.it~ Tabf~s 6 and 6A can ba preparad~

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!~'"' 93/~2fl4~ P'C.Tl~J592105972 Etr a ~-o Ph(~H2)3 N
~ ~CF#s Dissolve ~OOmg (0.47mmol) of the ~3-lactam of Example 3G
in 4mL Etf?Ac end add °~10mg 10% F'dlC. Hydrogenate at 1 atm for 4h.
. Filter the mixture throcsgh Celita and conc~ntrata. ~hromatograph the residue over 40g ~i~2eluting with 20% Ey~Ac-hexane to obtain '! 33mg (94%) of the title j3-Ibctam as a colorless oil, C! (U!S ~ (!VI+1 ) 423.1.
XP~ PLC 7 ~h(C~92)~/i T~ a refluxir~g solutipn of 4.33 grams (.0205 moles) 1J-(4-m~thoxyben~ytidina)-aniline and 7.6 grams (0.0410 moles) tributy!-arrtine in 4d mL hepta~~ add;in p~rti~ns, a s~lu~ion o~ 4.03 grams 0.0205 males) ~~phenylvaleroyl chloride in 15 mL heptane o~rar about 2 haute; then reflex the s~lution for an additional ~. h~ur~. E~r~porata the s~l~~r~t and take ~rp the rb~id~a in 150 mL ~t~~c. Vl~ash wi$h 1 ~l i°i~! (2 x 30 m~.), saturated ~a~iG~~ ( 1 x 30 mL) ahd brine (1 x 30 mL.), that? dry over ~lgy0~ and eva,p~ 'ate t~ give 7.69 gr~rns of a semisolid.
a~ry~t~6ii~tion from 15% EtOAc in hexane to obtain 3.fl3 grants of the ~0 title clomp~~nd, ~P ~5~76°~. An additional 2.3'f g is bbt~ined from the rr~~th~r liquors by chr~maf~graphy (sific~ gal, 5°/m ethyl ~catata in hax~na) ~nc~ recrystallization.
tfsing b procedure similar to that of Exannpla 7, the following cgmpounds shown in Tables 7 and ?Aden be preparado 1~~ ~3i~320~8 , ~LT/L1~92/~5~~2 (y I~~ U

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~ ;
~!~
~ ~GH3 Stir a mixture of 9~~ mg 63.01 mmot) of the cis ~3-lacta~n of Example 1 AK, above; aid 20mg 10~/° palladium on carbon in 10 rat"
$ . ethyl acetate under i atm hydrogen gas at room temperature for 24h.
Pillar the mixture throa~gh dvelite and concentrate in vacuo.
~hromatograph the re~id~e o~r~er 50g Si~~, slutir~~ ~rith ~#0% ethyl acetate-h~xarte to obtain ~i ~mg (92%) of tt~e tills compound as a yellowish soiid; mp = 1 x.2.0 - i 42.5°C.
Using ~ similar procedure, the foltov~ring compounds shown in 'T~bfes ~ and ~A can be prepared, and wing co~sverttionat procedures; the amine group of dompound gA arad the amino gr~up ~f c~mpound ~B can be protested with a t-but~x~carbonyt (~O~) group to ~btai~n compounds ~G and ~H, resp~ctivety:

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W() 93102048 PGT/I1S9210597~
w~.~

PIVI LL 9 .
r~CH~
Ph(C~)~
~ ~CH~
STEP 1: Combine 5-phanylv~aleric acid (89.9 g, 0.504 mot) and thionyf phtoride (~9.3 rraL, 1.225 mot), float to 70°C and reftux for 1 h.
~ Vacuum distill (50 - 100 mm ~Ig) the excess thionyl chlpride and add 200 rnl of dry tolu~n~ to the resultant residue. Vacuum distill again, then add 188 rnL ~f dry THF to the crude 5-phenytvaleroyl chloride and use thd resuttirag solution directly in the next step:
~'t'~P 2: Combine 7~ g (0.4289 mol) of R-(+)-4-ben~yl-,l o o~a~alidir~on~ and 1 ~B.L of dry l'HF finder d~r nitrogen atmosphere.
Cool they resulting soluti~~ t~ -7~°C and add 278 mL of a 1.~ Ps~
solution ~~ n-butyttithidm in hexane over 30-40 minutes. stir for an additions! 30 r~aihutesthen add the solution of step l ~ver a per''aod of 4.5 ruin. fellow the rni~ture to warm to 0°C~and stir for 1 h. Quench the reaction mixture 15 .by adding fi73:6 mL of K~C~~ (1 l~l aqueous so~uti~n) ~nd~ stir f~r 9 h.
L~istitl off the °~HF under vabuum at 30-35°r: l~ituts the residua with 1 L
ofwater. a,nd extract'with 3x800 mL of CH~Ct2. Combine the oceanic ~x~r~ct~ and ~~sh e~ith X00 r~L ~f water; then with 800 t~~ ~f-brine. Cry thg ~rganic erects over MgS~~., filter, th8n d~ncsntrate in v~cut~ to an 20 oil. ~i~sotve the oil ih 200 mL of hexane, there distill ~ff the he~~ne udder vacuum: i~epe~~ the hexane $reat~ent two yore times, then digs~i~e the '~it in 1.7 m!.' of CMZCIz. The resulting solution is used dirr~~tty ~n the e~ext step:
~T~P 3: fool the s~tution ~f step 2 td -5°C to 0°C sunder dry ~5 ~i~r~g~n dtmoaph~re: Add 1293 mL of di-n-~u~rtaorgn ~rift~tp;
.. _ maintaining fh~ temperature of tie read~i~h mixture at -6°C to °~°~.
~c~ttowing the addition, stir the mixture f~r 10 ~'nin., then add 97.'l 2 rxtL
~f .
~diis~~ropylethylarnin~, again maintaining the terraperatur~ at ~6°C to ~~rlu~~zl~s~~z 'V 93/02048 s~.~.~.~~
_3°C, Following the addition, stir the mixture at 0°C for 30 min., then cool thg mixture to -78°C and stir for 30 min.. Add 5'?.4 mL of p-anis-.
~dehyd~ and stir the mixture at -78°C for 30 min., then at 0°C
for 1 h.
VVhiie maintaining the temperature at 0°C to 5°C, quench the mixture by adding 688.2 mL of a pH 7 buffer solution (68 g KH2!'~~~ 12 g ~a~~
and 800 mL of water), then add 473 mt_ of 30% H2C3~ and stir the resulting mixture at 0°C for 1 h. Extract the mixture with 3x600 mL
hexane:ethyl actet~te (1:1 ), combine the organic extracts and wash with 800 mL of saturated NaHC(~3 (aqueous); then with 800 mL of brine, ~ry the ~rganic extracts over Na~04, filter, and evaporate to an oil.
C stallize the oil from hexanelethyl acetat~ (1:1 ) to give 9 76 g of the product as a white solid.
STEP ~: ~~mbine the product of Step 3 (170 g, 0.36 Mot), 1596 mL
E and 400 mt- of water, stir the mixture end cool to about 3°C. Add of TH
~ 5 226 mL (2:°i 56 Mol) of 30°/~ H202 to the mixture over 15 min., then add a .. lion of LiOH (~6:2 g, 0.862 Mol) in 400 mL ~~ water over a period of solu 30 h-,in: stir $he r~bction mixture at OpC to 5°C for 3 h. Add a solution of ~~2 ~f sedium sulfite in 850 ml_ of water over' 70 min., keeping the temperature under 2~°C. Concentrate the solvent ander vacuum and add 7 L of grater: Extraot with 4x1.7 L of toluene. Acidify tt~e aqueous ors to H 2.4 with 3 N HCI. Extract with one 2.6 t_ pottis~n and two 1.7 lay P
L portions bf ethyl acetate. Combine the ethyl acetate extracts, wash with brin~9 dry ~ver NaSO~, filter, then evaporate to give the product as d white s~lid, 112 g.
-~~p 6s Combine the product of Step 4 {19.4'7 g, 62 rnmol), 400 m~.
S
of acet~nitrile, 9:49 9 (62 mmo!) of 1-hydroxyben~otriazol~ (H~S~a 22:91 g (186 mrn~t~ ~f p-anisidine and 14.05 g (68.2 mmol) of dicyclo-x Icarbodiinnide (DCC). Stir the reaction mixture at 40°C for 4 h and he y ~nfirnl the consumption of starting material by '~L.C (6:4 hexaraed ethyl acetate). Concentrate the mixture to ll3 its volume and partition between 300. rnL bf water and 30~ mL of ethyl acetate. otter the organic .
layer, thin wash vuith 200 mL of 1 ~1 HCI, then with tyro '! 00 m~. portions of saturated f~aHCOs; and two 100 mL portions of brine. ~ry the PGTlUS92l~~7z w~ ~~loz~s organic layer over NaS~,~ and concentrate to give the product as a brown solid, 24 g.
S'~EP 6: Dombine the product of Step 5 (115 g, 0.2745 (~of) and 2.3 L of THF under dry nitrogen atmosphere and cool to -70°C. Stir the mixture whip adding a s~lution of 137 mL (0.551 f~liol~ of tri-n-butylphosphine in 113 ml. 'THF, anci 163 mL (1.03 ~/Bol) of di~thyla~odiparboxytate (DEAD} over 2 h. Allow the mixture to warm to room~temperature and stir overnight. Remove the solvent under vacuum. Filter th~ r~sidu~ through a plug of silica gel using ~H~GI2/
1 Q hexane/ ethyl acetate (76:24:6) as the etuant: Evaporate the solvent and ~~rify the residue by prep~rativ~ H~'LC (silica gel, 15% ~thyl act~tate!
h~xan~) to give ~88 g ~f the (3R,4S) enantiomerically pure tithe « 2s ~
compound, ~ Io ~ -19.3 (~~OH).

~CT/IJ~92/05972 a~/o2oas _oH
Ph(CH~J
~~o Ths compoursd of Example 7AtJ X0.686 g; 0.0012 mol~s) drs~olv~d in l :1 ati~anol~thyt acetate i~ hydrogenated over 0.70 grams 1 Q~/~ Pd ~n carbon ~t 50 psi fir °! 6 fours. The r~su9ting pr~duct is ohr~mat~graphed (~iiic~ gel; 60:x~ hexane:~thyl acetate) to give 0.42 grams ofi the title c~mp~u~d; mp 160-161 °C.
lJsihg suE~s~artially the same procedure tt~s foilo~rving comp~und can be prepared:
Example 10A
3 ~lem~n~~l ~n~lys>s calculated for C~sH2s(~C?s Ph(cH~~~A ~, 77.49; h1, 6~50~ ~1, 3.6~
Found: ~, x.47; ~, 6:46; fVa x:74 ~~.. mho P , _:._-._ .....__ _... . ..,,..,. . _ , . ...,~. , ... . .~. 4 ..~-' :; ..- -:' , . . ,.;

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Example 12!~ Example i 2~
s s a 194.-195°~ m 7 61.5-i 63°~
J~xamDl, a i 3 ~C 1 \ 5~
To a biphasic mixture of the product ~f Example 11 (0:8~ g, 1.8 mm~le), ~H~CI~ (i 5 nnl) and 30% aquaous fetrabutylammonium hydroxide (2.36 mi, 3a$ mmole) was added p-toiu~nesulfonylchloride (~:515 g, ~.~ mmole). After 2 h the reaction rralxture way wa,~h~d with i X
1 N ~!C!, ~3C t~2~ bpd the organic layer dried aver ll~gS~,~.
concentration folhwed by recrystillaztion from ethyl adetat~ aff~rded 0:3~ g (50°/~ yield) of the title compound, mp 204-Z05°~.
Exam_ lu a 14 ~H
..,..,. .2 ~.- .,.: ~,: :, ,.. ,< ~, . , -:«.,» ,_. ~ a: ''~ . . , -: ~~ sFw ,y ~'~t 93/02(D4~ P(:T/U~9~/05972 ~~1~~0 ~
_ g9 _ To a solution of the product of Example 11 (0.5 g, 1.5 mmoie), rraetharaoi (20 mi) and triethylamine (0.'19 g, 1.8 mmol~) was added.phenylacetaidehyde (0.44 g, 3.6 mmoie). After 0.25 h , Na~NaGN X0.172 g, 2.? mmole) and ZnCl2 (0.174 g, 1.3 mm~iey w~re added to the. reaction. After 3.5 h, the reaction was quenched with ammonium chloride, concentrated partially ire vacuo, and dissolved in CF1~CI~. The organic layer was washed 2X with water, dried and .concer~tr~ted to afford crude product: Recrystaliization from C~9~Ci~
afforded 0.44 g (65% yield) of the title compound, mp 135-13'9.5°C.
~ using substantially the same procedure, the following ... corcpound~ can be prepared:

1~' ' 93/~i2048 ~°o xam~[e 1 s Ph(CH2) p~/us~z/~~~7z ~i~GH3 0 Add ~9 mL ~~9 mmol) ~f l l~ t~trabu~ylammonium fluoride ~4g m~., 43 mm~l,11~"! in ~'1-iF)to a room temperature solution of the cdmppur~d caf ~xampl~ i AS (5.1 g, 9:5 rrdmol) in 'rHF X25 mL,}° Allow the r~nixture tb stn overnight. 'i"LC (5g°/v ~tQAc/he~an~s} ihdicates corisur~p~iora ~f ~tar~ir~g material: °fransfer the reacti~n mixture to a ~ sep~rat~ry f~anr~al, parti~r~ between saturated arrtmoniurra chloride and ether, extract kith ether. combine the e~heral extradts, wash ~rith v~rater end bris~~e dry ~ver anhydrous l~Ia~~t~~, filer and c~ncentrate to a residue. Chrbrnatograph (51~3~; 30-40°fo ~t~Ac/h~xane) affords 3.318 ~8~4%y of the title cornpot~nd, mp 91 X92°C.
The follawing compaunds can be prepared via substantialy the same procedure:
Example 15A Example 15~
CH2~H OCHg -.~, Ph~CN~
Ph(~H~j ~
~ ~ ~ ~ .
~ ~t-i ~CH~
nrsp 11 ~a913°~ mp 1 ~4-171 °~ °

VV~ 93/0204~i PCT/iJS92/05972 ~~t~~~~
71 _.
Ph(CH2) pdd ~n~~ (o.64g, 7.4 mmot) to a solution of tho pr~duot of ~x~~pl~ 15p (0:20g, 0.5 mmot) in ~H2~1~ (50 mLj at roonra tamp~ratura. . .
pttow the mixture to stir o~arnight. TLS (20°!~ EtOpclhexanas~
indicates .. consum~tinn of starting material. t=iitar the mixture through c~lite ~nrashing the filt~rcatca ~~ll with CH2Ctz. concentrate the fittrata ~~
1 ~ obtain 0.'~ 9g (95°/~, ~f the itle compound, rip 129-130 °rr.
~~ing substantially the game procedure, the following bori~~our<d can be p~epar~d:
~xampf~ '16p v ~ ~ 1~
~CH~
~ 5 ,gyp ~ oo-~ o~ °c , .
___..__ _ ._. _ __~. .. _ ~ ._ _ ~ ~ _. _. .. . T ._ . .~ z... "..

i' ' 93/0~48 Ph P~'/US92/059"TZ
..
add m-ehtoroperbenzoic aeid (.1 Cg; .092 mmat) to a solution of th~ c~mpound ofi Exarvpte l~~d (0.31 g, 0.74 mmol} in ~fH~~t~, (~ mt-) at ream temperature. tUtonitor the reacti~n by 'Tto~
(50°/~
~t0~4c~exanes). Upon eonsumption ofi staring mat~riat (~1 h), add ~~(~H)~ (O.i g; 1.3 ranmot~, Stir the tinixtura for an additianat 't5 min..
0 otter the mixture through celite washirtg the fiitterea~e vv~lt with ~H~~I~.
~~hen~~ra~e, ~~a fiiltr~t~ ohto silica get, using enough siti~a gel anti! a free ft~a~ing p~vuder i~ obtained. L~act the resulting p~wder onta a ehr~nr~atography c~I~mn loaded with silica get and 5% n/te~H/~H~~t~.
Mute with 5% tvle~t~IC~t2~t~ to ~~~ain 0:26 g ofi the title sutfi~xi~a 15 (Ex~r~pl~ '17), mp 134-1 ~5°C end 0.50 g of the analogous sutfione:
~xampte 17A
eH~
~~,~eH~3 -°' t~e&i3 mp 116-1 ~ 7°
The foito~ring compounds can b~ prepared via ~ubst~ntiatty the same pr~cedure:

s OCH~

VV~ 9~ro2~as PCT/L159~/~5972 _~3_ Exempla 1?B Example 17C
_ a~~ .. ' ~ .~°~ ' ~ ~ ~~ ~
~ ~ O
~ 0 ~ ~°
o°s~
mp 5~-5~~c mp 5z~5~~~
xa ye 18 Ph(cH~)a ~~p ° ~~
OCH~
F%~flux a rraixture of the compound ~f ~xarnpts 1 AVIV (1.7z g, 3.49 mrnoi), ~0 mL of 'fHF and 3N I-ICI (z0 rxtL~ ~ve~night, iVionitbr the reaction by 'ft_C (50% ~tOAc/hsx~nes). Upon consumption of ~tar~in~g ~atsrial~ ~ooi th~ m~xtbre t~ room temperat~ars, neutr~li~b with aaturtsd p ~IaHCC~3 and extract with ethyl acetat~. C~mbin~ the ~a~ctra~ta, ~nr~ah kith ~ratsr and brine; dry beret anhydrau~ Na~~~~, fitter ~r~d c~ncsnt~at~ td ~
~tid. ~sc~r~tal9izs from CH~CI2lNd~~H to obtair~ 0.~2zg of thb tilts compound; rrtp 190:5-191.5 gC.
LJ~i~g .substantially the same pr~c~durs th~ faltowing 7 5 , oornp~und can ba pcsparsd: ..:
y r r.. < .
~r:~.
S.S ~ ,f . .
1r ..r. ... ., ..........3_c .~...... . . w , .n,.. . s.. ._ ......, ...., ::'fS~s'e....,.... .. . .., ,........... ........,. n. . ...... n. n .... , ~.. .., .. . " .,..

vvc~ ~3iozod~ ~mvsgxro~9°~z Example 18A
N
Ph(CH~~,r~ ' NH ' a ~(iHg mp 189-191 °G
Exams I~ a 9 ~
I
~CH~
pdd a ~~lutibn of ~daBl~3C~d (0.19g; 3.0 rrsmo!) and ZnGI~
(0.~~g, i:5 mmol) in me~l~an~i to a room t~rraperatur~ solution of tha product ~f Ex~n ~ple l 6A ~l .Og; ~.5 rn~nol) and mo~hol~ne X0.44 mL, 5.0 s~mol) in THF. lV9onitor the reaction by TLS (50°/~ Ett~~d/hexanas):
't.)p~n consumption ~f starting material the rr~ixtc.~re uvas dilt~tad ~rith 0.1 N
f~a~~1 ~°1 ~0 rnis) and remove thd ~rganic sdlven~~ on a rotary avap~r~tor.

5 Extract the r~~~atting ~olu~idr~ with ethyl adefata: ~~mbis~~ t~~ ~xtr~cts, wash with water and brine; dry over anhydrous f~a~~~~, finer arid concentrate to ~ ~of°sd. i~ecry~tatl~za from ~t~~lhaxa~~~ to obtain 0.~1~
(fig°/A) of the tjtla cc3rnp~urid; mp 100-101 °~.
°fha foilouving connpounds c~~ ba prepared by ~ub~tantlally .
~~ the sarna nnc~th~d:

.. .. PG°T/US92/059'72 _7~_ ~'i..~.~~Q~
Exempla °I 9A ~xar~p~a '~ 9B
CH~t~

.. ~ N

~.crius9zl~~'z yvn ~~iozo~s N'~
N
p t~CH~
~aat a solution of the compound of ~xamplo 1A~ ~1.10g, 2.g5 ~nmdf); 15°la H2t'~~ (0.45 mL) in acetid acid ~~ mL) to a 100 °~ for ~:5~, enrith TL.G rr~onitoring (5% tillfeOl~lGHzCI~). Upon consumption of the darting ~~rnp~und, clot to ron~ temper~tura, neutralize with sat.
N~2~~~ end deiuta with ethyl acetate. ~Iter the mi~tur~ and gash the 1 ~ filtrate ~rith Yvater and brine; dry over anhydrous tVa,~SO~, fitter and ~~h~antrata to a r~si~t~~. ~hromatograph the residua silica gel, 90%
tUl~C3Hl~~l~~l~) to give the tith compound, ~A~ tutS ~ilA~1 ) ~ X59.
Fxamflle21 ~cH~
Add freshly prepared Age (0.40 g,1.'T3 n~rnot) to a solution , of the product ~f ~~cample 15A ~0.4figs 1.15 mrrtot) and rrrathyt iodide ~0 ~~.~1 nnL, 3:45 mrndl)~n dry DMF ~5 ~L). Meat the rhi~tura to 40-45 °~.~ri$h ~'t_~ ra~onitaring ~5~°/~ Et~Aclhax~ne~), add proporti~r~al outs of Ag~ and ~ethyt iodide until 'TLC indicates consurnpti~n ~f starting corhpound. foot to room temperature, pardon bet~vaan Qatar and ethyl aaeta?a, extract ~rith ethyl acetate. Corn~ina ethyl acetate W~ 9~r02048 P~'ri759zros9"r2 _ 77 _ extracts, wash with water and brine, dry wer anhydrous IVa~SC~~., ~Itor and concentrate to a residue. Chromatograph the residua (silica gel, 30°r'm EtOActhexanes~ t~ give the title compound, FAB ~dIS (~+i ) = 4~
fi.
-- The following compound can be prepared by substantially the same procedure: -...
Example ~'1 A
CHZGCH~
p ' -~.
~~H3 mp fi~~85°C .- . _ ~p~H
P6~(cH2~as., C? ~ '~e ~H3 '6 5 - Add freshly prepared Jones reagent ($ rroi.~ dropwise to a - solution ~t the ~ardduct of ~xampte ~ 6. (x.76, fi.9~ mmol~ In ac~tdne ( ' mL) maintaining the tes~perature of the reaction mixture between 15-20 °~: Monit~r by '~L~ (~°~~ hlle~I°li~l'12~1~~. lJpon consumptio~r o~ starting ~pour~d, quench th~ reaction with ~ethanal. -concentrate to a residue andypat~iot~ the residue b~t~veen .~H2~1~ and ~~ter. Extract with Ci~2~l~, cb~binb th~ extracts, gash with water, ~ O~d~ ~9~~~~s (aq~
and brine; then dry over anhydrous. Na2~~4. F'i~er and concer~trat~ to . .. afford 2.90g of thd title compound, mp 64-65 °~.

~(~ 931~2~t8 P~I'/IJ~92/05978 ~:~:~~~~7 _78_ The following compound can be prepared by substantiaiiy the same procedure.
Exempts 22A

~ mp ~ 58-159°G
~ ~ o ~w~; -Add ~D~l (0.28,1.03 mr~°~~L) t~ a r~~m temperature soluti~n ~f the prod~sct ~f Exa~pte 22A (0:30; 0.7~ mr~ol~$ ~6-methyimorph~tine (0:11 mL; 0.94 rramot)r morph~lin~ (0.13 mL, O.~~rt~m~I~ ahd ~~~~ ~~.12g, ~.8? ~rnol~ ire ~f~~~h (8 mL~. Stir the 15 mixture ~vernight. 6Vion~tor by 1'LC (5~/~ h~~C~HICH~~I~~. 3~p~n consuarrption ~~ thd starting compound, dilcate with ir~hCt2, wash with 1 M SCI, eater; dry ~uer anhydrous i~la~S~~y ~Olt~r ~~d concantrat~ t~ a residue. Chrorn~t~gaph the residue (Si~2, 3~/~ e~~t/~~l~~t~) t~ afford 0.38 (38~~~ yield, df the tile compound, mp 6~-62 °~.

~~ 9392048 P~L.'g'/tJ~92/QS972 ~:~. t~~
- ?9 _ .. aEt ~h O~H~
add E~~1 (0:2g,1.03 mr~~L) to a room temparat~ar~
solution of tha prodc~ot of Examp!~ 224 X0.30, 0.?2 mmo!?, !~-nothytmorphd!!n~ (0.11 mL, D.94 mmpi~, ethanol (0.1 rrtL, 1;44 mmol~ .
aid H~~'t (~:12g;,0.3~ mmol) ip ~H2~t2 (~ mL). ~tlr the mi~ur~
-dv~rnight. Monitor by TLir (5°l~ ~Ie~H/C~12~12~. Upon consaartroptioro of starting EOmpound; dilute pith Cii2~l2, wash with 1 Eli ~i~l, vvat~r~ dry twar anhydr~us I~~~~~~; #iltar and concentrate to a ra~idu~.
Chro~~tc~gaph the ra~idua (SIC~~, 3p/o iUleC~i-i/~H2~e23 to afford 0.3~g (100pJ~ Yield) ~f the title cbmp~und; rnp. T6-77 a~.
Tha ~allo~ring cocnpou~ad oars be pr~parod by substantl~!!y 1 ~ the same procedure:
~~~mple 24A
~O~IE=t Ph(CE-hj34.. ~:,:
~ '~
rrtp 74-'~aa~

f s :..; ..,. . ~:~:.. ... ' . '. ,:... ,, ~ .~~~. .. . ~:.":. , .., .., . ;
'.:.:. ; ~ :v . ~~.~.., ~ ,~: .. ,..: . ,.. . . .....,: ::, ~~' 9310208 P°~3'/Z3~9Z1~59~2 - ao -~v ~~3 NH ~~~
~c~~
. 5 Add mathanesuifpnyl chloride (0.05 rnL, 0.67 rrtrno~.) to a 0~~ solution of the produc$ of Bxampla 6B (0.:60.67 rremot), pyridine(3 dr~ps) in CH~~i2 (5r mL). Stir the rnixtur~ d~rernight. Ndonitor by TL.C
(50°l0 ~t~AcdhaXanas). Upon ~consu~npti~n ~f Starting rrtatarial, diiut~
~,,~h CFf~,~l~; wish with 0.5t1A H~t; 5°/~ Nadi~CJ~, ~vat~r and brine, dry ~ p ~~~r anhydrous sodium ~ulfat~, fitter aid condentrate to a reeid~aa.
~hr~r~atogaph the ~a~~due (Si~~, 50°h Stt~Ac~hexanes) t~ afford 0.~ 8g (56°l~ yield) ~f the $itle compound, CAB l~iB (6lJI+'1 ) = 465.
By aub~t~ntially the Lama procedure, the folto~ring Born ~und~ pan be re arad:
example 25A Exarnpl~ 25B
~_ Cat ~- G~i i '~ a ~ 1 ~~cc~ .4.
~'h(c~r~
~ ~ ~
~ i~
~ ~c~t3 ~.

J~3 . . ~.~:~:.. .'.:.:~ : , . ~:.. , .;..;: ::,:. ~ ,. ,.. ....~ ...:v';..
..::: .;. '.;., , :~....,:~.:~.;.. ,.... ;':~... ~ , ~ .,.... .
t.;:.~.. .'.,..~.;; .:..:.,' .. '.\..', . '. :; , ,....:'... , ~~ ~:.. ,. .
.''. .. '.'~:'' "'~'. - .,... ~' .,:: .:. , ~ ''.~. .',:; ~.: :'~.;~:. ~
....,: ~;. ~..
n :. .,.,.:. . ,; .., .:.: . , ;. ', ' ...: ~ :. . .,, ; ..:% .; .,. : , ;. ""
. : : v: ,. . ....,; .., . . _ . _'."
. .. , , . ' pro 9~o~zo~~ ~~~s~zpos~7z ~~arnple 25~
po CH3 . OCH~
~i HIS M 542 , le, 26 NH~QCH~
~nc~~o~~ ° ._.
~~
~CH~
Add acetyl ~h~lori~e (0:04 i-nL, 0:5'7 mrn~L) t~ ~a s~lution ~f the product of example 5~ (0.20, 0.52 mmcl) ~~d trget~y8a~in~(0.~ ~ mL, 0.79). ip ~l°6~CI2 (3 ~L) at ro~m temperature . ~~nitor by "fl-G (50%
~t~Adlhexana~). i<Jp~n ~~n~ur~pti~h of starting m2~tari~! (°~~h), dilute ~t 0 pith ~~~2~t~, w~~h with 5°l01~IaH~C~~: water end brir~~:, dry ~~~r arshydr~u~ ~9a2~~~; ~~ter ~n~ con~e.~~r~ta R~ aff~rd ~.l gg;.
(55°I° yield) ~f the title camp~und, rnp i 53-154 °C.

3 . .,"v ,..~, . :. ~ ~~~. .'. ': ,':. ,.. . ,.. ' '. :" :..r 1 , ...f.r. ~; ~~: ,m..'..; . ,..:..:.m. s.. .,...v.~. ..,~":-. .~ ~ ~ ~~.:,.~ , .
. : . , .~::. . "' . . . .'.' . ...'.., v.. ~ ...~. . .... , .,.~' ...'.."
7 3 t.....,.~,_ :..": ......._,. .' .:~ , ,, r,.. ~..'." :~ .:~'~~',. ~
......~.: , .~.:..~ :.., : . ..... :,.. ' , ...., .:... ...
~~ 93/02E~4~ ~Cd'~I1892/~5372 Nca~r~a ~r~~cs~)~
~cr~3 .5 FBefiux a suspension pf the produdt of t=xampie 15 (~.6g, ~:5 mrra~i), hydr~~r~arr~ir~e hydr~ohtoride (~.4g, 4.5 rnmoL), sodium a~et~t~ (O.~g 4.5 rrimol), methanol (~2mL) end water (5mL) overnight.
~~nito~ by TLC (5a°!n ~tOAc/hexanes). ~6pon o~nsurnption of starting material, evap~rate ~~ dryness, partition the residu~ bet~reen water and .t ~ ~tflyt "~' Cletat$~.e P.xtr°dC°ot lNlth Et~~1C, Gom~?6ne the extr'dlCts, W'dlsh ~litt'9 i~VI~teH' and brim, dry over anhydr~us t~a~S~~; filter and oonoentrate to a rdsidu~. Chrorrat~graph the residue (sitioa gala ~0'~!~ ~tCA~hexa~nes) to provade the title enr~apound; mp 9~-99 °G; and example 2~A:
~ ~' N~CH3 p~lt~i~"'~2~3aP,~, '~ 5 ~~i~"~~
mp 63-64~ ~

,,. : : ::: .:':.: ,:'° ::, -t: . .. .,. ..; ; . , '~J.:';..."...::.'.'.~.~~:::"...'..':.'. .:.v. ..,.,:., .. -.:
,,;.'..,'.,,;..:. w.w.;.;~ '.:..'; .: .":~ .v:'..:... ..,..~..-.:... ; '...,.~
.~.':'" . ...
t . : ,... .'....:...., ..'..'....:..~. .. '., . ~ ...:.. .:.~. ~'~':v ~:.:,' . ,' -.~,'~~.. ~ '~~ . , ..: ~;.:. . :.:.: , . '., " .'. . ......,.~..' .. ' .. . :.. ' , ,.. '~.':.. .. , ':':~ . .:::~." . :.~~"~ .,.. .'.... :.'.,~..
,':-:...! ..~.,.~..:.:.. ,',:., ~. '.:,',..'.,. . .; ,. ._..,:...,~.~ ' ., vv~~ ~m~x~~r~u~~xio~~~x s~
O~' OCH~
Reflux a solution of the product of ~xarnpla 1? ~3.2g, ~.3~
nnrn~~)a GH~Gt2 t9 5 rnL~ trifluoracetic anhydride (15 rnL) for 9 a ruin.
lulonitor th~ ra~cti~n by TLC (100°/a ~t~,~c~. lJpon consumption of stacking rreat~ri~l, distill t~ remove most of solvent, coo! to morn t~rr~paratura., ~n~l evaporate to a residue. 8~issolv~ the r~sid~a~ in 50% -.
~! 0 triathyisnninalrn~th~not solutibn (30 n~L) stir for 15 ruin., evaporate to dryness ~~ a rot~vap. Ftadissolva in ~~l2Gl~, v4rash with Ni~,~Gl ~sat.~.
dry ~yer anhydr~us ~4a2~~~, f'sltcr and concentrate onto ~n~ugh silica gel ~~ g ~i~~i c~mo! ~ubstrat~) that a free flowing p~wder results. Load the p~wdor-ont~ a chromatography cdlurron packed with sllica~ ga! and ~ ~ 30 °/~ ~tQ,~o/hax~anas. Elutavwlth 30-60% Et~Ac/h~xan~s to provide' 2.C5g ~59~/~) of a resid~re. Recrystailiz~ froix~ ~tzGlG~I~~I~ ~o give the title c~rnpound, ~np °I34-13~°G.
E~m w29 ~ ~ ~ ..
c.)CCl~3 ~issolve the product of Ex~rnpda 29 ~ ~! .~1 g, 4..49 rnmol) in T'MF X25 '~nL~ coot to 0 °~. add 1 N ~a~?H (5.39 mL, 5.39 rrtrrtol), and a ,:.;:, ' ':. .. . '. . '' ' . , '; '; ' , ; . . .: , ... ;.:.
.rd ..; .. , :.. ;::. :;,, : , ': . ~ ~, ..~: . " ... , _.. ~;',;~ ~. ,...' , , ,. , . _.
. t. ,' ~.~, , ... ... . ~.~. . . ,,.., .. ~ . , . ,. ..
wo ~~rox~c-rr~.rs9x'os~7x solution ofi aqueous amrs~onia (16.8 mL, 5.33 mmol), followed by cholorox (6.7 mL, 5.39 mmol). lvlanitor the reaction by 'TLC (5~°/~
Et~.Rclhexane). ~Dpon consumption of starting material, dilute with Et~~c, wash with wat~r and brine, dry over anhydrous Na~~~4 and concentrate to provide the sutfinamine (1.88gj.
Dissolve the sulfinamin~ {1.888, 4.49 mmolj in CH~CI~ {50 mL), add m~chloroperbenzoic acid {1.70g, 9:88 mmol). Monitor the reaction by 'TLC (50°/~ EtC3Ac/hexane). lJpon consumption of starting btateriat, quench with solid Ca{~Hj2 {1.78g, X4.0 mmolj, stir for 20 min., filter and concentrate onto ~~tough silica gel (i g xiC)~! mmot substrate) that a free-flowing powder results. Load the powder onto a chromatogrbphy c~lurrtn packed with silica gel and 50 °/~
Et~Acfhbxanes. ~ibte with 50% EtCAc/hexanes to provide 0.49g (24°!°) of the title compound, mp i T4-1 ~6°C.
~x~,ml l ~d~ ~Brs {5.15 mL; 5.15 mm~t,1 M in Ct~l~Cl~) to a 0 °C
solution of the ~ornpoun~d of Example 7~ (0.~88g, x.06 rnmotj in CH~Ct~
{~5 mLj. Mpnitor the reaction by 'TLC (30% Et~Ac). ~Jpon consumption of starting rnat~rral; quench with P~al-tC~~ (sat.j and methanol, stir for 30 min:, wa~i~ with N°tCC~3 (sat.) and water, dry over anhydrous Na~~~~, .
~5 fitter and conc~r~trate onto enough silica get {1 g Si~2! mmol substrate) such that a free flowing powder results. Load the powder onto ~ -chromatography column packed with silica get and 100°/~ ~t~Ac. Elute with 100°!° Et~P~c followed by 5% t~Ae~ti/Et~Ac to provide ~.2348 {~2%~
of the title compound, Ct MS {l1~+1 ) = 359.

. ,i .n..'..:.~.; . .....':~ w.'....n'. ,.,.....~:. ,,..'., v., ',. . ..".. .
~:,~. ~: ,'.- ., '..: .."...~:~ '.'.. '. .;. . ~.;... .. ::: .....
,..p... .. ,.,......,.... . .. ..t ,._.,... . .,. . .,~.':. , ....,. , .:. .
;".; .. ~",., . :..w.:~.'. ~~. _...,... , ':.::.~ .._;.:. . ",........,... .,.
. ,.
'..1 ...... .. _ :: .,.u, ..'., ... . ... a... ~.;~..:. .,.;,..,.. ' s,~.. , '~ . ~'~~:
.~,~~:y.~ ,. ~_.. , , '.:'~.~'. ,. "..~ .~.. ....:'.~.', .. ..
uW r, , .. . . . ~ . ,.n. .. .: . . .. ., W(3 9~i~204~ ~"C'I'/LTS92J~~972 g5 _ ~xam~le 31 ~~' F~eflux ~ mixture ~f the pr~duct ~f Exampl~ iia (0.~3~, 0.6 mmoi) ethyl~n~ g9yc~1 (0.2rn~., 3.6 nnm~i), p-t~duer~e suif~.ni~ arid end t~lu~ne (5 rriL) ~~~rni~ht. tu!~nit~r by 1 H NtVt~i end °fL~ (50~~0 ~tC~A~lhexanes)., ~~~l to r~br~ temper~t~r~, ~r~~h with NbHC~~(sat.), wit~r end brinb, dried dyer anhydr~us ~1~~~~~,, end ~r~r~c~ntr~tg to give 0.2Tg (10~'~!~) ~f the title ~~rr~pound; irI IUIS (N9) a'443.
'~°h~ tb!t~wing c~rnp~u~d pan b~ pr~par~d by subst~ritia!!y the ~~me pra~edur~: ..
Example 31 ~
Ed NI~ {t~) = 4~3 a (!u..r4,M ' ~ ~' . '. ~,.: r ,...ru'.. >. ~~~~' ~~ ' ~ ~ ~'~. ,. .: . ~,. .~~
, :.;,~ ~.:.. . . -...' _~v . :. . .~:.~:.. .,.'.', WC) 9~/02tt48 PC'I'/I1~92AOS972 _g~_ a ~~iH~
stir a solution of 333mg (1.00 mmol) of the compound ~f sample ~~; and 180mg {1.20 mrr~ol~ chloramina-T' Nal in 4.6 rnl. ~I4A~.
,qdd ~~mg {~ .~mmoi) aid stir for 13h at room temperature. &'ar~ition the r~~c~timn between 30 rhL ~i iV HMI and 30 mL ethyl acetat~. tAlaah th~
organic layer with ~ 0~B~ aqueous Na2~t~~ and dry the organio aole~c~n ~~h ~g~~~. ~~~~e~trat~ in vacuo and chromategraph the residue eserer (silica gel; ~0% ethyl acetate-hex~ne~ to gie~e ~7~rrtg ~f the title compound; ~I ~IIS {~+1 ) 5~ ~; and ~1 mg of thd diddo anaaog (~~arnpt~
~2A~
a ~ -.; .
9~
CI M~ {f1A+'f ~ - X40 y ~ . . ' _ i -~'. . '. " .., , :,.;. . .' ' ~.. v .,' 't~0 9~/U2P~'H'lIJ~92I~S972 ~.~ _~~
~CN~
N~
' C)CH3 Stir 400 rng (0.96 mmol) of the c~rnpound of ~xannpla ~~, i~ 25 rnL acetic acid and 6mL ~watar at 0~'G d,nd add 1 ~~ r°~g (1:92 rnmol~
~a~~z i~ ~:7 mL water. Stir fir 20 yin. at 0~~ add 212 mg (3>~~ rnrri~!~
~aN~ in 9 mL w~t~r end stir for 3h while warrnirag to r~orn tarr~parat~rra.
pilut~ pith ethyl ~detat~ and neutralize with NN~~H: ~ry the ~thy! .
~ 0 a~tat~ iayar ~rith ~dlgSO~ and concentrate to a residua. F3acrysta!!iz~
the ra~idu~ frog athsr~h~xanes to give the titled compound, rnp = E0 ~4°~.
!,~x~.,rr~~l,~ ~~l ...
~ (~~C3(CHz~~~~a~t~~
Ph~~fl~~~ ~ f ~
~~s~~iv~ 300 rng (x.77 tttmoi~ of the Compound of ~x~r~p1~
9F; in ~ mL C~l~~l~ and add 9~ pL (t 2~ rrsg, ~.80 mcnol~
~0 carb~tn~~h~~ypr~pion~l chioeide ~hd 146 ~L (~ 09 rrtg~. 0.~4 rn~rtol~
~O~i~'~ a~sa: fir ~~ room te~nparature f~r 1,5h. add another full portion of ~~d chiodd~ arid li0~ig's ~a~e :and stir fi~r ~n additlona! hour.
pa~ltiun the raac~i~n bet~vee~ e~thy! acetate and ~ !~ l~~l. r~r the ethyl acetate layer v~ith l~gS~4 and concentrate to a residue. hror~atograh ~i'''.z . ,,_;,, ..~: , .. .. .: .:: .' .:' '., , .;'. ,::.; . . . ' °:~: . ,v:;:: - ;._ , ~o ~~eo~~~-r~s~~/~sg7z _~s_ the residue (Si~2, 4~p!m ethyl acetate-hexane) and filter through grade i basic atumina eluting with 50~loethyl acetate-hexane to give 33~ mg (86~1~) of the title compound; ~l fUtS (B~I9+) -°- 501.25.
~~~f~~
OCH~
Q
OCF~~~3n ~~nzyt bromide (0.~4 g) eras added to a solution ofi the impound ofi ~xanrtpB~ 15~ (1.0 g) in acetone (15 mL) contalnlng K~C~~
~.x'15 g): "1-t1~ reaction was heated at reflex for 26 h. 'The reaction rr~ixture was then poured into water and the product extracted with ethyl acetate: The crude product was recrystallized from ethyl acet~telhaxane to give ~~.908 g, 74°Jo yield) ~f the desired product, mp 115-11 C°'t~.
'The f~ltornring compounds were prepared via substantially tha game procedure:
Fxarnple 35A example ~5~
O~ G02~i ph(C~~~3,~
~~ ~
c~~t ~~~~ ~l~r~ent~l ~nalyslss calculated for ~~~~12~~~~:
~l I~~ (1~1~1 ) - 474 1~, X8:04; Vii; 7.03;1i13.3~
Found: ~, '?8.00; l~, °T.02; ~l, 3.55 . . ... . W ,.. .. ,._ . ., ;~ y, .. . ,. . i: ~~:!i:
~~ 93/69z~48 P~.°I"/~~9~/Oa972 _89_ "fhb oompound of Example 7~1 (0.19 g~ eras c~ool~d to ° 20°~~ "T'o $his w~ added a solution of diethyl zing in toluan~( 4.3 mL of a 1.,1 ~ s~fution) fiollov~r~d by diiodotinethbn~ (2.56 g). 'fha reaction ~i~~re w~~ slowly ~Ilowed to warm to ambient temperature over thr~a -h~urs. ~'h~n the rb~otion mixture was warnnbd t~ 45°~ f~r 5 Enir~:
After 1 ~ poling the r~a~tion mi~t~ra was trsafed with aqueous NH~~i and pr~duct ~~r~cted with diethyl ether. The organid layer was v~ashbd with wata~°; brim ~.nd conoentrated to a residua. Thb residue vas puri~ad by chromatography (StC3~, ethyl aoetate/hexana (~:7~) to give the title ..
d~mpour~d (x.17 g; 6~~/e yield), Elembnt~l anaiysi~:
~afcuiat~d - ~. . . ~l, ~e5~, ~, .
lound° V', 7~.~~~ i"!, 6.~~y IVy ~.~~.
... ~X~l~ 7 ~CI-93 ...
. ~' ,.,;,~ . . .

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-90_ c00~ ~ COC6 .
v v ~ombins 5-phenylvaleric acid (89.9 g, 0.504. mo!) and ~~~I~ (89.3 mL, t.2~5 rno!) in a 500 m~ round bottom flask as~uippgd with a condenser and drying tub~. . !Meat the flask to 70°C and maintain thsa reaction at reflex for t h. Vacuum distill (50 -100 mm ~!g) the excses r ~~Ch and add 200 mL of dry toluene to the remaining mixture.
°l 0 ilacuurn distill a second time to remove the toiu~ne and any ~°esidua!
~~~1~. Add t 8~ mL of dry THF t~ the crude acid chloride remaining in the reaction ve~eel and use the resulting solution directly !n the next step.
~~
~) ~-bratyllitk~ium ~ (Ot-t~~
~ PttH
1, LOCI
~ ~
~ ~~
~~rnbir~e 7s g (0.289 rnol) of R-(+)-4-benzyl-~xa~olidinon~ and 1.3 L of dry Tf-!F under dry nitrogen atmosphere.
~0 Cool he resultihg s~lution t~ -78°~ and add X78 mL ~f a ~i .5 IUi solution of n-butyll6thium in hexane over a period of 30-~d0 minutes. stir the rni~ta~r~ fdr a~n additionb! 30 mindtes following the additipn. Add the solutian of 5-plten~lvaieroyl chloride from step (a) over ~ period of 45 ' minutes. Allow he mixture to v~arm to 0°G and stir for 1 h> Quench the z5 reaction rnixtur~ by adding fi73.6 tnL of i~2~~~ (t ~A aqueous solution) and stir for 1 h: Distill off the °I'fi'F under vacuum at 30-35°~. ~iluta th~
residue w~h 1 L of v~ater and ~xtract vrith three 800 rnL portions of ~~~~1~. ~orrobine the organic extracts and wash ~rith 500 rn~. of uwat~r~

~Ip 93/p2pq~ P~°°i°/US92/05972 g~
then with 500 mt_ of brine. tJry the organic extracts over f~ltg~~~, filter, then concentrat~ in vacuQ to an oii. ~issoiv~ the oil in 200 mL of .
hexane, then distill off the hexane under vacuum. Repeat the hexane treatment two more times, then dissolve the oil in ~ .7 mt_ of CHZCh. They resulting solution is used directly in the next step.
Ph ~uz~~~'~~3~ha diisopropylethyi-' ~ (C~ ~ 4 -Ph a m i n a ~ H
Cl-Ig~ ~ Cl' Cool the ~ofution of the product from step (b~ to -5°C to 1 ~ O~C, under dry ni~rog~n atmosphere. Add 129.5 rr~L of di-n-butylboron trifi~te at a rate that maintains the temperature of the reactson mixture at .6°~ t~ -~nC. Following the addition, stir the mixture for ~ 0 minutes, then add g~.12 ~nL of this~propyl~thylamine ~.t a rate hat maintains the femper~tur~ of the reaction mixture at -6~C to -~°~. ~oliovbring th~a.
..
t 5 addition, stir the r~iacture at 0°C for 30 rhtnutes, then cool the mixtur~ to -76aC end ~t~r for 30 minutes. Add 57e4 mL of p-anisaldehyda and stir tire mixtur~ at -°~~°C for 30 minutes, thin at 0°~ for 9 h. V~hiia tvaint~~r~ing the temperature at 0°C to 5°C, quench the mixture by adding 658:2 mL ~f ~ pN 7 buffer soi~rtion ~~~ g I~H~PC,~~., 12 g Na~~t 20 apd X00 rryL. of water; then add 47~ mt_ of 30°f~ t-i~~~ and stir the . .
resulting mixt~ra at flaC for ~ h. ~xtrac~ the mixtur~ ~rith thr~a fi00 m1.
pa~rtipns of haxane:ethyt aot~tat~ ('9 :1 j. Combine th~ ~rgan~o axtr~c~ts and wash ~rith 500 rnt_ of saturated P~aRC~s ~aque~u~~, than ~nrith 500 mL of brine. Dry the ~~g~ani~ extracts over i~a~~~, flt~r, and w~p~rat~
25 td are oil. Crysta~tix~ the oil from hexanelethy! acetate ~~ :9 ~ to give 1'76 g of the product a~ at v~hite solid. . ..

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'VVC! 93/UZikt~ PCT/~35~2/dDS~r'2 _ 92 C
~~, I:iOH
. aH I32C)Z HC H
t~~~a i f G~mbine the product of step tc) ('i70 g, 0.36 Mol)i 1585 rnL
of 'fH~' and 400 rnL of v~rater, stir the mixture and cool to about 3°G. Add ~s m~, ~~,1 ~6 ~~1) of 30% H2G2 to the mixture over 1 ~ minutesi th~n add a soluti~n of Ls~~! (~6.2 g, 0.362 &vtol) in 400 mL of water over a pe~od c~f 30 minutes: ~~ir th~ reaction mixture at 0°G to 5°G
for ~ h. ,add a selution of 2?2 g of t~a~~G~ in 850 mL bf vrat~c ~ver 70 minutes vrhiie 'l 0 Keeping the temperature under 27°G. ~istill oft the bulls of th~
solvent under vacuurr~ arid add 7 L of water. Ex~racfi with flour 1.7 L portions of toluene: Acidify the ague~ua layers to pH 2.4 with 3 N HGI. Ex$ract ~rith one 2:6 L portion and tw~ 1.7 L portions ~f ethyl pcctate. Combine tl~e ethyl acetate axtra~ts, rash with brines dry oust NaS~~, frlter, then arr~p~rate t~ give the pr~duct as a white selid, 112 g.
g-anisidinc H
HC D
~~.
~~H~3 Ck~IgCJ

.:'. :. ,:: ,. .: . ,, ° , :.:'.~ ~:' ~ : ~ , .., ~V~ 93/02~4~ ~CT/ZJS92/Oa972 .. ~3 _ Combine the product of step (d)'(19.4'~ g, 6~2 mmo!),'400 mL of acotonitrile, 9.49 g (S2 mmol) of 1-hydrouyben~otriazol~ (I-f~~T'), .
~.9t g (1 ~6 .mmol) of p-anisidine and 14.05 g (fiB.~ mmol) of dicyclohexylcarbodiimide (~CC). Stir th~ reaction mixture at 40°C for 4 h and confir~ra the cconsumption of starting rreaterial by Tt_G (6:4 h~xanel ethyl ac~tat~). Concentrat~ the rr~ixtur~ to 1/3 Its volume and partition between 300 n~L of water end X00 mt. of ethyl acetate. Filter th~ organio layer, then ~nrash with 200 ml- of 1 Id HCI, thin vuith tdnro i 0~ mL.
portions.. _..
of saturated hIaHC(~s, and two 100 mL portions of brine. try the organic layer ov~~ ~IaS~4 and concentrate to give the product as a solid, 24 g.
Combine the product of step (~e) (115 g, 0.2'45 l~lol) and ~.~ t_ of TI-!I° undgr.drU nitrogen at~n~sphere and cool to -7~°C. Stir the mixture and si~nuft~n~~~sly add a solution of 137 mL (0.551 oi) of trl-n-butylphosphina in 9'l3 mL'~H~; and 163 mL (1.03~tUi~t~ of di~thylodicarb~~ylata C~EA~) over ~ h. ~610~ the rnixtura t~ warm to r~om t~rnp~rature and stir overnight. Fiemo~re ~th~ solvent under vacuum. Filter the residue through a plug. of silica gel using ~l-l~~t~l hexane/ ~thyl acetate ('70:24:fi) as the eluant. Evaporate the solvent and.

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'~V~O 93102t)4~ PC:I'/IJ~9~f05972 _9 purify the residue by preparative HPLC (silica gel, 15°/~ achy!
actetatel °
hexane) to give 88 g (8~% yield) of the ~i-tactam product.
~x ~H~
~ Tl~t~a T~.~A ~~.
~iichloa~~nnecth~nc 1 ~ ~~~~~-~~
~~
ph Cool a solution of 33.7 g (0.t m~!) of the product of 1 ~ ~xhrnple 37, step (b), 4n ~00~ rnL of G~l~Cl2 t~ -~0°C. Stir thp cold solution and add °i l rrDL (Oa mol) of TiCI.~. Stir the mixture for 1 ~
ruin. at -2t~~C; then s9o~srly ddd 30 mL. (3 equiv.) of t~~ram~th~lethylenediamlne ~!°Nt~~A) over a peri~d of t 0 min., while keeping he temperature below -~ t~°C. Stir thb mixture at ~15° to -10°C for ~4 min., then add 24 mi. (2 equiv:) ~f p-anisal~Pehy~le: Stir at -'! 5° to -1 ~°C f~r 9 hour, then allow the rrtixtur~ to warm to 't 0°C v~hile stir~ir~g for 40 min: ~uendh the r~~dti~n by adding fia0 mL. of i D°/~ aqueous ta~aric acid, then add C00 rnL ~f ~ethy! acetate: Agitate ws!!, thin sep~ratb the layers; e~ctr~cting the ~q~bous layer with mother ~~00 rnL ~f ~~hy! acetate. C~mbirie th~
~0 or~anac extracts end wash successively with water, saturated NaH~C~
(aqdeous) and brim: Dry the org~~lc ~sofution ~ver anh~dr~u~ ~a~a~~.
fi~~r, thin concentrate to a residue. ~rystalllze th~ r~sldue from a mi~cture~ of 1AO m~. of ~thy! acetate -~ ~1Q mL of hexane t~ gi~re 3~.~ g ~f th~ desired pound, which can be used in step (d) of Exarnpl~ ~7.

."v.. '~;.; , ..
...,;. .:, ,'.: ,,',; .. ~_ '- , w~ g3rox~~ ~~ru~~xr~sg~x '~1~~~~
s~
H
hr.
~1~"
~~3 ~ ..
~Mg ~ ~ .~
' Y r~I
(Cti~~ ~, (CH~~ ~I
~ 1 ~ F'h ~h (~H~ 1~3 bass~1v~ 500 g (0.~5 r~oi~ of the prodcact of ~xarnpi~ ~'T,.
staple), in ~~00 a~nL ~~ CH2~B~, then add 4.0 g (°!2 mrhot) of sera-nrbutyi-a~~b~p~~ hydrogen sulfate. Stir th~ mi~t~r~ while ~~Ii~g to ~ 0~ to 20°~ and add 50b/~ a~uedus Na~H X200 9). Siwa~6y add 60 g (255 ~r~oij of 2,6-diohi~robenzoyl chloride to the stirred mi~tdra wer a padod pf 30 smin. Cor~tinus stirring ~t 15° to 20°~ for 3 h:, third pour tha rni~'ture into 2000 rnL of ooid water. Separate th~ layers end ash the . ~ ~ organic layer with water anti! r~e~ral p!-! as attasr~~d. ~istit! the ~;:~ ;;...:.. ,, ~y;: ;. ;.:.,_, :. .;, , ''!~~ 93f02t~8 FC.'T/US92~&5972 rnathyt~ne chloride solution to r~duce th~ volume to 0~0 rnL. Meat tha solution to refiux and add 800 mL of heptane. Cool the hot s~lutior~ to 0°~ to crystat(i~e. C~Ilect the product by ~Itration to give 1 t 6 g of the dichlorbben~oate product.
°so. _ ~~
Ph ~t~~
~c~
combine 500 g (0.55 mol) of tE~e product of step (a~ with X50 g (1.1 mol) ~f benzyltriethytammonium chloride, X000 rr~~. of ~H~~6~
0 and 5000 rnL of methye t-butyl ether. Stir the mixture ~rhile cooling to ~t5°
to ~~°C; thin add 1000 rn~L of 50°/~ aqueous t~a~H ~ver a period of °D 0 mix: stir the rniure for 4 h., then pour into 5000 mL of water and ~ Icg of icy: S~par~td the (~y~rs and wash the organic layer u~i~h water ~r~tll the pH is neutral. Di~tilt the solvent to reduce the vo~ur~e to X00~ anLa then ~Iter ~~ap~rat~ the filtrate to a residue end purify the residue by chromatography ~n silica gel to obtain the crude product. ~rystatlize th~
produce from 6 ~olurn es of a ~ :~ mixture of methyl t-butyl ether and heptane dt 0°~ tp give-the produo't ~24~ gj.

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'~'~'~ 9~f0204~ PG'I'»JS92>05972 ~,;
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931~~PG'~'°/~JS921059?Z
_98_ ~issolva 3:23 g (10 mmol} of the product of Exampta 37, step (bj, in 50 mL of CHZ~i~, thin stir under nitrogen atmosphere whiia cooling to -20°~. Add ~ 0 mL (10 mmo!} of a 1 t1~ solution of "t"i~l~
in G~hCf~, stir the mixture far 5 min., then add 1.5 mL ('f 0 mmol} of ~'tviEf?A. stir the mixture at -25° to -20°~ for 1 h., then siowly add 4.g g (20 mmol) of the Schiff s base derived from anisdidehyde and p-anisidine as a solution in 50 mL of ~N~Ci~ over a period of 30 min. stir the mi~ttu~e at -20°C for 30 min; than gradually warm to 0°~.
°°f"'hs reaction is ~nonitorad by ~1PLC (~orbax~ ail colusr~n~ 1 ~4 ethyl dcetatelhexane}; while stirring ~t 0°C, until complete: C~uench the mi~ctur~ by pouring' into 50 n~t~ of 10°/~ aquepus tartaric acid.
Extract with ethyl ac~tata, then wash the organic extract successively with saturated ~IaHCt)~ (aquepus} and brine: Dry the organic solution over anhydrous ~a~S~~, filter, then c~ncdntrata to give the crude product. Crystalti~~
from ethyl acetatelhexahe to give the p~rifiad product.

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~ ocH3 ~~2~ ~~°t~9 T~fF Nay °rnn~
~ ~ ~.
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~ ~~i~tti~n of~ 0.505 g (0.~9 mmol) ~f the produce e~f step (a) in 25 rnL ~f ~~H~Ci~ is stirred at 0°~: the0 t~~at~d with 1.7°l rn~. (1."77 srnr~tdl) of a 111 s~lutiora of sodium bistrim~thyisilyfa~nid~ in ~t°Hi°. Stir the fixture while warming to room temperature, then o~ntinue stirring until the ~tartin~ c~at~riai is gone ~s determined by ~tF'LC (iypicaily 9 t~ 1 'ice h.~ ~uendh the mixtur~ into 10°f° tartaric void (aqueous).
9~lash tha ~ ~rganio lay~r sucxessiveiy with saturated NaHC~~ (que~us) and l~rin~, thin dry d~r~r anhydrous N~2~~~. Miter and conodntrata t~ gi~~ the title . . impound.

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w~ 9~~oxoas ~~rus9xios~~x The foilovuing formuBations exemplify some of the dosag~
forms of this invention. In each the term "active compound" designates a compound of formula I or II, Preferably (3R,4S)-1,4-bis-(4-methaxyph~nyl)-3°(3-phenylpropyl)-~-azetidin~n~e. However, this compound rnay be replaced by an equally effective amount of other compounds of formula I or II.
jt~~~die~$
1 active Compound 140 540 2 Ladtos~ k~~P' 1 ~,2 11 ~
~ Corn March; Food Grade, as a 10~!~ 30 40 piste in i'~rified Water 4 Corn March, F~od Grade 45 40 5 I~lagnesium ~te~rat~ ~ Z
Total 304 700 tha ~f '(~a~ufaeture ~i~ ttern ~los: 1 and ~ in suitable mixer for 10-15 minutes.
G'ranuiate the mi~ure with Iterh ~I~. 3. ~liill the damp granules through a coarse screen (e.g.,1/4", 0.63 cm) if necessary. Cory the damp granul~s.
Screen the dried granules if necessary and mix with item ~9~. 4 and miac for 10-15 r~inut~~~ Add Item t~~. 5 and mix f~r 1 ~~ mina~tes. Compress o the rr~i~ture to ~pprbpriate size and weight on a suitbbie tablet machine.

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dVf? 93/0204 PC'I'a~US~~/0597~
- 10t -_ ~ ' ~ ,$
1 ~otiv~ compound 100 500 2 L.act~sa lf~F' 106 123 3 ~~rn Starch, food grade 40 ?0 ~ Niagn~siurrv 3tearato IVF
'fotai 2~0 700 ethQ ~, iVla ufa ~ ll~
Mix It~rn I~Jos> 1, 2 and 3 in a suitabl~ blander fir 10-15 ., ~BiflUt~~. /~Cid l$~rl'9 I~P,. 4 acid ml7C fi~r ~-3 rrilnUtas. ~lil the rr~i?Ctl~r~ il'lt~
suit~~ie ~uvo-pi~cp hard getatir~ capsules on a suitable encapsulating rnddhina.
. .using the test pracedures dasbribpcl above, the follov~ing hand ' data wary abtairtad for the preferred compounds, which are r~farrad to ire the foilowic~g table by the aorrasponding .
~~arvpi~ numbers. for tt~e 't vrt° r,~ A~,~T data, n~gativa percent inhibition denotes ~ppar~r~t stimulation, while positive nurrabars denote ir~~ibition; ~~r the ' vresuits, data is r~ported as percent change v~rsu~ o~ntrot; therefbre, negative nu~nbars indicate a positive lipid-irwv~ring effabt.

'~VV~ 9~/a204~ PC'I°/US92/0597~

ACAT !~ Reduction v~
in in vi vita Esc. IC50 ~!a Cdne. serum ChOlest. D~s~

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-5g

Claims (22)

1. A compound having the structural formula (I):
wherein A is -CH=CH-B;
C.ident.C-B;
-(CH2)p-X-B, wherein p is 0, 1 or 2 and X is a bond, -NH- or -S (O)0-2-;
heteroaryl, benzofused heteroaryl, W-substituted heteroaryl or W-substituted benzofused heteroaryl, wherein heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N-oxides thereof, and wherein W is 1-3 substituents on the ring carbon atoms selected from the group consisting of C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, C1-6 alkoxycarbonyl-C1-6 alkoxy, (C1-6 alkoxyimino)-C1-6 alkyl, C3-6 alkanedioyl, C1-6 alkyl-C3-6 alkanedioyl, allyloxy, -CF3, -OCF3, benzyl, R14-benzyl, benzyloxy, R14-benzyloxy, phenoxy, R14-phenoxy, dioxolanyl, NO2, -NR10R11, NR10R11(C1-6 alkyl)-, NR10R11 (C1-6 alkoxy)-, OH, halogeno, -NHC(O)OR5, -NHC(O)R5, R6O2SNH-, (R6O2S)2N-, -S(O)2NH2, -S(O)0-2R10, tert-butyldimethylsilyloxymethyl, -C(O)R12 and and wherein the substituents on the substituted heteroaryl ring nitrogen atoms, when present, are selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, -C(O)OR5, -C(O)R5, OH, NR10R11(C1-6 alkyl)-, NR10R11(C1-6 alkoxy)-, -S(O)2NH2 and 2-(trimethylsilyl)ethoxy-methyl;
-C(O)-B; or wherein k is 1 or 2;
D is B'-(CH2)m C(O)-, wherein m is 1, 2, 3, 4 or 5;
B' (CH2)q-, wherein q is 2, 3, 4, 5 or 6;
B'-(CH2)e-Z-(CH2)r-, wherein Z is -O-, -C(O)-, phenylene, -NR8- or -S(O)0-2-, e is 0, 1, 2, 3, 4 or 5 and r is 1, 2, 3, 4 or 5, provided that the sum of a and r is 1, 2, 3, 4, 5 or 6;
B'-(C2-C6 alkenylene)-; B'-(C4-C6 alkadienylene)-;
B'-(CH2)t-Z-(C2-C6 alkenylene)-, wherein Z
is as defined above, and wherein t is 0, 1, 2 or 3, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;
B'-(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1, 2, 3, 4 or 5 and g is 0, 1, 2, 3, 4 or 5, provided that the sum of f and g is 1, 2, 3, 4, 5 or 6;
B'-(CH2)t-V-(C2-C6 alkenylene)- or B'-(C2-C6 alkenylene)-V-(CH2)t-, wherein V and t are as defined above, provided that the sum of t and the number of carbon atoms in the alkenylene chain is 2, 3, 4, 5 or 6;
B'-(CH2)a-Z-(CH2)b-V-(CH2)d-, wherein Z and V are as defined above and a, b and d are independently 0, 1, 2, 3, 4, 5 or 6, provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6;
T-(CH2)s-, wherein T is cycloalkyl of 3-6 carbon atoms and s is 1, 2, 3, 4, 5 or 6; or naphthylmethyl, heteroarylmethyl, or W-substituted heteroarylmethyl, wherein heteroaryl and W are as defined above;
B is B' is naphthyl, heteroaryl or W-substituted heteroaryl, wherein heteroaryl is as defined above, or R is hydrogen, fluoro, C1-C15 alkyl, C1-C15 alkenyl, C1-C15 alkynyl, or B-(CH2)h-, wherein h is 0, 1, 2 or 3;
R1, R2 and R3 are independently selected from the group consisting of H, C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, C1-6 alkoxycarbonyl C1-6 alkoxy, (C1-6 alkoxyimino)-C1-6 alkyl, C3-6 alkanedioyl, C1-6 alkyl-C3-6 alkanedioyl, allyloxy, -CF3, -OCF3, benzyl, R14-benzyl, benzyloxy, R14-benzyloxy, phenoxy, R14-phenoxy, dioxolanyl, NO2, -NR10R11, NR10R11(C1-6 alkyl)-, NR10R11(C1-6 alkoxy)-, OH, o-halogeno, m-halogeno, -NHC(O)OR5, -NHC(O)R5, R6O2SNH-, (R6O2S)2N-, -S(O)2NH2, -S(O)0-2R10, tert-butyldimethylsilyloxy-methyl, C(O)R12 and or R1 is hydrogen and R2 and R3, together with adjacent carbon atoms to which they are attached, from a dioxolanyl ring;
R1', R2' and R3' are independently selected from the group consisting of H, C1-6 alkyl, hydroxy C1-6, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, C1-6 alkoxycarbonyl-C1-6 alkoxy, (C1-6 alkoxyimino)-C1-6 alkyl, C3-6 alkanedioyl, C1-6 alkyl-C3-6 alkanedioyl, allyloxy, -CF3, -OCF3, benzyl, R14-benzyl, benzyloxy, R14- benxyloxy, phenoxy, R14-phenoxy, dioxolanyl, NO2, -NR10R11, NR10R11(lower alkyl)-, NR10R11(lower alkoxy)-, OH, halogeno, -NHC(O)OR5, -NHC(O)R5, R6O2SNH-, (R6O2S)2N-, -S(O)2NH2, -S(O)0-2R10, tert-butyldimethyl-silyloxymethyl, -C(O)R12 or R1' is hydrogen and R2' and R3', together with adajacent carbon atoms to which they are attached, form a dioxolanyl ring;

R4 is wherein n is 0, 1, 2 or 3, indanyl, benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl or quinolyl;
R5 is C1-6 alkyl, phenyl, R14-phenyl, benzyl or R14-benzyl;
R6 is OH, C1-6 alkyl, phenyl, benzyl, R14-phenyl or R14-benzyl;
R7 is C1-6 alkyl, C1-6 alkoxy, OH, halogeno, -NR10R11, -NHC(O)OR5, -NHC(O)R5, NO2, -CN, -N3, -SH, -S(O)0-2-(C1-6 alkyl), -COOR9, -CONR10R11, -COR12, phenoxy, benzyloxy, -OCF3, or tert-butyldimethylsilyloxy, and where n is 2 or 3, the R7 groups can be the same or different;
R8 is H, C1-6 alkyl, phenyl C1-6 alkyl, or -C(O)R9;
R9 is H, C1-6 alkyl, phenyl or phenyl C1-6 alkyl;
R10 and R11 are independently selected from H
and C1-6 alkyl;
R12 is H, OH, alkoxy, phenoxy, benzyloxy, -NR10R11, lower alkyl, phenyl or R14-phenyl;
R13 is -O-, -CH2-, -NH- or -N(C1-6 alkyl)-; and R14 is 1-3 groups independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, -COOH, NO2, -NR10R11, OH or halogeno;
or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 wherein R is hydrogen.

3. A compound of claim 1 or 2 wherein D is B'-(CH2)q-, B'-(CH2)e-Z-(CH2)r-, B'-(C2-C6 alkenylene)-or B'-(CH2)f-V-(CH2)g-, wherein B', Z, V, q, e, r, f, and g are as defined in claim 1.

4. A compound of claim 3 wherein D is B'-(CH2)q-, wherein B' is phenyl and q is 3 or 4; B'-(CH2)e-Z-(CH2)r-wherein B' is p-fluorophenyl or p-methoxyphenyl, e is zero, Z is -O-, and r is 2; B'-(C2-C6 alkenylene)- wherein B' is phenyl and (C2-C6) alkenylene is 1-propenyl; or B'-(CH2)f-V-(CH2)g- wherein B' is phenyl, f is 1, V is cyclopropylene, and g is zero.

5. A compound of claim 1, 2, 3 or 4 wherein A is -(CH2)p-X-B wherein X, B and p are as defined in claim 1.

6. A compound of claim 5 wherein p is zero and X is a bond.

7. A compound of claim 6 wherein R1, R2 and R3 are selected from the group consisting of H, OH, C1-6 alkoxy, NO2, C1-6 alkoxy-C1-6 alkoxy, m-halogeno, C1-6 alkyl-C3-6 alkanedioyl, NR10R11 (C1-6 alkoxy)-, allyloxy, phenoxy, C1-6 alkoxycarbonyl-C1-6 alkoxy and -C(O)R12.

8. A compound of claim 1, 2, 3, 4, 5, 6 or 7 wherein R4 is phenyl, R7-substituted phenyl or indanyl.

9. A compound of claim 8 wherein R7 is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, halogeno, -OCF3, C1-6 alkylthio, -NR10R11, -CN, OH, and -COR12.

10. A hypocholesterolemic pharmaceutical composition comprising a cholesterol-lowering effective amount of a compound of formula (II) wherein R20 is phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzofused heteroaryl and W-substituted benzofused heteroaryl, wherein heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxazolyl and furanyl, and for nitrogen-containing heteroaryls, the N-oxides thereof;
R21, R22 and R23 are independently selected from H or R20;

W is 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, C1-6 alkoxycarbonyl-C1-6 alkoxy, (C1-6 alkoxyimino)-C1-6 alkyl, C3-6 alkanedioyl, C1-6 alkyl-C3-6 alkanedioyl, allyloxy, -CF3, -OCF3, benzyl, R14-benzyl, benzyloxy, R14-benzyloxy, phenoxy, R14-phenoxy, dioxolanyl, NO2, -NR10R11, NR10R11(C1-6 alkyl)-, NR10R11(C1-6 alkoxy)-, OH, halogeno, -NHC(O)OR5, -NHC(O)R5, R6O2SNH-, (R6O2S)2N-, -S(O)2NH2, -S(O)0-2R10, tert-butyldimethylsilyloxymethyl, -C(O)R12 E, F and G are independently a bond; C3-C6 cycloalkylene; C1-C10 alkylene; C2-C10 alkenylene; C2-C10 alkynylene; an alkylene, alkenylene or alkynylene chain as defined substituted by one or more substituents independently selected from the group consisting of phenyl, W-substituted phenyl, heteroaryl and W-substituted heteroaryl, wherein heteroaryl is as defined above; and alkylene, alkenylene or alkynylene chain as defined interrupted by one or more groups independently selected from the group consisting of -O-, -S-, -SO-, -SO2-, -NR8, -C(O)-, C3-C6 cycloalkylene, phenylene, W-substituted phenylene, heteroarylene and W-substituted heteroarylene; or an interrupted alkylene, alkenylene or alkynylene chain as defined substituted by one or more substituents independently selected from the group consisting of phenyl, W-substituted phenyl, heteroaryl and W-substituted heteroaryl; or one of R21-E and R22-F is selected from the group consisting of halogeno, OH, C1-6 alkoxy, OC(O)R5, -NR10R11, -SH and -S(C1-6 alkyl);

R5 is C1-6 alkyl, phenyl, R14-phenyl, benzyl or R14-benzyl;
R6 is OH, C1-6 alkyl, phenyl, benzyl, R14-phenyl or R14-benzyl;
R8 is H, C1-6 alkyl, phenyl C1-6 alkyl or -C(O)R9;
R9 is H, C1-6 alkyl, phenyl or phenyl C1-6 alkyl;
R10 and R11 are independently selected from H and C1-6 alkyl;
R12 is H, OH, C1-6 alkoxy, phenoxy, benzyloxy, -NR10R11, lower alkyl, phenyl or R14-phenyl;
R13 is -O-, -CH2-, -NH- or -N(C1-6 alkyl)-;
R14 is 1-3 groups independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, -COOH, NO2, -NR10R11, OH
and halogeno;
provided that when G is a bond, R23 is not H, and provided that when R23 is W-substituted phenyl, W is not p-halogeno;
or a pharmaceutically acceptable salt thereof;
in a pharmaceutically acceptable carrier.

11. A compound of claim 1 selected from the group of compounds listed in the table hereinafter:

12. A compound of claim 1 or 11 which is (3R,4S)-1,4-bis-(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone.

13. Use of a compound of the formula (II) in the manufacture of a medicament for lowering cholesterol:
wherein R21-E-, R22-F-, R23-G-, R20 and relative stereochemistry between R21-E- and R23-G- are as defined in the following table:

14. The use of a compound of formula (I), as defined in any one of claims 1 to 9, 11 or 12 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for lowering serum cholesterol.

15. The use of a compound of formula (I), as defined in any one of claims 1 to 9, 11 or 12 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting the enzyme aryl CoA:cholesterol aryl transferase.

16. A pharmaceutical composition comprising a cholesterol lowering amount of a compound of formula (I) as defined in any one of claims 1 to 9, 11 or 12 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

17. A hypocholesterolemic pharmaceutical composition comprising a cholesterol-lowering amount of a compound of formula (I) as defined in any one of claims 1 to 9, 11 or 12 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

18. Use of a compound of formula II, as defined in claim 10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for lowering serum cholesterol.

19. Use of a compound of formula II, as defined in claim 10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting acyl Co A: cholesterol acyl transferase.

20. A compound of formula (II), as defined in claim 10, or a pharmaceutically acceptable salt thereof, for use as a hypocholesterolemic agent.

21. A process for the preparation of a pharmaceutical composition as defined in claim 10 which comprises admixing a compound of formula II, as defined in claim 10, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.

22. Use of a composition as defined in claim 10 for the manufacture of a medicament for inhibiting the enzyme acyl CoA:cholesterol aryl transferase.