CA2205202C - Sulfur-substituted azetidinone compounds useful as hypocholesterolemic agents - Google Patents

Abstract

Sulfur-substituted azetidinone hypocholesterolemic agents of formula (I), or a pharmaceutically acceptable salt thereof, wherein: Ar1 is aryl, R10-substituted aryl or heteroaryl; Ar2 is aryl or R4-substituted aryl; Ar3 is aryl or R5-substituted aryl; X and Y are -CH2-, -CH(lower alkyl)- or -C(dilower alkyl)-; R is -OR6, -O(CO)R6, -O(CO)OR9 or -O(CO)NR6R7; R1 is hydrogen, lower alkyl or aryl; or R and R1 together are =0; q is 0 or 1; r is 0, 1 or 2; m and n are 0-5; provided that the sum of m, n and q is 1-5; R4 is selected from lower alkyl, -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10CONR6R7, -(lower alkylene)-COOR6 and -CH=CH-COOR6; R5 is selected from -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7 -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10CONR6R7, -CF3, -CN, -NO2, halogen, -(lower alkylene)COOR6 and -CH=CH-COOR6; R6, R7 and R8 are H, lower alkyl, aryl or aryl-substitued lower alkyl; R9 is lower alkyl, aryl or aryl-sybstituted lower alkyl; and R10 is selected from lower alkyl, -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, COR6, -SO2NR6R7, -S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10CONR6R7, -CF3, -CN, -NO2 and halogen; are disclosed, as well as pharmaceutical compositions containing them, and a method of lowering serum cholesterol by administering said compounds, alone or in combination with a cholesterol biosynthesis inhibitor.

Description

CA 0220~202 1997-0~-13 .
SULFUR-SUBSTITUTED AZETIDINONE COMPOUNDS
USEFUL AS HYPOCHQLESTEROLEMIC AGENTS
BACKGROUND QF THE INVENTION
The present invention relates to sulfur-s~h~tit~
a~lidi,,ù,~s useful as h~",ocl~ol~ ,ult:",ic agents in the treatment and 15 prevention of athe,u:,H~,usij and to the Culllbilld~iull of a sulfur-5llh~titl~t-d d~livi"ùne of this invention and a ~:I,ole:,L~,ul biosynthesis inhibitor for the treatment and prevention of c.l,~t:,u~ u~is.
All,~,uscl~,vli~ coronary heart disease (CHD) ,ep,~st:"l, the major cause for death and cardiovascular morbidity in the westem world.
20 Risk factors for dll~,vscle,uli.; coronary heart disease include h~u~ "~io,~ diabetes mellitus family history male gender cigarette smoke and serum N ,olt,~l~.ul. A total cholesterol level in excess of 225-250 mg/dl is acsociA~A~ with significant elevation of risk of CHD.
Cholesteryl esters are a major co,,,uull~lll of dlll~luacl~lulic 25 lesions and the major storage form of ~ ol~ ,vl in arterial wall cells.
Formation of cholesteryl esters is also a key step in the intestinal absû,~liu,, of dietary Cl~ol~al~lul. Thus inhibition of cholesteryl ester formation and reduction of serum cholesterol is likely to inhibit the ~lVylt::~aiVI~ of dlllt~lUS..l~lVlic lesion formation decrease the 30 accumulation of ~ ole~ ryl esters in the arterial wall and block the intestinal dbso",liull of dietary ~I,ole~lt,vl.
A few d~lidi,lu,~es have been reported as being useful in lowering ullol~sl~rol and/or in inhibi~ing the formation of cholesterol-COI llail li~g lesions in mammalian arterial walls. U.S. 4,983 597 discloses 35 N-sulfonyl-2-azetidinones as anticholesterolemic agents and Ram et al.
in Indian J. Chem.. Sect. B. 29B. 12 (1990) p. 1134-7 disclose ethyl 4-(2-oYorf7.^ti~fi ,-4-yl)phenoxy-alkanoates as hypolipidemic agents. European Patent Publication 264 231 discloses 1-sllhstitl~t~d-4-phenyl-3-(2-oxo-alkylidene)-2-d~lidi"ones as blood platelet agy~ dliul~ inhibitors.

CA 0220~202 1997-0~-13 European Patent 199,630 and European Patent Application 337,549 disclose elastase inhibitory sllhstitutod d~ v,1es said to be useful in treating illlldlllllldlUIy colldili~5 resulting in tissue destruction which are AcsOr;~l~cl with various disease states, e.g. dllltllVS~I~IusiO.
W093/02048, published February 4, 1993, discloses .
5~h5ti~ d ,~-lactams useful as h~",o~;l,uleOIt:,vl~",ic agents.

3, published July 7, 1994, discloses the culllbilldliul~ of s~hstitt~ -lactams as defined in W093/02048 with .,I,~leOl~,ul biosynthesis inhibitors.
The regulation of whole-body ,llO~ lul homeostasis in humans and animals involves the regulation of dietary t~l,ol~ rul and modulation of ,~I,olt-OL,-rul biosynthesis, bile acid biosynthesis and the cdldbo'i~"ll of the ~,I,ole~,ul-cu,,ldi,,i,,g plasma liuuu~ult i~S. The liver isthe major organ ~S,uùl-Siult~ for cl)ol~Ole,ul biosynthesis and cdldboliOIll and for this reason, it is a prime dtlle~ ,i, Idl 11 of plasma ~:I lol~ , ul levels.
The liver is the site of synthesis and secretion of very low density li~uu~lult:ills (VLDL) which are 5~hse~ ntly ~ vl;~--cl to low density li,uuu~ult~i~ls (LDL) in the circulation. LDL are the ,cl~do",i,~d"l cholesterol-carrying li~,o~ lulc:i"s in the plasma and an increase in their cvl,ce"l,dliv"
is correlated with increased dll,e,uscl~,uOiO.
When intestinal cl,ole~ lul absv"uliv,! is reduced, by whatever means, less cholesterol is delivered to the liver. The consequence of this action is dt~ ased hepatic lipoprotein (VLDL) production and an increase in the hepatic clearance of plasma t~llOI~alt:lul, mostly as LDL. Thus, the net eflect of inhibiting intestinal ~:llol~ ,ul abso"~,liv,~ is a decrease in plasma cholesterol levels.
The inhibition of ~;I,oleOI~,ul biosynthesis by 3-hydroxy-3-methylglutaryl coenyme A (HMG CoA) reductase (EC1.1.1.34) inhibitors has been shown to be an effective way to reduce plasma cholesterol (Witzum, Circulation, 80, 5 (1989), p. 1101-1114) and reduce dlllt:lUSCI~lUoi~. Culllbilldliul) therapy of an HMG CoA reductase inhibitor and a bile acid sequestrant has been t~lllvllolldlt d to be more effective in human hyperli,uidt ",ic patients than either agent in monotherapy (Tl I~ 11 Drugs, 36 (Suppl. 3) (1988), p. 63-71).
SUMMARY OF THE INVFNITION
H~uo~:l,oleOL~,ul~,,,ic compounds of the present invention are ,~ s~"~d by the formula I

X~ l1 Y~ ,~
or a pl~allllac~utically acct,~ salt thereof, wherein:
Ar1 is aryl, R10-s~hstit~ltpd aryl or heteroaryl;
Ar2 is aryl or R4-s~hstitl~t~d aryl;
Ar3 is aryl or R5-s~ Ih5titllt~rl aryl;
X and Y are i,~ pendt" ,lly selected from the group consisting of -CH2-, -CH(lower alkyl)- and -C(dilower alkyl)-;
R is -OR6, -O(CO)R6, -O(CO)OR9 or-O(CO)NR6R7; R1 is hydrogen, lower alkyl or aryl; or R and R1 together are =0;
10 qisOor1;
risO, 1 or2;
m and n are i"~p,:,Idt:l,lly 0, 1, 2, 3, 4 or 5; provided that thesumofm,nandqis1,2,3,40r5;
R4 is 1-5 substituents illd~p~lld~ ly selected from the group consisting of lower alkyl, -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1 sOR6, -o(Co)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(Co)NR7R8, -NR6So2R9, -CoQR6~ -coNR6R7~ -coR6~ -so2NR6R7~ S(0)o 2R9, -O(CH2)1.1o-COOR6, -O(CH2)1 1oCoNR6R7~ -(lower alkylene)COOR6 and -CH=CH-COOR6;
R5 is 1-5 substituents il ld~ l ld~ ly selected from the group consisting of -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1 50R6, -o(Co)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(Co)NR7R8, -NR6S02R9, -COOR6, -CoNR6R7, -COR6, -so2NR6R7~ S(0)o 2R9, -O(CH2)1 1o-COOR6, -O(CH2)1 1oCONR6R7, -CF3, -CN, -NO2, halogen, 2~ -(lower alkylene)COOR6 and -CH=CH-COOR6;
R6, R7 and R8 are incl~ "d~"lly selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-cuhctitllt~d lower alkyl;
- R9 is lower alkyl, aryl or aryl-sllhctitllt~ri lower alkyl; and R10 is 1-5 substituents i"dtl,ae,~dt:"lly selected from the group consisting of lower alkyl, -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1 sOR6, -O(Co)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR8, -NR6(Co)NR7R8, -NR6S02R9, -COOR6, -CoNR6R7, -COR6, -SO2NR6R7, S(0)o2R91-O(CH2)1 1o-COOR6,-o(CH2)1 1oCONR6R7,-CF3,-CN,-NO2 and halogen.

CA 0220~202 1997-0~-13 Within the scope of formula 1, there are two preferred structures. In formula IA, q is zero and the remaining variables are as defined above, and in formula IB, q is 1 and the remaining variables are as defined above: R .
Ar1~Xm`Y~S(O)r~ Ar1~ ~1 ~ ~S(O)r~Ar2 `Ar3 R1 N~Ar3 IA IB
R4, R5 and R10 are each preferably 1-3 illdt:p~lld~lltly selected substituents. Preferred are compounds of fommula I wherein Ar1 is phenyl, R10-sl Ihctit, ~e~ phenyl or thienyl, especially (4-R10)-sllhctitl ~ted phenyl or thienyl. Ar2 is preferably R4-c~hctit~t~d phenyl, especially (4-R4)-sllhstitllt~d phenyl. Ar3 is preferably phenyl or R5-cllhstitllt.od phenyl, especially (4-R5)-~h.stitllt~d phenyl. When Ar1 is R10-~Cllhctitllt~d phenyl, R10 is preferably halogeno, especially fluoro. When Ar2 is R4-s~hstit~ted phenyl, R4 is preferably -OR6, especially wherein R6 is hydrogen or lower alkyl. When Ar3 is R5-cllhctitl~ phenyl, R5 is preferably halogeno, especially fluoro. Especially preferred are compounds of formula I
wherein Ar1 is phenyl, 4-fluc.lu~ , Iyl or thienyl, Ar2 is ~(alkoxy or hydroxy)phenyl, and Ar3 is phenyl or 4-fluorophenyl.
X and Y are each preferably -CH2-. The sum of m, n and q is preferably 2, 3 or 4, more preferably 2. When q is 1, n is preferably 1 to 5.
Pl~ ces for X, Y, Ar1, Ar2 and Ar3 are the same in each of formulae IA and IB.
In compounds of formula IA, the sum of m and n is preferably 2, 3 or 4, more preferably 2. Also preferred are compounds wherein the sumofmandnis2,andrisOor1.
In compounds of formula IB, the sum of m and n is preferably 1, 2 or 3, more preferably 1. Especially preferred are compounds wherein m is zero and n is 1. R1 is preferably hydrogen and R is preferably -OR6 wherein R6 is hydrogen, or a group readily m~t~ho~ hl~ to a hydroxyl (such as -O(CO)R6, -O(CO)OR9 and -O(CO)NR6R7, defined above), or R
and R1 together fomm a =0 group.
This invention also relates to a method of lowering the serum ~,I,ole:,le,ul level in a mammal in need of such treatment Culllpli~ill9 a~",i"i~ ,i"g an eflective amount of a compound of formula I. That is, the wo 96/16037 PCI/IJS95/14134 use of a compound of the present invention as an hypocho~ ,ult7"~;~
agent is also claimed.
In still another aspect the present invention relates to a ~JI,a,~ ce~tir~l cc.""uo:.ilion c~"",lisi"~ a serum cl,ole~ ,ul-lowering 5 effective amount of a compound of fommula I in a pl~ar".~e ~' "y e carrier.
The present invention also relates to a method of reducing plasma ~ ole~ ,ul levels and to a method of treating or preventing ath~u~cle~uais co"".ri~i"g a,i", ,iaLt,ri"g to a mammal in need of such 1û treatment an effective amount of a cu~llLi,ldlio~ of a sulfur-sl~hstitll~ed d~ idil~u~1e ~I,ùl~ ,ol aL.su,~ ) inhibitor of formula I and a H lol~ ,ul biosynthesis inhibitor. That is the present invention relates to the use of a sulfur-~l~hstit~tPd azetidinone 11101e~ UI abso"~ioll inhibitor of formula I
for combined use with a cI~ol~a~ul biosynthesis inhibitor (and similarly 15 use of a u l ~ule~ ul biosynthesis inhibitor for combined use with a sulfur-s~hstit~tPd a~ i"ù,~e cholesterol abso,u~iùn inhibitor of formula I) to treat or prevent dl~ u~cl~,o~ia or to reduce plasma cl,ole~l~,vl levels.
In yet another aspect the invention relates to a pl,a""ace~tical co,,,posi~iu~ c~,,,u~isi~g an effective amount of a sulfur-20 s~hstit~ o' a~ li"u"e cholesterol dl,s~",~iu" inhibitor of fommula I a~:I,ole~,ùl biosynthesis inhibitor and a pharmaceutically ~ P
carrier. In a final aspect the invention relates to a kit cu""~ ,i"g in one container an eflective amount of a sulfur-s~hstit~tPd a~ idi"or~e cl,ole~l~,ul abso"-liol~ inhibitor of fommula I in a pharmaceutically 25 ~crept~hl~ carrier and in a separate container an effective amount of a ~;I,ole~ ,ul biosynthesis inhibitor in a pl,a""acttutically ~rC~rt~hl~ carrier.
DETAILED DESCRIPTION: .
As used herein the term "lower alkyl" means straight or 30 branched alkyl chains of 1 to 6 carbon atoms.
"Aryl" means phenyl naphthyl indenyl tetrah~/d,ullaullll~yl or indanyl.
~ Heteroaryl~ means pyridyl isoxazolyl furanyl pyrrolyl thienyl imidazolyl pyrazolyl thiazolyl pyrazinyl pyrimidinyl or pyridazinyl.
35 All positional isomers wherein the heteroaryl ring is attached through a carbon atom are co"~t:",l,ldl~d e.g., 2-pyridyl 3-pyridyl and 4-pyridyl and 2-thienyl and 3-thienyl. "Halogeno~ means fluorine chlorine bromine or iodine atoms.

CA 0220~202 1997-0~-13 The above statement, wherein R6, R7 and R8 are said to be illdt~ Ild~llIly selected from a group of substituents, means that R6, R7 and R8 are i, Id~ dt" Illy selected, but also that where an R6, R7 or R8 variable occurs more than once in a molecule, those occurrences are i, Idt~ dt:l ,Ily selected (e.g., if R is -oR6 wherein R6 j5 hydrogen, R4 can ..
be -oR6 wherein R6 is lower alkyl).
Compounds of the invention have at least one asymmetric atom and therefore all isomers, including t:"a"liu",~,:, and dia:,L~,~c.",~,~
are co"lt:"",ldltd as being part of this invention. The invention includes d and I isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting chiral starting materials or by separdIi~g isomers of a compound of formula I. Isomers may also include geometric isomers, e.g.
when a double bond is present. All such geometric isomers are cc"~ ""~l~ledforthisinvention.
Those skilled in the art will a~ idl~ that for some compounds of formula I, one isomer will show greater pha",.~r:ol~ ".
activity than another isomer.
Compounds of the invention with an amino group can form pharmaceutically ~CR~ ' salts with organic and inorganic acids.
Examples of suitable acids for salt formation are hydl.J~:I llol ic, sulfuric, pllo~l)o,ic, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt.
The free base form may be r~ eldIt:d by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium biCd~Olldlt:. The free base form differs from its respective salt form s~",~. ',al in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base form for purposes of the invention.
Certain compounds of the invention are acidic (e.g., those compounds which possess a carboxyl group). These compounds form pharrrlR~e~lti~RIly ~rceptRhle salts with inorganic and organic bases.
Examples of such salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically Rf~CPrtRhl~ amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methyiglucamine and the like.

CA 02205202 1997-0~-13 wo 96/16037 PCr~7Sg5~141~4 _ 7 _ Cholesterol biosynthesis inhibitors for use in the culllbil,dlio, of the present invention include HMG CoA reductase inhibitors such as lovastatin, pravastatin, fluvastatin, simvastatin, and Cl-981; HMG CoA
synthetase inhibitors, for example L-659,699 ((E,E)-1 1-[3'R-(hydroxy-5 methyl)-4'-oxo-2'R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoic acid);
squalene synthesis inhibitors, for example SnlllAl~StAtin 1; and squalene inhibitors, for example, NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yl)methoxy]benzene-methanamine hyd~u.:l,lù~ ) and other cllole~l~,ul biosynthesis inhibitors such as DMP-10 565. Preferred HMG CoA reductase inhibitors are lovastatin, pravastatinand simvastatin.
Compounds of formula I can be prepared by known methods, for example those described below.
Method A:
R~ ) agent R o~N, ~3 ) N la 1 5 ~Ar3 Compounds of formula I wherein r is zero, R11 is a protected hydroxy group, wherein the protecting groups are as defined below in Table 1, and the remaining variables are as defined above, i.e., compounds of formula la, can be prepared according to the above 20 reaction scheme, wherein a carboxylic acid of formula ll is reacted with an imine of formula lll in the presence of a base such as triethylamine and a suitable dehydrating agent such as dimethyl~.l,o:,~uho,d,,,idc,us dichloride.
The resultant compound is treated with an acid such as hydrofluoric acid to obtain the thio compound of formula la. When the protected hydroxy 25 group R11 is an alkoxy or benzyloxy group, such a protecting group need not be removed to obtain a compound of formula l, but other protecting groups can be removed using conventional techniques to obtain compounds of formula l wherein R is hydroxy.
Compounds wherein R is hydroxy can be converted by well 30 known techniques to other compounds of formula l wherein R is fu~.,liu~ldli~ed, i.e., it is-OR6a, -O(CO)R6, -O(CO)OR9, or-O(CO)NR6R7, wherein R6, R7 and R9 are as defined above and R6a j5 lower alkyl, aryl, or CA 0220~202 1997-0~-13 7 PCT/US9~/14134 aryl-lower alkyl. For example, treatment of the alcohol with an alkyl halide in the presence of a suitable base such as NaH will afford alkoxy-s~hstitl~t~d compounds ~i.e., R or R2 is OR6, wherein R6 is lower alkyl);
treatment of the alcohol with an acylating agent such as acetylchloride will 5 result in compounds wherein R or R2 is -OC(O)R6; treatment of the alcohol with phosgene followed by an alcohol of the formula HOR9 affords compounds s~hstit~t~d with a -OC(O)OR9 group; and treatment of the alcohol with phosgene followed by an amine of the formula HNR6R7 affords compounds wherein R or R2 is -OC(O)NR6R7.
Compounds of formula la wherein q is 1, and R and R1 form an =O group can be converted to the COrl~a,uO~ lg compounds wherein R1 is hydrogen and R is OH by treatment with a reducing agent such as sodium borohydride.
To prepare the corresponding sulfinyl compounds, i.e., 15 compounds of formula I wherein r is 1, and the remaining variables are as defined above (compounds of formula Ib), treat the hydroxy-protected thio compound of formula la with 1 equivalent of an oxidant such as a peracid, e.g., m-~:l,lu,~.p~ "~,i.. acid, or sodium metaperiodate:
oxidation (1 eq.) Ar1-Xm--(C)~--Yn--S~;~A13 To prepare the corresponding sulfonyl compounds, i.e., compounds of formula I wherein r is 2, and the remaining variables are as defined above (compounds of formula Ic), treat the hydroxy-protected thio compound of formula la with 2 equivalents of an oxidant as ~ ed.
above: R1 1 O
la oxidation(2eq) Ar~Xm~(C)q~Yn~;~ k Compounds of fomulae Ib and Ic can be deprotected at R11 as necessary to obtain compounds of formula 1.
Q--S~CO H 1) dehydratingagent Q S~Ar2 IV 2) ~ lll V N~Ar3 CA 02205202 1997-0~-13 ~0 96116037 PCT/~595/14134 _ g 1) deprotect A ~ (C)q y~S Ar2 2) alkylate m R1 ~
= O Ar3 Compounds of formula la wherein the variables are as defined above, can be prepared by reacting a protected ",er~ a~
acid of formula IV wherein Q is a sulfur-protecting group such as benzyl or 5 cllh~tit~tPd-benyl with an imine as described in Method A. The protecting group Q is then removed and the mercapto group is alkylated with a compound of the formula Ar1~ (C)q y L wherein L is a leaving group such as bromo or iodo.
Using the methods described in Method A compounds of formula la prepared by Method B can be converted to sulfinyl and sulfonyl 10 compounds compounds wherein R and R1 are =O can be converted to compounds wherein R is H and R1 j5 OH and compounds wherein R is hydroxy can he converted to functionalized hydroxy groups.
Method C:
Compounds of formula I wherein r is zero and the remaining 15 variables are as defined above can be prepared in an enantioselective manner as follows:
Ar1-xm-(c)q-yn - sH + o~N~O I ~q ~LN O
Vl Vll ,Ar3 i) TiC4 0 0 HN
ii) Hunig'sbase OJ~NJ~Ar2 R11 iil) Irninelll ~Ph Yn-(c)q-xm-Ar1 lX

CA 0220~202 1997-0~-13 WO 96/16037 PCT/US9~/14134 Ar1-Xm-(C) -Y--S"_~Ar2 Ar1-Xm-(C)q-Yjl s ~Ar2 ii) TBAF R o~N~ 3 R O~LN~ 3 Id le The chloroacylated ~ -" " ,ù,-e auxiliary of formula Vll is reacted with the Illelud~tdl~ of fommula Vl, wherein the variables are as defined above, in the presence of a base such as triethylamine in an inert solvent such as 5 CH2CI2. The resultant compound of formula Vlll is treated with TiCI4 in the presence of a base such as diisopropylethylamine (Hunig's base), reacted with an imine of formula lll, and then the reaction is quenched with an acid such as acetic acid. The resulting compound of formula IX is then cyclized by reaction with a silylating agent such as bib(l,i",t:~l,ylsilyl)acetamide 10 (BSA) and a fluoride catalyst such as tetra butyl ammonium fluoride (TBAF). The cyclization product is separated into cis and trans isomers of formulae Id and le using conventional purification techni~ues, e.g., flash chromatography.
Compounds of formulae Id and le can be converted to the co"~b~ol,di"g 15 sulfinyl and sulfonyl compounds by reaction with a peracid as described above or with a reagent such as (R) or (S) (1 0-camphor-sulfonyl)-oxaziridine. For example, a compound of formula Id can be converted to the cu"~,uul~di"9 sulfinyl compounds, If and lg, as follows:
R11 ,~ R11 Id ~ Ar-Xm-(c)--yn-s~ Ar2 Ar1-Xm-(c)q--yn-s~ Ar2 (P.) or (S) R1 ~N R1 ~--N~
sulfonyl)- O Ar3 Ar3 oxsziridine If Ig Before or after st:~drdliul, into cis and trans isomers, as suitable, compounds of formulae Id and le can be dt~plult:u~d at R1l, and compounds wherein R is OH can be functionalized as described in Method A.
Starting compounds ll, lll, IV, Vl and Vll are all either c~r,,,,,~,uic~lly available, well known in the art, or are prepared via known methods.
Reactive groups not involved in the above p,ucesses can be protected during the reactions with conventional protecting groups which CA 02205202 1997-0;i-13 wo 96/16037 PCT/VSg5~14134 can be removed by standard procedures after the reaction. The following Table 1 shows some typical protecting groups:
Table 1 Group to be Group to be Protected and Protected Protecting Group -COO H --COOalkyl -COObenzyl--COOphenyl _NH ~ NCOalkyl~, NCObenzyl ` NCOphenyJ
,NCH2OCH2CH2Si(CH3)3 NC(O)OC(CH3)3 cr3 ~N-benzyl. ~NSi(CH3)3 NSi-C(CH)3 o CH3 --NH2 -N~
o ICH3 --OH --OCH3 --OCH2OCH3 --OSil-C(CH)3 --OSi(CH3)3 or--OCH2phenyl We have found that the compounds of this invention lower serum iipid levels in particular serum I,ol~ ,ul levels. Compounds of this invention have been found to inhibit the intestinal aLso",liu" of ~ olesl~,ul and to Si~v,lli~ hllLly reduce the formation of liver cholesteryl 10 esters in animal models. Thus compounds of this invention are hypo.il ,ole~l~,vl~")ic agents by virtue of their ability to inhibit the intestinal abs~ livnand/ore~ dliOI1ofcl,ole:,L~rvl theyare therefore useful in the treatment and prevention of dlll~luscl~,u~is in mammals in particular in humans.
The ~ activity of the compounds of formula I can be determined by the following procedure:
In ViVQ Assay of Hy~olipidemic AQents UsinQ the Hyuerliuid~",ic Hamster Hamsters are separated into groups of six and given a controlled c l ,ole~l~, ul diet (Purina Chow #5001 Cul lldil lil ly 0.5%
20 cl~ol~ ,ul) for seven days. Diet consumption is monitored to determine dietary cholesterol exposure in the face of test compounds. The animals are dosed with the test compound once daily beginning with the initiation CA 0220~202 1997-0~-13 WO 96/16037 PCI/US9~/14134 of diet. Dosing is by oral gavage of 0.2mL of corn oil alone (control group) or solution (or suspension) of test compound in corn oil. All animals moribund or in poor physical condition are euthanized. After seven days, the animals are ane~ d by intramuscular (IM) injection of ketamine and sacrificed by ~ . Blood is collected into vacutainer tubes ..
containing EDTA for plasma lipid analysis and the liver excised for tissue lipid analysis. Lipid analysis is conducted as per published procedures (Schnitzer-Polokoff, R., et al, Comp. Biochem. Physiol., 99A, 4 (1991), p.
665-670) and data is reported as percent reduction of lipid versus control.
The present invention also relates to a pharmaceutical cu""uosi~ cu",~ ,i"g a compound of formula I and a pharmaceutically carrier. The compounds of formula I can be a.il"i"i~ d in any conventional dosage form, preferably an oral dosage form such as a capsule, tablet, powder, cachet, suspension or solution. The formulations and pharmaceutical cu""~osiliol1s can be prepared using conventional }Jlldrlllaceutically ~C~IJI ~ excipients and additives and conventional techniques. Such pl, r",aceutically R~cprtRhle excipients and additives include non-toxic cu"",dli~le fillers, binders, ~ibillleyldllt:~, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like.
The daily hypocl,ole~ ",ic dose of a compound of formula I is about 0.1 to about 30 mg/kg of body weight per day, preferably about 0.1 to about 15 mg/kg. For an average body weight of 70 kg, the dosage level is therefore from about 5 mg to about 1000 mg of drug per day, given in a single dose or 2-4 divided doses . The exact dose, however, is determined by the attending clinician and is d~ d~"l on the potency of the compound adl"i"i~ d, the age, weight, condition and response of the patient.
For the colllL.illdliol1s of this invention wherein the sulfur-sllh5titllt~CI a~ li,lu"e is ad",i"i~ d in combination with a cholesterol biosynthesis inhibitor, the typical daily dose of the ul ,olesl~lul biosynthesisinhibitor is 0.1 to 80 mg/kg of mammalian weight per day administered in single or divided dosages, usually once or twice a day: for example, for HMG CoA reductase inhibitors, about 10 to about 40 mg per dose is given 1 to 2 times a day, giving a total daily dose of about 10 to 80 mg per day, and for the other ullol~ ul biosynthesis inhibitors, about 1 to 1000 mg per dose is given 1 to 2 times a day, giving a total daily dose of about 1 mg CA 0220;i202 1997-O;i-13 WO 96/16037 PCTJrJS95J14134 to about 2000 mg per day. The exact dose of any Golllpoll2ll1 of the COIIIJ;I IdLiOll to be administered is d~l~ll"i, l~d by the attending clinician and is dtl~ tllll on the potency of the compound adl";"i~ .l the age weight, condition and response of the patient.
Where the co"",on~"l:, of a co",L,inalio" are a~l";"isL~,~d separately, the number of doses of each GOI~pOlie~l given per day may not l7ecessa"1y be the same, e.g. where one c~",~Jùn~"l may have a greater duration of activity, and will therefore need to be adl";"i~ d less frequently.
Since the present invention relates to the teduction of plasma Cl,olt,~ ,ul levels by treatment with a c~",L,i"dlior, of active i"g,~.lit:"l~ wherein said active illy,~dit:"ls may be administered separately, the invention also relates to combining separate plld""ac~LItical co"",osilic"~s in kit form. That is a kit is co"L~""Jldl~d wherein two separate units are combined: a ~ lul biosynthesis inhibitor phammaGeutical composition and a sulfur-sllhctitllt~d d~ i"u"e clloleslt" ul abso,~Liol, inhibitor ~,lia""~e. ~tif ~l cu""uosilio". The kit will preferably include directions for the adllli~lial~dlioll of the separate CUII,fJo"tl"l:,. The kit form is particularly advantageous when the separate c~""~,ol,e"l~ must be administered in different dosage forms (e.g. oral and parenteral) or are adl";"i~ d at different dosage intervals.
Following are examples of preparing compounds of formula 1. The terms cis and trans refer to the relative uli~nldliulls at the 2~ azetidinone 3- and 4-positions uniess otherwise indicated. The term "J"
refers to the proton NMR coupling constant in hertz (Hz) between the 3-and 4-.CIlh~titll~^~ protons of the d~ Ji"ol-e. CD spectra were obtained as solutions in methanol.
3û Example 1 O H
Ph~S~ ~
~ F

CA 0220~202 1997-0~-13 WO 96/16037 PC~I~S95/14134 ~L~ Heat a mixture of 4-fluoroaniline (128 ml) and 4-t-butyldimethyl-siloxy b6.~ .ydi3 (290 9) in toluene (1.2L) to ref~ux under a Dean-Stark trap. After 24 h, col ,Ctll l~l dl~ in vacuo and dissolve the residue in warm hexane (0.2L). Cool to -20C and collect the resultant imine (378 9, 94% yield) by filtration; mp 51.4-52.2C.
~L~ To a mixture of phenethyl"~ dl~lu acetic acid (0.55 9) [prepared in two steps by i) reaction of phenethyl mercaptan and ethyl L"u",oac~ldl~
and ii) sapolli~kidliu,, with ethanolic aqueous NaOH], the imine prepared in step 1 and triethylamine (TEA) (1.2 ml) in CH2CI2 (20 ml), add dimethyld", )opl,c,~lJl,olyl~ lo(icle at 0C. Stir overnight while allowing the reaction to warm to room temperature (rt). Partition the mixture between ethyl acetate (EtOAC) and 10 % NaHCO3. Wash (H2O), dry (MgSO4) and col1ccl Illdl~ the organic layer, then purify the residue by flash chromatography on silica using hexanelEtOAc (20:1) to obtain a yellow oil (0.48 9, 34%). Resolve this oil by HPLC with a Chiralcel OD
column using hexanelisopropyl alcohol (66:1) and collect the second peak.
Step 3: Treat the product of step 2 (215 mg) in CH3CN (21 ml) at 0C with 48% HF (2.5 ml). Stir overnight while allowing the reaction to warm to rt.
Partition the mixture between ether (Et2O) and cold water and wash the organic layers with 10 % NaHCO3 and water. Dry (MgSO4) and col~ccl Illdl~ the organic layer and purify the residue by flash C~ Jllldl~ldlJIly on silica using hexanelEtOAc (5:1) to collect the title compound (1) as a colorless solid (0.16 9, 96%). SIMS 394 (M+H), 256 (100%); Elemental analysis calculated for C23H2oNo2sF-o.25H2o:
C 69.41, H 5.19, N 3.52; found C fi9.42, H 5.26, N 3.45; [CC]D25= + 44.8 (1.25 mglml CH30H); 1 H NMR CDCL3: 2.95 (m, 4H), 3.93 (d, J=2.4Hz, 1H), 4.67 (d, J=2.4Hz, 1H), 5.06 (s, 1H), 6.85 (d, 1H), 6.92 (dd, 2H), 7.15-7.3 (9H)-Method B:
~S,~ Ph~ ~OH
~3 F 1 ~ F 1 a CA 0220~202 1997-0~-13 WO 96~16037 PCr/US95~14134 Step 1: Add d~opwise a solution of .;I,Iuruac~ chloride (9.76 ml) in CH2CI2 (110 ml) to a 0C solution of (S)-4-phenyl, ' " ,ùl1e (10.0 9), TEA (35 ml) and dimethylaminopyridine (DMAP) (0.5 9) in CH2C12 (150 ml). Gradually warm the reaction to rt, then add silica gel ( approx. 50 9) 5 and cù"c~ ldl~ in vacuo. Purify the residue by flash chromatography on silica using EtOAc/hexane (1:4) to give a colorless solid (11.3 9, 77%).
Step 2: Add phenethyl Ill~r~,d~tdll to a solution of the product of step 1 (6.0 9) and TEA (5.1 ml) in CH2Ci2 (0.1 L). Stir at rt for 16 h, then add silica gel (approx 50 gm) and co,~ct:"L,~I~ in vacuo. Purify the residue by 10 flash clllull~dtvyld,vlly on silica using EtOAc/hexane (1:4) to give a colorless solid (7.81 9, 92 %) which can be crystallized from EtOAc/
hexane (1 :4).
Step 3: Add titanium tetraisc~,,ûAi i~ (7.5 ml) to a stirring solution of TiCI4 (75 ml of 1 N TiCI4 in CH2C12) in CH2C12 (200 ml) at 0C. After 15 min., add the product of step 2 (34.1 9), and 5 min. Iater add the imine from Method A, step 1 (66 9). Cool the reaction to -40C, wait 20 min. and add d;;~.op,u~"~l ethylamine (35 ml). After 15 h at -40C, cool the reaction to -70OC and add isopropyl alcohol (250 ml). Graduaily warm to rt over 6 h, then add 0.1N HCI (500 ml) and partition the reaction mixture with Et20.
Wash (H20) and dry (MgS04) the organic layer, co,)c~"~ , and purify the residue by crystallization from CH30H to give a colorless solid (30.9 9, 46%).
~: Heat a solution of the product of step 3 (10 9) in toluene (0.51) to 90C and add N,~bis(trimethylsilyl)~l~tf~",i.l~ (BSA) (7.4 ml). After 1 h, cool the reaction to 45C and add tetrabutylammonium fluoride (TBAF) (0.47 9). Periodically over the next 18 hr add additional BSA (a total of 3 molar equivalents) and continue stirring at 45C. After a total time of 24 h, dilute the reaction with CH30H (150 ml) and stir at rt for 1 h. Cùnce"l,dlt, the mixture in vacuo and purify by flash ~ ullldloyld~lly on silica using hexane/EtOAc (10:1) to elute the trans isomer. Continue to elute with hexane/EtOAc 5:1 to give the cis isomer.
~: Separately treat solutions of the trans and cis isomers from step 4 in CH3CN with aqueous HF according to the procedure of Method A, step 3, to give the trans and cis azetidinones 1 and ia, respectively.
1a: CIMS 394(M+H) 100%; Elemental analysis calculated for C23H20NO2SF: C 70.21, H 5.13, N 3.56, S 8.15; found C 70.33, H 5.43, N 3.71, S 8.20. 1 H NMR CDC13: 2.78 (m, 4H), 4.52 (d, J=5Hz, 1H), 5.23 (d, J=5Hz, 1H), 6.82-7.3 (13H).

CA 0220~202 1997-0~-13 WO 96/~6037 PCT/US95/14134 Usin3 the procedure described in Example 1, method B, steps 3 and 4, use 4-methoxybenzylidene anisidine to prepare the following compounds:
OMe Ph~S".~ .
~N
O Ph 1 b 1 b: Elemental analysis calculated for C24H23NO2S: C 74.01, H 5.95, N
3.6, S 8.22; found C 74.19, H 6.0, N 3.73, S 8.03; [~] 232nM = +3.4x104, [~] 248 nM = -3.07 x104; 1 H NMR CDCI3 2.95 (m, 4H), 3.82 (s, 3H), 3.95 (d, J=2.2Hz, 1H), 4.72 (d, J=2.2Hz, lH), 6.9-7.3 (14H); SIMS 390(M+H), 252 (100%).
~OMe Ph~S~
O Ph 1 c 1 c: 1 H NMR CDCI3: 2.78 (m, 4H), 3.8 (s, 3H), 4.53 (d, J=5.5Hz, 1 H), 5.27 (d, J=5.5Hz, 1H), 6.9-7.3 (14H).
Example 2 ~ ~ Ph~S,~O H
~F 2a ~F 2b Heat a solution of compound 1 from Example 1 (2.3 9) and (1s)-(+)-(10-camphorsulfonyl)ox~i,i,ii"e (1.48 9) in tetrahydrofuran (THF) (40 ml) to reflux. After 14 h, CO~ ldle the reaction mixture and purify the residue by flash chromatography on silica using CH2CI2/isopropyl alcohol (100:1) to elute first diastereomer 2a (0.69, 25%): Elemental analysis calculated for C23H20NO3SF: C 67.47, H 4.92, N 3.42; found C 67.12, H
5.02, N 3.43; [~] 219nM = -5.49 x104, [~] 254 nM = +5.2 x104; [a]D25=
+214.4 (1.25 mg/ml Ch30H); 1H NMR CDCI3: 3.15 (m, 3H), 3.92 (m, 2H), 5.25 (d, J=2.5Hz, 1H), 6.0 (bs, 1H), 6.8-6.9 (4H), 7.15-7.35 (8H);
CIMS 410(M+H). Next, elute ~idbl~l~ulll~l 2b, then crystallize dia~ u"~er 2b from isopropyl alcohol (IPA) to give a colorless solid WO 96/16037 PC7~/US95/14134 (1.48 g, 62%). Elemental analysis calculated for C23H20NO3SF: C 67.47, H 4.92, N 3.42; found C 67.28, H 4.89, N 3.45; [~] 233nM = +5.56 x104, [~] 251 nM = - 2.79 x104; [~]D25= -16 (1.25 mg/ml CH30H); 1 H NMR
CDCI3: 3.1-3.4 (m, 4H), 4.2 (d, J=2Hz, 1H), 5.39 (d, J=2.Hz, 1H), 6.7 (d, 5 2H), 6.95 (m, 2H), 7.15-7.35 (8H); CIMS 410(M+H).
Use the procedure from Example 2 with compound 1a from Example 1 to obtain the following compounds:
O, Ph~S~
~F 2c 2c: Elemental analysis calculated for C23H20NO3SF: C 67.47, H 4.92, N
10 3.42, S 7.83.; found C 67.21, H 5.0, N 3.5, S 7.48.
,O, ~OH
O N~3 F 2sL
2d: Elemental analysis calculated for C23H20NO3SF: C 67.47, H 4.92, N
3.42, S 7.83; found C 67.5, H 5.11, N 3.6, S 7.71.
IExample 3 Fh~S ~3 Ph~ '~3 O N,Ph 3a O N.ph 3b Treat compound 1 b from Example 1 (0.36 g) in CH2C12 (15 ml) at 0C with m-cl,lo,up~ "~ic acid (mCPBA) (0.16 9) at -78OC. After 2 h, add dilute NaHSO3 and warm the mixture to rt. Partition with EtOAc 20 and sequentially wash the organic layer with 10% NaHCO3 and brine, then dry (MgSO4) and concentrate in vacuo. Purify the residue by HPLC
on silica using EtOAc/hexane (1:2) to elute compounds 3a (0.185 g) and 3b (0.10 9).
3a: Elemental analysis calculated for C24H23NO3S: C 71.09, H 5.72, N
25 3.45: found C 70.87, H 5.55, N 3.52; [~] 220 nM = -5.36 x104, CA 0220~202 1997-0~-13 [~] 257 nM =+5.46 x104; 1H NMR CDC13: 3.15 (m, 3H), 3.8 (s, 3H) 3.9 (m, 1H), 3.94 (d, J=2.5Hz, 1H), 5.33 (d, J=2.5Hz, lH), 6.9-7.35 (14H).
3b: Elsmental analysis c~ t~d for C24H23NO3S: C 71.09, H 5.72, N
3.45, S 7.83; found C 70.90, H 5.72, N 3.55; [~] 220 nM = -4.8x103, [~] 233nM = +7.4 x104, [~] 250nM = -4.0 x104; 1H NMR CDCI3: 3.18 (m, -4H), 3.8 (s, 3H), 4.12 (d, J=2Hz, 1H), 5.5 (d, J=2Hz, 1H), 6.9-7.35 (14H).
Use the procedure of example 3 with compound 1c obtain the following products:
o ~OMe Fh~S~
o~N,Fh 3c 3c: Elemental analysis~ t~ for C24H23NO3S-0.2 H2O: C 70.46, H
5.77, N 3.42; found C 70.49, H 5.78, N 3.52; 1 H NMR CDC13: 2.85 (m, 1H), 2.95 (m, 1H), 3.12 (m, 1H), 3.62 (m, 1H), 3.8 (s, 3H), 4.4 (d, J=5.6Hz, 1H), 5.35 (d, J=5.6Hz, 1H), 6.9-7.35 (14H).
~0~ ~O M e Flh~S~
o~Nph 3d 3d: Elemental analysis calculated for C24H23NO3S-0.2 H2O: C 70.46, H
5.77, N 3.42; found C 70.32, H 5.78, N 3.46; 1H NMR CDCI3: 3.17 (m, 3H), 3.4 (m, 1 H), 3.83 (s, 3H), 4.69 (d, J=5.2Hz, 1 H), 5.55 (d, J=5.2Hz, 1 H),6.95-7.4 (14H); [o~]D25 = -136 (CH30H).
Example 4 OAc ~3F 4 Treat compound 2b (60 mg) in CH2CI2 (5 ml) with TEA
(0.025 ml) and acetic anhydride (0.017 ml). After 2 h, concentrate the reaction mixturs and purify the residue by flash (;ll~ullld~uyld~lly on silica using EtOAc/hexane (1:1). to give a white solid. Elemental analysis calculated for C25H22NO4SF: C 66.5, H 4.91, N 3.1, S 7.1; found C
66.28, H 5.10, N 3.29, S 6.99.

WO 96/16037 PCr/US95/14134 Use the above procedure for preparing compound 4 with compounds 2c and 2d to obtain the following products 4a and 4b, respectively:
Q ~OAc Ph~S~
~F ~
4a: Elemental analysis c~l~ul~t~d for C25H22NO4SF: C 66.5, H 4.91, N
3.1, S 7.1; found C 66.36, H 5.13, N 3.23, S 7.02; 1H NMR CDCI3: 2.32 (s, 3H), 2.92 (m, 2H), 3.14 (m, 1H), 3.7 (m, 1H), 4.42 (d, J=5.7Hz, 1H), 5.38 (d, J=5.8Hz, 1H), 7.0 (m, 2H), 7.12-7.35 (9H), 7.44 (d, 2H).
Q ~ OAc ph~S~ ~
`0F 4b 10 4b: 1 H NMR CDCI3: 2.32 (s, 3H), 3.15 (m, 3H), 3.38 (m, 1 H), 4.72 (d, J=5.3Hz, 1H), 5.58 (d, J=5.2Hz, 1H), 7.0 (m, 2H), 7.15-7.35 (9H), 7.40 (d, 2H).
Example 5 ~,S,~
SteD1: Add TEA (14 ml) to a mixture of 4-methoxybenzyichloride (13 ml) and ethyl-2-",~",~ .A.,~ (10 ml) in CH2CI2 (0.2L) under N2. After 48 h, dilute the reaction with Et20 (0.5 L) and sequentially wash the organic phase with 0.3N HCI (3x) and 10 % NaHCO3. Dry and co~ ,c~"I,~I~ the organic layer to give an oil (22 9). Dissolve a portion of 20 the oil (5 g) in THF (75 ml) and water (75 ml) and add LiOH (1 9). After stirring for 72 h, dilute the reaction with water (0.15 L) and extract with hexane (0.2 L). Acidify the aqueous phase with 1 N HCI and extract with EtOAc. Wash (H20), and dry (MgS04) the organic layer and cu~ lllldl~
to give a yellow solid (4.25 9, 96%).

CA 0220~202 1997-0~-13 Step2: Treat a mixture of the product of step 1 (1 9) and the imine from Example 1, Method A, step 1 (1.55 9) in CH2C12 (40 ml) with dimethylamino phosphoryldi~:l,lo,ide (0.56 ml) at 0C. Warm to rt and stir for 16 h. Dilute the reaction with Et2O (100 ml) and wash sequentially with lN HCI, 10% NaHCO3 and brine. Dry (MgS04) and conc~"~,d~ the .
organic phase and purify the resultant residue by flash cl,,ul,,a~y,dpl~y on silica using h~Adll~.CtOAc (20:1) to yield an oil (0.759, 30%).
Step 3: Add mercuric acetate (121 mg) to a solution of the product of step 2 (0.2 9) in trifluoroacetic acid (5 ml) at 0C. After 15 min., partition the reaction mixture between H2O and Et2O. Wash, dry and Cûl)C~ ldl~ the organic layer and purify the residue by flash ul ll Ul l ldlUyl d,C I ,y on silica using hexane:EtOAc (10:1) to give an oil (0.159).
Add 2-bromo-4'-fluoroac~lu~ u,)e (86 mg) to a mixture of the product of step 3 (0.15 9) and TEA (0.06 ml) in CH2CI2 (5 ml) at rt under N2. After 5 h, dilute the reaction with Et2O and wash sequentially with 1 N
HCI, 10% NaHCO3 and brine. Dry and collce"l,dle the organic layer and purify the residue by flash clllullldluy,d,ul,y on silica using hexane:EtOAc (9:1) to give an oil. Resolve this by HPLC using a Chiralcel AS column with hexane:lPA (85:15) to elute enantiomer 5(1) ([~] 228nM = -3.77x103, [~] 244nM =+3.34 x103) and then enantiomer 5(2) ([~] 228nM =
+3.65x103, [~] 244nM = -3.24 x103).
Step 5: Treat enantiomer 5(2) with HF according to the procedure of Example 1, Method A, step 3, to obtain compound 5. Elemental analysis calculated for C23H,7NO3SF2: C 64.93, H 4.03, N 3.29, S 7.52; found C
64.87, H 4.39, N 3.31, S 7.25.
Example 6 OH ,~OH
~J S". ~ 6a (did~l~r~",er a) FJ~ ~N~0~ 6b (~id:,L~ u,,,er b) F
Ster~ 1: Add NaBH4 (28 mg) to a solution of enantiomer 5(2) from step 4 of Example 5 (0.4 9) in CH30H (20 ml). After 2 h, partition the reaction 30 mixture between Et2O and H2O. Dry and cu~lc~ dle the organic layers and purify the residue by flash ~l llullldluuld~l ,y using EtOAc:hexane (1:6) to give did~ Ulllt~ 6(1) and 6(2).

CA 0220~202 1997-0~-13 WO 96/16037 PCT/US9~i~14134 ~: Individuallytreat did~ ulllers 6(1) and 6(2) from step 1 with HF
according to the procedure of Example 1, Method A, step 3, to obtain 6a and 6b.
6a: 1 H NMR in CDCI3: 2.85 (dd, J=6, 12Hz, 1 H), 3.04 ( dd, J=3, 12 Hz, 1 H), 4.06 (d, J=2.4Hz, 1 H), 4.7 (d, J=2.4Hz, 1 H), 4.9 (d, J=3, 9Hz, 1 H), 6.85-7.35 (12H).
6b: 1 H NMR in CDCI3: 3.01 (m, 2H), 3.97 (d, J=2.2Hz, 1 H), 4.7 (d, J=
2.2Hz, 1H), 4.92 (d, J=4, 8Hz, 1H), 6.85-7.36 (12 H).
Example 7 ~J S".~OH 7a: diastereomer a 7b: ~idal~rtl~l "~r b F N~ 7c: did~ o",er c ~F 7d: did:,Lt,,c v,,,er d ~;tep 1: Treat did~ V111el 6(1) from Example 6, step 1, with mCPBA as described in Example 3. Purify the products by HPLC on silica gel, eluting with EtOAc:hexane (1:2) to obtain diastereomers 7(1) and7(2).
$tep 2: Individually treat diastereomers 7(1 ) and 7(2) from step 1 with HF
as described in Example 1, Method A, step 3, to obtain 7a and 7b.
1H NMR CDCI3 with 10% CD30D:
~L: 3.35 (d, lH), 3.75 (dd, 1H), 4.22 (s, lH), 5.20 (m, 2H), 6.80 (d, 2H), 6.9 (m, 2H), 7.04 (m, 2H), ~.24 (m, 4H), 7.38 (m, 2H).
7b: 3.02 (dd, lH), 3.26 (m, lH), 4.21 (d, J=2.1Hz, lH) 5.14 (dd, 1H), 5.41 (d, J=2.1Hz, lH), 6.78 (d, 2H), 6.9 (m, 2H), 6.98 (m, 2H), 7.18 (m, 4H), 7.28 (m, 2H).
Melting points: 7a: 207-211C; 7b: 110C (dec.l.
Using the procedures of steps 1 and 2, treat diastereomer 6(2) from Example 6, step 1, to obtain 7c and 7d.
lH NMR CDCI3 with 10% CD30D:
. ~: 3.12 (dd, lH), 3.30 (m, lH), 4.45 (d, J=2.2Hz, lH) 5.04 (dd, 1H), 5.39 (d, J=2.2Hz, 1 H), 6.78 (d, 2H), 6.88 (m, 2H), 6.94 (m, 2H), 7.20 (m, 6H).
7d: 3.10 (dd, lH), 3.72 (m, lH), 4.07 (d, J=2.5Hz, lH), 5.09 (dd, J=2.3, 11.0Hz, lH), 5.17 (d, J=2.5Hz, lH), 6.78 (d, 2H), 6.85 (m, 2H), 6.98 (m, 2H), 7.18 (m, 4H), 7.30 (m, 2H).
Melting points: 7c: 98C (dec.); 7d: 106.5C (dec.).

CA 0220~202 1997-0~-13 WO 96/16037 PCT/USg3/l4134 Example 8 , ,~
Ph~S"
O~N
O Ph 8 (+/-) Treat a solution of the racemiC product from Example 1, Method A, step 2 (0.185 9) in CH2CI2 (20 ml) with mCPBA. After 3 h, add 5 NaHSO3 and NaHCO3 and stir for 10 minUtes, then extract with EtOAc.
Purify the organic fraction by flash ~ u",dli~ld,~lly on silica using hexane:EtOAc (4:1) to give compound 8 as a white solid (0.159, 76%).
Elemental analysis calculated for C24H23NO4S: C 68.39, H 5.5, N 3.32;
found C 68.12, H 5.49, N 3.37. EIMS 421 (M+). 1 H NMR: 3.2 (m, 2H), 10 3.55 (m, 2H), 3.80 (s, 3H), 4.23 (d, J=2.4Hz, 1 H), 5.53 (d, J=2.4Hz, 1 H), 6.9 (d, 2H), 7.1 (m, lH), 7.28 (11H).
Example 9 ~_ ~0~ ~OH reomer a F N~ 9a. dlaste F

Ster~ 1: Treat the product from Example 5, step 4, i,lldll~iiJIIIi'l 5(2) 15 according to the procedure of Example 3. Purify the product by flash i;l IIUIIId~ slld~JI Iy using EtOAc:hexane (1:3) to yield ~ia~ ulller 9(1 ) and diastereomer 9(2).
Ster~ 2: Individuallytreat i~id:,lt"c:u",ers 9(1) and 9(2) from step 1 with HF
according to the procedure of Example 1, Method A, step 3, to obtain 9a 20 and 9b.
9a: lH NMR in CDCI3: 4.39 (d, J=2.4Hz, lH), 4.93 (d, J=16Hz, lH), 5.25 (d, J=16Hz, lH), 5.32 (d, J=2.4Hz, 1H), 5.55 (bs, lH), 6.85-6.95 (m, 4H) 7.18-7.30 (m, 6H), 8.05-8.09 (m, 2H); m.p. 112.5-117"C.
9b: lH NMR in CDCI3 with 5% CD30D: 4.39 (d, J=2.1Hz, lH), 4.46 (d, J=15Hz, lH), 4.62, (d, J=15Hz, lH), 5.42 (d, J=2.1Hz, lH), 6.75 (d, 2H), 6.9 (dd, 2H), 7.08-7.20 (m, 6H), 7.90 (m, 2H); m.p. 188-195C.

CA 0220~202 1997-0~-13 wo 96/16037 PCT/US9~/14134 Exampie 1 0 ~,S,~
S N`[~
steD 1: Use the procedure of Example 1, Method B, Steps 1 to 4, substituting p-methoxybenzyl r,,~r.;d~ld,l in Step 2 for phenethyl mercaptan.
SteD 2: Treat the trans isomer of Step 1 with mercuric acetate to obtain the product of Example 5, Step 3, in optically pure form.
steD 3: React the product of Step 2 with 1'-bromo-2-acetylLl~ e according to the procedure of Example 5, Steps 4 and 5, to obtain the title compound as a solid, m.p 148-150C.
Example 1 1 ~S,F~
Carry out the procedure of Example 10, Step 3, using 1'-bromo-3-acetylll ,i-,,ul ,~"e to obtain the title compound as a solid, m.p. 176-178C. Elemental analysis calculated for C21H,6NO3S2F: C 61.01, H 3.90, N 3.39, S 15.48; found C 61.33, H 4.12, N 3.51, S 15.37.
Example 1 2 ¢~ oF~
Carry out the procedure of Example 10, Step 3, using 1'~
- 20 bromo-3-acetylpyridine to obtain the title compound as a solid, m.p. 74-90C. FAB MS 409 (M+H).

CA 0220~202 1997-0~-13 Example 1 3 F~;
Carry out the procedure of Example 10, Step 3, using 1'-bromo-4-acetylpyridine to obtain the title compound, m.p. 65-69C.
Elemental analysis c~lc~ t~ci for C22H17N203SF: C 64.69, H 4.20, N 6.86, S 7.85; found C 65.00, H 4.43, N 6.77, S 7.65.
Example 1 4 ~ 0~
Carry out the procedure of Example 10, Step 3, using 1'-bromo-2-acetylpyridine to obtain the title compound, m.p. 59-64C.
Example 1 5 ~ 0~
Treat the compound of Example 11 with NaBH4 in CH30H to obtain a mixture of dia~ u",~,:, as a soiid, m.p. 65-70C.
Elemental analysis calculated for C21H18NO3S2F: C 60.711 H 4.37, N 3.37, S 15.4; found C 60.67, H 4.48, N 3.40, S 15.87.
Example 1 6 ~S, F

-CA 0220~202 1997-0~-13 Treat the compound of Example 12 wiih NaBH4 in CH30H at 0C. ARer 30 min., pour into CH2CI2-water, separate the CH2CI2 layer and purify the product by flash .,l ll v" Id~ JI dpl Iy on silica gel, eluting with CH2CI2 CH3OH (g5:5) to obtain the title compound as a solid, m.p. 85-Example 17 OH r~OH
~ 0~
Using the procedure of Example 16, treat the compound ofExample 13 to obtain the title compound, m.p. 95-98"C.
Elemental analysis calculated for C22H1gN203SF: C 64.38, H 4.67, N 6.82, S 7.81; found C 64.09, H 4.95, N 6.67, S 8.06.
Example 1 8 F~O~
Step 1: Treat the cis isomer prepared in Example 10, Step 1, according to the procedure of Example 10, Step 2, to obtain a solid.
SteD 2: React the product of Step 1 according to the procedure of Example 5, Steps 4 and 5, to obtain the title comound as a solid, m.p. 180-185C. Elemental analysis calculated for C23H17NO2SF2: C 64.93, H 4.03, N 3.29, S 7.54; found C 65.13, H 4.16, N 3.43, S 7.70.
Example 19 ~ ~,S ~
Treat the product of Example 18, Step 1, with NaBH4 according to the procedure of Example 16, and treat the resuitant product CA 0220~202 1997-0~-13 with HF according to the procedure of Example 1, Method A, Step 3, to obtain the title compound, m .p. 95-1 05C.
The following formulations exemplify some of the dosage fomms of this invention. In each the term ~active compound~ desiu,,dlt,s a ..
compound of formula I.
FXAMpl F A
I~!~
No. Il lu, l~di~ mQ/tablet m~/tablet Active Compound 100 500 2Lactose USP 122 113 3Corn Starch, Food Grade, as a 10% 30 40 paste in Purified Water 4Corn Starch, Food Grade 45 40 5Magnesium Stearate 3 7 Total 300 700 Method of Manufacture Mix Item Nos. 1 and 2 in suitable mixer for 10-15 minutes.
Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4~, 0.63 cm) if necessary. Dry the damp granules.
Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the 15 mixture to d,U,UlU,Ulidl~ size and weight on a suitable tablet machine.
EXAMPI FB
Capsules No. I, I,ur~di~l ,l mp/t~hl~t m~/tablet Active Compound 100 500 2Lactose USP 106 123 3Com Starch, Food Grade 40 70 4Magnesium Stearate NF 4 Total 250 7ûû
Method of Manufacture Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 20 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine.

=--WO 96/16037 PCr~US95~1413 R~p,~s~"ldlive formulations c~",p,i~i"g a ~llol~ ,ul biosynthesis inhibitor are well known in the art. It is c~" llpldltld that where the two active il,~ul~di~ are ad",;~ d as a single c~,npo:,iliu", the dosage forms disclosed above for sllhstitl~
5 d~lidi"~l,e compounds may readily be modified using the k"o..'adye of one skilled in the art.
Using the test procedures described above, the following in vivo data were obtained for It!plt:s~llldli~le compounds of formula 1. Data is reported as percent change (i.e., percent reduction in 1:11010at~1UI esters) versus control, therefore negative numbers indicate a positive lipid-lowering effect.
% Rec uction E~ # Serum Cholest. Dose Cholest. Esters mg/kg 3b -20 -82 4a -22 -55 =

For racemic compounds of formula I or active dia~ u""_,~
or enantiomers of compounds of formula 1 compounds ad",i"ial~l~d at dosages of 0.1-25 mg/kg show a range of -21 to -97% reduction in ~I,ole~ ,ul esters, and a -57 to û% reduction in serum ~I,ole~ ,ul.
Compounds preferably show a range of -21 to -97% reduction in .;1 ,ole~ ,ul esters at a dosage range of 0.1 to 3 mg/kg, more preferabiy a range of -21 to -97% reduction in .:I,ole~l~,ul esters at a dosage range of 0.1 to 1 mg/kg.

j,,., , -' ,., I

Claims (11)

1. A compound represented by the formula or a pharmaceutically acceptable salt thereof, wherein:
Ar1 is aryl, R10-substituted aryl or heteroaryl;
Ar2 is aryl or R4-substituted aryl;
Ar3 is aryl or R5-substituted aryl;
X and Y are independently selected from the group consisting of -CH2-, -CH(lower alkyl)- and -C(dilower alkyl)-;
R is -OR6, -O(CO)R6, -O(CO)OR9 or -O(CO)NR6R7; R1 is hydrogen, lower alkyl or aryl; or R and R1 together are =O;
q is 0 or 1;
r is 0, 1 or 2;
m and n are independently 0, 1, 2, 3 or 4; provided that the sum of m, n and q is 2, 3 or 4;
R4 is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR6, -O(CO)R6, -0(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, =NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10CONR6R7, -(lower alkylen)COOR6 and -CH=CH-COOR6;
R8 is 1-5 substituents independently selected from the group consisting of -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7 -COR6, -S0 2NR6R7, S(0)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10CONR6R7, -CF3, -CN, -NO2, halogen, -(lower alkylene)COOR6 and -CH=CH-COOR6;
R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
R9 is lower alkyl, aryl or aryl-substituted lower alkyl; and R10 is 1-5 substituents independently selected from the group consisting of lower alkyl, -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9 NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10CONR6R7, -CF3, -CN, -N0 2 and halogen.

2. A compound of claim 1 wherein Ar1 is phenyl, R10-substituted phenyl or thienyl, Ar2 is R4-substituted phenyl and Ar3 is phenyl or R5-substituted phenyl.

3. A compound of claim 1 or 2 wherein q is 0, X and Y are each -CH2- and the sum of m and n is 2, 3 or 4.

4. A compound of claim 1 or 2 wherein q is 1, X and Y are each -CH2-, the sum of m and n is 1, 2 or 3, R1 is hydrogen and R is -OR6, wherein R6 is hydrogen, or wherein R and R1 together form a =O group.

5. A compound of claim 1 selected from the group consisting of trans-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-[(2-phenylethyl)thio]-2-azetidinone;
trans-4-(4-methoxyphenyl)-1-phenyl-3-[(2-phenylethyl)thio]-2-azetidinone;
cis-4-(4-methoxyphenyl)-1-phenyl-3-[(2-phenylethyl)thio]-2-azetidinone;
trans-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-[(2-phenylethyl)-sulfinyl]-2-azetidinone;
cis-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-[(2-phenylethyl)-sulfinyl]-2-azetidinone;
trans-4-(4-methoxyphenyl)-1-phenyl-3-[(2-phenylethyl)sulfinyl]-2-azetidinone;
cis-4-(4-methoxyphenyl)-1-phenyl-3-[(2-phenylethyl)sulfinyl]-2-azetidinone;
trans-4-[1-(4-fluorophenyl)-4-oxo-3-[(2-phenylethyl)sulfinyl]-2-azetidinyl]-phenyl acetate;
cis-4-[1-(4-fluorophenyl)-4-oxo-3-[(2-phenylethyl)sulfinyl]-2-azetidinyl]-phenyl acetate;
(+/-)-trans-4-(4-methoxyphenyl)-1-phenyl-3-[(2-phenylethyl)-sulfonyl]-2-azetidinone;
trans-1-(4-fluorophenyl)-3-[[2-(4-fluorophenyl)-2-oxoethyl]thio]-4-(4-hydroxyphenyl)-2-azetidinone;
trans-1-(4-fluorophenyl)-3-[[2-(4-fluorophenyl)-2-hydroxyethyl]thio]-4-(4-hydroxyphenyl)-2-azetidinone;
(3R,4R) 1-(4-fluorophenyl)-3-[[2-(4-fluorophenyl)-2-oxoethyl]sulfinyl]-4-(4-hydroxyphenyl)-2-azetidinone;
1-(4-fluorophenyl)-3(R)-[[2-(4-fluorophenyl)-2(R)-hydroxyethyl]-sulfinyl]-4(R)-(4-hydroxyphenyl)-2-azetidinone;

1-(4-fluorophenyl)-3(R)-[[2-(4-fluorophenyl)-2(S)-hydroxyethyl]-sulfinyl]-4(R)-(4-hydroxyphenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-[[2-(2-thienyl)-2-oxoethyl]thio]-4-(4-hydroxyphenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-[[2-(3-thienyl)-2-oxoethyl]thio]-4-(4-hydroxyphenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-[[2-(3-pyridinyl)-2-oxoethyl]thio]-4-(4-hydroxyphenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-[[2-(4-pyridinyl)-2-oxoethyl]thio]-4-(4-hydroxyphenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-[[2-(2-pyridinyl)-2-oxoethyl]thio]-4-(4-hydroxyphenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-[[2-hydroxy-2-(3-thienyl)ethyl]-thio]-4-(4-hydroxyphenyl)-2-azetidinone;
(3R,4R) trans-1-(4-fluorophenyl)-3-[[2-hydroxy-2-(4-pyridinyl)ethyl]-thio]-4-(4-hydroxyphenyl)-2-azetidinone;
(3S,4R) cis-1-(4-fluorophenyl)-3-[[2-(4-fluorophenyl)-2oxoethyl]thio]-4-(4-hydroxyphenyl)-2-azetidinone;
(3S,4R) cis-1-(4-fluorophenyl)-3-[[2-(4-fluorophenyl)-2hydroxyethyl]-thio]-4-(4-hydroxyphenyl)-2-azetidinone;

6. A pharmaceutical composition for the treatment or prevention of atherosclerosis, or for the reduction of plasma cholesterol levels, comprising a compound as defined in any one of claims 1, 2, 3, 4 or 5, alone or in combination with a cholesterol biosynthesis inhibitor, and a pharmaceutically acceptable carrier.

7. A process for the preparation of a pharmaceutical composition as claimed in claim 6 which comprises admixing a compound of any one of claims 1, 2, 3, 4 or 5, alone or in combination with a cholesterol biosynthesis inhibitor, with a pharmaceutically acceptable carrier.

8. The use of a compound of any one of claims 1, 2, 3, 4 or 5 for the preparation of a medicament for the treatment or prevention of atherosclerosis, or for the reduction of plasma cholesterol levels, comprising a compound of any one of claims 1, 2, 3, 4 or 5, alone or in combination with a cholesterol biosynthesis inhibitor, and a pharmaceutically acceptable carrier.

9. A kit comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat or prevent atherosclerosis or to reduce plasma cholesterol levels which comprises in one container an effective amount of a cholesterol biosynthesis inhibitor in a pharmaceutically acceptable carrier, and in a second container, an effective amount of a compound of any one of claims 1, 2, 3, 4 or 5 in a pharmaceutically acceptable earner, said effective amounts representing an effective serum cholesterol lowering amount.

10. A compound of any one of claims 1, 2, 3, 4 or 5, for use alone or in combination with a cholesterol biosynthesis inhibitor lowering serum cholesterol levels in a mammal in need of such treatment.

11. A process for preparing a compound of claim 1 comprising Reacting a carboxylic acid of formula II, wherein Ar1, X, Y, m, n, q and R1 are as defined in claim 1 and R11 is a protected hydroxy group, with an amine of formula III, wherein Ar2 and Ar3 are as defined in claim 1, in the presence of a base and a dehydrating agent, followed by an acid, to obtain a compound of formula 1a, wherein the variables are as defined above, and, when R11 is not alkoxy or benzyloxy, converting R11 to hydroxy; or Alkylating a mercapto-substituted azetidinone of formula V, wherein Ar2 and Ar3 are as defined in claim 1 and Q is a sulfur-protecting group, with a compound of formula X, wherein Ar1, X, Y, m, n, q and R1 are as defined in claim 1, R11 is a protected hydroxy group and L is a leaving group to obtain a compound of formula 1a as defined above in process A, and, when R11 is not aikoxy or benzyloxy, converting R11 to hydroxy; or Cyclizing a chiral compound of formula IX, wherein Ar1, Ar2, Ar3, X, Y, m, n, q and R1 are as defined in claim 1, R11 is a protected hydroxy group and Ph is phenyl, with a silylating agent and a fluoride catalyst to obtain a mixture of cis and trans isomers Id and Ie, wherein the variables are as defined above for formula 1a in process A, and, when R11 is not alkoxy or benzyloxy, converting R11 to hydroxy, and optionally separating said isomers; or D) Oxidizing a compound of formula Ia, Id or Ie to the corresponding sulfinyl and sulfonyl compounds; or E) Converting an R11 alkoxy or benzyloxy group in a compound of formula Ia, Id or Ie to the corresponding hydroxy group; or F) Converting a compound of formula I wherein R is hydroxy to a compound of formula I wherein R is -OR6, -O(CO)R6, -O(CO)OR6, or -O(CO)NR6R7, or wherein R and R1 together are =O.