CA2105655A1 - Multicyclic tertiary amine polyaromatic squalene synthetase inhibitors - Google Patents

Abstract

2105655 9215579 PCTABScor01 This invention relates to polycyclic compounds containing two mono and/or bicyclic rings and a basic tertiary amino group capable of forming an ammonium ion at biological pH and which reduces levels of serum cholesterol in the body without significantly reducing mevalonic metabolite synthesis. This invention relates also to pharmacological compositions and method of treatment for lowering serum cholesterol levels using the compounds of this invention.

Description

W(~ 92/1~579 PCr/~S92/O~f773 21 ~ :~ 6 5 S

' ' ::
;, MUL~ICYCLIC TERTIARY AMINE POLYAROMATIC
SQUALENE~ ~YNTHETASE INHIBITORS
.~.

Field of thQlnv~ntiQn ~ 0 This; applica~ion is a continuation-in-part application of U.S. Application ;
Senal No. 07/667,686, filed March 8, 1991.

;~ ~ The ~present inv;éntion rela~s to a class of novel compounds useful in 15 ~ ~ the treatm~nt of diseases~ associated with undesirable cholesterol lev~1s in ~he body,~ and~partiGuiarly of diseases of the cardiovascular system, :such as arthero ,clglosis. ~

Only~about 7% of`the~tota! body~çholesterol circulates~ in the plasma, 20~ ~ where~ it~has~b~en !inked to ~atherosc~1erosis.; The rema'lning 93% is loca~ec~ in cell~,~;whe~e it~performs~vital~structural and~ metabolic functions. Although~ al I
animal ~cells~ require ~chol~sterol~, they face a~complex problem~in ~regulatlng the amount~;of~ Intracellular :cholesterol ~present. ~ Unde~r normal~:oonditions, choles~érol can be synthesiz~ed~endogenously~ (se~ Figure` ~ or it can be 25~ ~ obtained~ex~genously by~re~moving ~low den~sity lipoprotein~(LDL) 1r~m thebloodstream. Approaches~to ~the; control~af plæsma cholesterol levels have been~ varied,~ howevér it has been~ shown ~that inhibiti~ng endogenous ~
choiesterol biosynthesisi forces the cell to rely~ more ~n LDL uptake~ Increased; LDL uptake by cell's,~ ~spe;~ially ~llver cells,~has been shown to lower~ plasma 30; çh~lester~ level.s. ~

LC)L binds to~ specific receptors found on the surfaces of the cells and is internaliz~d~by receptor-mediated endocytosis. inside the~ cell, th~ cholesterol; çster::coffnponent is hy~drolyzed by Iysosomal enzymes to liber~te ~ree s ~ 35~ cholesterol. The f~ee cholesterol has the following ~our important regulatory f ~ ~ a~l~ns on the cell's cholesterol metabolism: ~ ~

:: : ~: :

WO 92~1~57~ PCr/llS9~/01773 ~6~'j 2 ?~
~1 ) Suppression of cholesterol biosynthesis by down-regulation of the rate Iimiting enzyme, HMG-CoA reductase;

(2) Suppression of th~ synthesis of LDL r~ceptors;

(3) Activation of the QCAT erlzyrne, which catalyzes the formation ot cholesteryl esters tor storage; and . ~

(4) Suppression ot squalene synthetase activity.
~ '''''' The first ~hree regulatory actions are taken to prev~n~ an overaccumulatiorl of fr~e cholestcrol in the cell. Supprcssion of s~ualene ~ ' synthetase activity by free cholesterol, the ~ourth response above, occurs only ~'-'`
a~ter the HMG-CoA reductase anzyme has been supressed by more than 90%, which,~accordingly, ~reduces the~synthesis ot mevaionic acid and all of its metabolites. Farnesyl pyrophusphate (FPP), is an important mevalonate .'' met~b~olite, located at~the branch~point ot the mevalonate pa~hway. It is tha immediate ~recursor of ~squalene, whose sole fat~ is cholesterol synthesis, as 'well~as of s~me vlta!~nonsterol products (e.g. dolichol, ubiquinone, and~the ~:
20 ~ arnesy!ated proteir~s),~w~hich are essential for c~ll grou~h. C;holesterol is ~ ;' réquired~in much lar~er amounts`than the:~nonster~l product~and in ~he '~
absenc~ of LDL supplied cho!esterol, the~va~t ~blJlk of farnesyl pyrophosphate .' is~used~t~ produce cholesterol by way~of squalene. ~However, when tree ~-~
cholesterol is present~and~HMG-CoA reductase has been supr0ssed, squalene synthetase is also~supressed~ln order to divert~tarrlesyl pyrophosphate trom the~
sterol pathway, into the~ crucia! ~nonsterol pathways. I~ should~be pointed~out ~'~
that even though squalene synthetase is suppressed abou~ 90% by free ~ -cholesterol, the enzyme is still present in large excess in the cell. Thus '~
suppression of squalene synthetase does not influence thë rate~ di cholesterol bi~ynthesis. F~ather i~s ;purpose is to support ~he synthes~s of the nonstèrol s ~ products by maintaining'adequate concentrations~of farnesyl pyrophosphate.
!: ~ : : This is important at~a ~ims when the synthesis of farnesyl pyrophosphate has been grea~ly reduce~d. ~ ~

~; ~ 35 Treatrnent with an HMG-CoA reductase inhibitor blocks the production of mevaloniG acid and ~hus inhibits the biosynthesis of cholesterol. But unlike the, normal physiological regulation of the rnevalonate pathway1 there is no ,~ : .
, ,, .. , ,. - -,, W~ 92/1~579 P~/US92/~1773 210S6~5 conourrent suppression of the squalene synthetase enzyme. The small amounts of farnesyl pyrophosphate still being produced still follow the sterol pathway. The intracellul~r concentration of farnesyl pyrophosphate dr~ps to Ievels so low that tha farnesylated prot~ins prepared therefrom can no longer

5 be synth~sized. It should be noted that farnesylated proteins are involved in feedback supr~ssion regulation of HMG CoA reductase, and, accordin~iy, the loss of this feed~ack regulation results in a 5- to 10-fold increase in the amount of the HMG-CoA reductase enzyme present in the cell. The increas~d amount of enzyme can also be inhibited ~y the HMG CoA reductase inhibitor, bu~ at a 10 higher dose than would have been necessary had the amoun~ of the HMG-CoA
reductase ~nzyme remained the same.
.
Since HMG CoA reductase is a rate-limiting enzyme in cholesterol biosynthesis, inhibitors of HMG CoA reductase are potent hypocholesterolemio 15 agents in humans. Although these inhibitors are relatively safe, side e~fectsîike hepatotoxicity and myopathy have been observed. Inhibitisn oS squalene synthetase wilt not result in reduction of vital mevalonate metabolites and thusa squalene synthe~ase inhibitor may offer the advanta~e of fewer side effects ~; compared to that observed with inhibitors o~ HNlG GoA reductase. It may also 20 result in feed-back inhibition of HMG CoA~and thus become a more useful hypocholesterolemic agent ;.
Re~ DeveloDment~
:
, The literature describes the cholesterol biosynthetic pathway and possible means for thè inhibition of squalene synthetase. In a series of papers including J Am Çhem.~o~, 1982, 104, 7376-7378 and 1 Am (~;hem. ~oc, 1989, 1 11, 3734-3739, G. Daie PolJiter, et al disclose tha~ ammonium substituted cyciopro~yl polyene cornpounds mimic ths topologicàl and `
electrost~ic properties of the primary cation and tertiary cation of presqualenepyrophosphate. and in the presence of phosph~te buffer, inhibit squalene synth~ta~e. Soott A. Biller et al in J Med- . Chem., 1 9B8, 31, 1869-1871 disclose th~ a series of stable, non-ionizable analogues of farnesyl pyrophosphate, comprisin~ phosphomethylene phosphate polyene compounds, inhibit squalene synthetase.

"~ :
~"

WO 92/15579 PCr/US92/V1773 ~'J36'~3~ 4 .
U. S. Patent No. 4,839,369 discloses chemical compcunds, having two aryl rings attached through a chain which may contain one to several atoms in length, and to which is attach~d.to one of the aryl rings an acidic function such ' as a2acyclic ~roup, carboxlic acid or tetrazole group,are lipoxygenase ', ~' 5 inhibitors and possess anti-inflammatory and anti-allergic prope~ies, &irnilar' compounds are disclosed in U.S. Patent No. 4,631,287, EP û206751, and EP ' -~
0219308. None of these r~fsrences disclose that any of the aforesaid acidic a2acyclic compounds cxhibit cholesterol reducing properties, The present invention is directed to a class of novel tertiary amino ~, polycyclic compounds which sxhibit squalene synthe~ase inhibition properties, ~ ~
,: "
Summarv of the Inventlon ~, ~ 15 ~ This inventlon comprises polycyclic~ompounds ccntaining two mono~
~: ~ and/or bicyclic rings and a basic tertiary amino group, Preferred polycyclic c ompounds contain a ter~iary amino group capable o~ forrning an ammonium , .
n at bio!ogical pH, ~The~compounds of this invention possess proparties ,''-whieh reduce levels of s~rum cholesterol in the body without significantly ., reducing m~valonic mètabolite synthesis and thus provide a ~herap~utic agen~
. ~ having fewer side effects than agen~s which act by inhibiting the HMG-CoA
reductase enzyme, This~inven~ion relates alsoto pharmacvlo~ical ,, compositions and method of treatment for !owering s~rum cholesterol levels - using the compounds of this invention.
~, ~ 25 Descriotion o~ ~he D,r~w~
. ~:
Figure 1 is a schematic diagram of the biosynthetic pathway of ~;, cholesterol. ' ~
0 ~:
Detailed Description and Preferred_Embo~iments The compounds of the present invention com~rise polycyclic ring compounds con~aining two rnono- and/or bicyclic aryl and/or carbocyclic and/or ~¦ ~ 35 heterocyclic rings and a t2rtiary cyclic amino group.

.~

'., WO 92/15579 PCI`~US92/01773 ` `

2 1 ~ 5 6 h 5 - ;`
More specifically, the polycyclic tertiary amino cornpouncls are described ; .
by Forrnula l:
3 ~ 15 1 7 ~ ~

( R ~o ~ 6 ( R~ ) Formula l wher~
, ,.
Ar I and Ar II are independently a substituted or unsubstitutsd mono-, bi-or tricyclic ring;
:~ 10 ~ :
:; ~ A is preferably selected from the group consistin~ of R' ~N ~ ~>

n~¦ \ ~N~

S (CHZ)m ~ J
o r N

where~Y is NR', O, or S, Z is NR', O, S or a bond and m is 1-2;
,: . : ~ ~ , : 15 B~is~CR'R', O,:S, NR', SO,~SO2, NR'--C=O, O=~NR',O=C
7 ~ =CR' or C-C;
D is CR'R', O, S, NR', SO, SO2, NR'~=O, O=~NR', O-C, : ~ =0, 0=~0, O=~C=O, O-~CH=CH, R'C7=CR', C_C, (::-CHR', ::~
~ C=S, C=NOH orabond;
.~ ~ 20 : R1, R2, F/~3, R4, Rs, R~" R7 and R8 are independently hydrogen or W~ 92/1557~ PCr/U!~;92~01773 ~ 6 .
(CH~ )~X where x is 0-5 and X is hydrogen, alkyl, alkenyl, aralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, acyloxy, aryl, halo, amino, mono-and di-alkylamino oracylamino;
R1 and R3, tog~ther and/or Rs and R7 together rnay b2 ~ CH2 )n where n 5 is 1-4:
~, geminal R1 and R2, R3 and R4, Rs and R6 or R7 and R8 groups may bc , ( CH2 )p where p is 2-5; ;
R' is hydrogen, alkyl or aralkyl;
R is hydfogen, alkyl, aralkyl, hydroxy, alkoxy, aralkoxy, acyloxy, halo, 10 haloalkyl, arnino, mono- and di-alkylamino or acylamino; and a,b,dandeareO-4;or a pharmaceutica Iy acceptable salt thereo~.

Preferably, Ar 1 and Ar II are independently a substituted or ~ ;
15 unsubstitu~ed mono-,~ bi- or tricyclic ~system of about 5 ~o about 14 atoms whioh may be pa~iaily or compl0t~1y unsaturated carbocy~lic or heterocyclic and ~.
where~each~ring of said;system contains 0 to about 2 hetero atoms ~elected 1rorr:~N, O and S~provided said hetero atoms are not vicinal ~xygen and/or sulfur atoms~and where~the substituen~s may be located at any appropriate . 20 ~ posjtion of the~ nng system ancl are ctescr~bed by the R detin tion~above.

Preferred monocy~lic~ rings include aryl and unsaturated carb~cyclic and heterocyclic rings. Ex~emplary rings are substi~ut~d or~unsubstituted pyrrole, :~
ihiophene, furan,~cyclopantadiene, imidazole, pyrazole, 1,2,4-triazole, pyridine, 25 pyrazine, pyrimidine, pyridazine, thiazol~, isothiazole, Isoxazole, s-triazine and n ~ - benzerle.
: ~
Pre~erred bicyclic rin~ systems incjlude bicyc!io aryl and bicyclic ~
unsaturated carbocyolic and heterocyclic rings. Exernplary bi yclic rings ; -30 i nclude substitu~ed and unsubstituted indene, isoindene, benzofuran, :~,5.~ dihydrobenzofuran, benzothiophene, indoie, 1H-indazote, indoline, irnadazole, ~} ~ ~ azulene, ~etrahydroazulene, benzopyrazole, benz~imadàzole, benzoxazole, b~enzothiazole, 1,3-benzodioxole, 1,4-benzodioxan, purine, naphthalene, tetralin, coumarin, ohr~mone, chromene, 1,2-dihydrobenzothiopyran, 35 tetrahydrobenzo~hiopyrarl, quinoline, isoquinoline, quinazoline, pyrido~3,4-b]-I ~ pyriclin~ and 1,4-benzisoxazine.
., ,; ,~ ~
", ., ", , WO 92/1 5579 Pcr/uss2/ol 773 7 21056~

Preferred tricyclic ring systems includ0 tricyclic aryl and tricyclic unsaturated carbocyclic and heterocyclic rings. Exemplary tricyclic rings ~`
include substituted and unsubstituted phenanthrene, anthracenet acenaphthylene, perimidine, phenothia~ine and phenoxazine.
The lertiary amino groups de~cribed by A are preferably the ~ollowing:

--N~ !IR [~N b~
~ '~ r ~' - ~

As ~employed above and throughout this disclosur~, the ~ol!owing terms, unless otherwise indicated, shall be understoo i to have the foilowing ~ :
meanings~
:: :
"Biological pH" refers to that pH of blood, plasma or serum in the body ~15- ~ between abcut 7.2~ and about ~.5 and which does not inter~erQ with normaldegradatiorl o~ materials present~therein. ThR normal pH o~ blood, plasma or serum values is about 7.35-7.45 and is prefer~bly about pH 7.39-7.41.
, "Monocyclic aryl"~means a carbocyclic and/or~hcterocyclic aromatic ring.
20 Prefe~rred groups include ;phcnyl, thienyl,~ pyridinyl, furyl and pyrimidinyl.

"Bicyclic aryl" means a bicyclic nng system composed o1 two fused carboc)!clic and/or,heterocycllc aroma~ic ~ings. Preferred groups inclyde naphthylt indolyl, benzothienyf, benzofuranyl, quinolinyl, chrom~nyl and ;~
25 purinyl.
~ , "Tricyclic aryl" means a tricyclic ring system composed of three fused carb~cyclic and/or heterocyclic aromatic rings. Pre~erred groups include ac~naphthylene, phenanthrsne, phenothiazine and phenoxazine. ~, ; "Aryi" me~ns a carbocyclic or heterocyclic aromatic ring. -:. ~

'I ~
~.

Wo 92/15579 P~r/llS9~/01773 ;,6~

"Alkyl", either alone or with various substitu~nts defined herein, m~ans a saturated aliphatic hydrocarbon, either branched- or straight-chained.
Preferre~ alkyl is "Loweralkyl" having about 1 to about 6 carbon atoms.
Examples of alkyl include methyl, ethyl, n-propyl, isopropyt, butyl, sec-butyl, t-S butyl, amyl and hexyl.

"Alkoxy" refers to an alkyl-O-group.
..
"Alkenyl" refers to a hydrocarbon having at least one point of ur~saturation and may be branched- or straight-chained. Pr~ferred alkenyl ;:
groups have 2 to about 6 carbon atoms. Exemplary alkenyl groups include vinyl, ally!, ethynyl and isopropenyl. ;~

The preferred aryloxy group is phenoxy.

"Aralkyl" means~an alkylgroupsubstituted by an aryl radical. The preferred aralkyl groups are benzyl or phenethyl.

he preferred aryloxy group is phenoxy.
The preferred aralkoxy groups are benzyloxy and phenethoxy.

~;; The preferred acyloxy group is acetoxy.

~ "Halo" means a halogen. Preferred halogens~include chloride, bromide and fluoride. The preferred haloalkyl group is~trifluorornethyl.

The more preferred compounds~ of this invention include those ~ ~ i cornpounds of Fotmula I where ~ :~

Ar I is phenyl or naphthyl;
, : ...
Ar II is phenyl, naphthyl, benzothiazolyl, benzofuryl, benzoxazolyl benzothienyl, benzodioxanyl, benzodihydrofuranyl, benzofuranyl, 3~ benzodioxolyl, quinolinyl, indolyl, acenaphthyl or dihydroacenaphthyl;

I
~ , il :

~NO 9~l5579 PCr/Uss2/01773 . ~;

Ais ~ ~ ~~ or b~;

BisCR'R,C),Sorl~

5 1:) is CR'R, O, S, NR', NR'--C=O, O=~NR', O C=O, O=C, R'C_CR', C-C, C=CHR', C=S, C=NOH or a bond;
, .
R1, R~, R3, R4, R5, R6, R7 and R8 are independently hydrog~n or (CH2)~X
where x is 0-5 and X is hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, or ~.
1 0 aryl;
R1 and R3 toge~her and/or R5 and R~7 together may be (CH2)n where n is 1-4:

eminal R1 and R2, R3 and R4, R5 and R~ or R7 and R8 groups may be (CH2)p 15; wherepis:2-5;

R'~ ls h~ydrogen, alkyl or aralkyl; ~ :

R is hydrogen, alkyl, hydroxy, alkoxy, halo~or haloalkyl; and:~

a, b, d and~ e are O-4.

The tertiary amino A group is most preferably:one of the ~ollowing:

25~ ~

The;most preferred~compounds are~described by Formula I where:

: : Ar I is phenyl or naphthyl;
Ar II is phenyl,~naphthyl, benzothiazolyi, benzofuryl, benzoxazolyl, ~i b~n~athienyl, benzociioxanyl, benzodihydrofuranyl, benzofuranyl, .~ ~ b~nzociioxolyl, quinolinyl, indolyl, aoenaphthyl or dihydroacenaphthyl;
. ~ , ~" ~ , WO 92/15579 P~/US92/~1773 ~,r~ 6~ ;

Ais ~3 or ~:

E~ is CR'R or O; :~
~ , D jS CR~R, O=C, R~C=CR~, CEC, C=CHR~ or a bond;
~ '.

R1, R2, R3, R~, Rs, R6, R7 and R8 are inctependently hydrog~n or (CH2)~X
where x is 0-3 and X is hydrogen, alkyt, hyd~roxy or ph~nyl;
:

R' is hydrogen or loweralkyl; : ~:

R is hydrog~n, loweralky!, hydroxy, loweralkoxy, halo or trifluoromethyl; and , 15 a, b, d~ and e are O-4.
~, , A special embodiment ot the compounds of this invention is described by Formula 11 CH2~-B (GH~)h ~ ch2d D-~cH2 2~
.: , Formula ll ~ :
where : ~
;, i j ! ! ' ~: 25 B is CR'R' or O; ~
is CF~'R', O=C, R'C=(~R', C--C, C=CHR' or a bond, R is hydrogen, loweralkyl, hydroxy, loweralkoxy, halo or trifluoromethyl; and 3~ :
a,b,dandeareO-4.
'1 '.' ,,, s, ~

WO 92/lS579 PCr/USg2/01773 . ~ .

1 1 ' 210S6.jS ,:~

The compounds of this invention may be prepared by employing procedures known in the literature star~ing from known compounds ~r readily preparable intermediates Exemplary general procedures follow.
Since the compounds of this invention have c0rtain substituants which are necessarily prescnt, the introduction of each substituent is, of cours~, dependent on the specific substituents invoived and the chemistry necessary for their forma~ion. Thus, consideration of how one substituent woutd be affected by a chemical reactiGn when forrning a second substituent would involve techniques ~amiliar to the skilled artisan. This would further be dependent on the ring involved.

It is convenient to synthesize these molecules by ernploying condensativn reactions at the above-described reactive B and D sites of the m~l~cule. Exemplary general procedures are shown below and~ for convenience, describe the benzene and quin~clidine ring system. Of course, ;;
while the ~oliowing reactions involved are basic to developing substitut~d phenyl-quinuclidine molecules having desirable substituent groups present, ~he:substitution pattern for other mono- or bicyclic:rings depends on the ~
chemistry:of the particular ring. Any such iadjustments to the chemistry would - -be familiar to one skilled in the art. : :

~: . Jhus, in order to prepare those compounds where B or D is O, S or NR' : 25 the following reactions or combination of reactions are employed:
:

~: '.' j~

~:
, :.

':

WC) 92~1ss7s PCr/~S92/~1773

6~ 1 2 ~( C ~--L + H3- 1 C )b~ ( C )d--D--( C )~

~( C ),--BH + L-~ Cl)b~ C )d--D--( ~

~(c)~ - u1c)b ~ (C)d--L + HD--(C),~]

~(C),-- B-(C)b ~ (C)d-DH + L--(C)~

BH3 : :
.
where L is a leaving group, preferably halo, tosylate or mesylate.
; ~
The cyclic amine is protected with the usual protecting groups such as 5 hydroborane~complex~which is removed at the appropriate time with dilute acid such as tlCI. ~ , Where B and D are~ O or S, any base normally employed to d~protonate an alcohol or thiol may be~used, such as sodium hydride, sodium hydroxide, 10 triethyl amine, sodium bicarbonate ordiisopropylethylamine.

Reaction temperatures are in the range of -78C to reflux depending on the réactants involved. (Preferably 0C to room temperatwrë). Reaction times vary from abcut 2 to about 96 hours. The reaction is usuaily carried out in a ~ -solvent tha~ will dissolYe both reactants and is inert to both as well. Solventsinciude, but are not limlted toi diethyl ether, tetrahydrofuran, N,N-dimethyl formamide, dimethyl sulfoxide, dioxane and the like.

In the case where B or D is SO or S2, then treatment cf the thio 2~ compound with m-chlorobenzoic acid or sodium perioda~e results in the sulfinyl compound. Preparation of the sulfonyl compound may be accomplished by , ,., WO g2/15579 PCrtUS~2/01773 . ' ' 13 210~6~i.5 known procedures such as dissolving the sulfinyl compound in acetic acid and treating hydrogen peroxide, preferably about 30% aqueous H22-In certain of the following reaction s~hemes a mstal salt may be used.5 Any appropriate metal salt such as Li, K, Na, Mg, Br or the like may be used.

Those compounds where D is -C=O are prepared by one of the E f~llowing two reaction sequences, where in sequ~nce 1 I treatment of the - substituted metal salt cornpound, such as the lithium, sodium po~assium or ~:
10 Grignard compound, with an N-alkyl-N-alkoxyb~nzarnide following the procedure of S. Nahm and S.M. Weinreb in Tet Letters, 22, 3815 ~1981) results in the ~ormation of the carbonyl chain.

1~ Sequence I

N ~ , 8113 :

~,1 2(~
', ~1 .

wo 92/15579 Pcr/lJs92/~1773 ~ 1 4 Sequence 2 ~' Condensation o~ the ketone with an appropriate hydroxylamine results in tha ~ormation of the oxirne, while Witti~ condensation of the ketone using Ph3 1 5 P=CH2 results in the methylene cornpounds; Wittig condensation also may '~ take place at the D position of the molecule of Formuta I as foilows:
,~ .

~( C ) -B`( C )b ~ ( C )d--C-R' + (Ph)~P=C - ( C ).~j ~

~(C)~ tC)b~ (C)d'(=C-(C)~ ~

:10 : ::
:: : This~may b~ carried ou~ using normal Witting reaction conditions When ~ -the appropriate aldehyde or ketone is reacted with a Wi~tig reagent then condensation results in formation of the double bond. This may Ihen be ;~
reduc~d cata!ytically by known procedures such as Pd/C or any other suitable ~:
hydrogena~ing condition. The Wittig reagent isprepared by known~
recognized proced~res such as reaction o~ triphenylphosphine or die~hylphosphone, with a substituted alkyl bromide fol!oweci by treatment with a:~ strong organometallic or alkoxide base, such as n-BuLi or NaOlt, result~ in the ~: desired ylide. Of course this Witting condensation may also take:pla~e when 20 the Wittig reagent is formeai on ~he qulnuclidine position of the mol~cule which is then condensed with the aldehyde from the Ar I portion.

Halog~nation with Br~ in C~4 on the double bond followed by double dehydration ~ith NaNH2 / liq NH3 results in the triple bond oompounds.
:
~ ~l When B or D is -NR'-CO- or-CO-NR'- then condensation of the acid halide with the appropriate aniline wiil give the desired compound such as ~¦ examples in ~he follQwing schemes. :~

', "

WO ~2/15579 PCr/US92/01773 210;~6~

~ ~ O-C-N~
~ ~J ` ' ~ .. :
' :~
~: BH3 0 ~0 /J ~ ~ , o--~l~ ,`

Sequence 3 ondénsation~o~the ~metal~salt~with a substituted phenyllsocyanate results in;the~correspor~ding~:~amide,~as shown~ above. ;:Reverss cond~nsation~
5~ ~will ~give: the correspond~ing~ reverse amide.

~CH.-D ~ N~2 + ~CICO~

sequenGe 4 ~

Condensation of ths acid~ halide with the appropriate~:aniline~ will give: the:
10 desired ~amide compound~ as~shown in sequence ~

ondensation~ of the metal sa~lt with~ an aldehyde or hetone: ~ollowed by dehydration results in the appropri:ate ring addition, as shown below.
' , WO 92JI~S79 P~/US92/01773 S~ 1 6 ~ , '', O ~LI ~ :
~ ";
EIH3 `

~ HCI

N
BH3 : :~.

Certain compounds~o~-this Invention ~may have at least one 5 ~ asymmetric~arbon atom~such~as~those~cQmpounds having differen~ geminal groups or those compounds which contain ~an asymmetnc carbon ato~m. ~ :
Further,~certaln ;compo~nds~ o~ this~invention: may~ ~xist in~their ~ or ~
configuration~such as those~co`mp~ounds where~B or ~ i~ CR1=C:R1. As a~ result, those compounds o1 this~invention may~;be obtain~d either as racemio~mixtures, 10 ~ diastereolsomenc~ mixturss; or a~s~ individual enantiomers. When ~two or three; ~:
asymmetric centers ar~present the product may exist as mi~ures o~ two~ or four j ~-diastereomers. Of course it is understood~hat cer~ain other compounds within ~;
the sc~pe o t this in~er~ti;on i~o~ld have a n~imber o1 stereocenters. ~1n benleral, a compound with x stereocenters can~ have a~maximum of ~x stereoisomers. .
15~ ~ Ther~fore,a~compound~havingthree~suchcentersi~givès~risetoamaximumof eight stereoisomers, while ~one having four produces sixteen, etc. The product may~be synthesized as a mixture of the isomers and then the desired Isomer separated by conven~ional techniques such as chromatography ~r ~ractional rystallization from which each diastereomer may be resolved. On: the othier 20 hand, ~ynthesis may be carried out by known stereospecific proce~ses using ~ .
: ~, : ; ..

Wo 92/l5579 P~r/u~s2/~l773 ~7 ~1056i5 `

the desired form o~ the intermediate which would rcs~lt in obtaining th0 desireds~ereospecificity.

Reference to the separation of ~ and ~ isomers by chroma~ography S may be tound in W.K. Chan, ~ al, J. Arn. Chem. Soc. ~, 3642, 1974.

It is to be und~rstood that the scope of this invention encompasses not only ~he various isomers which may exist but also the ~various mixture of isomers which may b0 ~ormed. :;
Ths resolution of the compounds of this invention and their starting materials may be carried QUt by known procedures. Incorporation by reference is hereby macie to the four volume compendium Qptiçal Resolution Procedures for c-h-emi~L(;~QmpQui~: Optical Resolution Information Center, Manhattan College, Riv~rdale, New York. Such procedures are useful in the practice of this invention. A~urtheruseful reference is EnanliomQ~, R~ema~n~
Jean Jacques, Andre Collet and Samuel H. Wilen; John Wiley &
Sonsi Inc., ~New York, 1981. Basically, the resolution of the compounds is based on the ditferences in the physical proper~i s of diastereQmers. ',~5'',' ~onversion~of the racemates into a mixture of diastereomers by attachment of an~ snantio~nencally purê ~moiety.results in forms that are separable by fractional crystailiza~ion, di~stillation or chromatography.

The present compounds form salts with a~ids when à basic amino ~;
25 func~ion is present and ~salts with bases when an acid- function, i.e., carboxyl, is present. All such salts~are useful in the isolatlon and/or purification o~ the new products. Of particular value are~ the pharmaceutically acceptable salts with ~oth acids and bases Suitable acids include, for exampie, hydrochloric, sulfuric, nitric, benzer~esulfonic, tdlu,enesulfonlc, acetic, maleic, taRaric aind the 30 like which are pharmaceutically acceptable. ~ Ba$ic salts for pharmaceutical use are the Na, K, Ca and Mg salts.
,, .,, :
~- ~ Various substituents sn the present new compounds can be present in ~-~ the starting compounds, added to any one o~ the intermediates or added after formation of the final produots by known methods of substitution or conversion reactions. If th~ substituents themselves are reactive, then the substituents can J thernselves be protected according to the techniques known in the art. A
~, : ~

WO g2~1~579 PCltUS92/01773 " 6~ 18 ~9~3 ~ariety o~ protectin~ groups known in the art, may be employed. Examples of many of these possible groups may be found in "Proteclive Groups in Organic Synthesis" by T.W. Green, John Wiley and Sons, 1981. For example, nitro groups can be added by nitration and th~ nitro group converted to other ~roups, such as amino by reduction, and halo by diazotization of the amino group and replacement of the diazo group. Acyl groups can be added by ~riedel-Crafts acylation. The acyl sroups c~n then be transformed ~o the corresponding alkyl groups by various methods, includir)g the Wolff-Kishner ~
reduc~ion and Clemmenson reducticn. Amino groups can be alkylated to form ~ -mano- and di-alkylamino groups; and mercapto and hydroxy groups can be alkylate~ to form corresponding ethers. Prirnary alcohols can be oxidized by oxidizing agen~s known in the art to form carboxylic acids or aldehydes, and secondary alcohols can be oxidized to form ketones. Thus, substitution or :
aiteration reactions can be employed to provide a variety of substituents throughout the molecule of the starting material, intermediates, or the final product.

The compounds of ~the present invention may be~prepare~ by the ~ollowing representative examples.

~3-hy~
:
To an Ice cold suspension of 38 9 (300 m mole)~of 3-quinuclidinol in 200 ml of anhydrous THF is added 300 ml (300 rn mole) o~ a 1 M borane-TffF
complex dropwise over 1 hour. The mixture is stirred at room temperature for 1 hour, poured into 700 ml of water and extracted with 70Q ml of chloroform (2x).
~ The chloroforrn layers are combined, washed with brine, and dried over magnesi~m swlfate. The mixture is filtered and ~vaporated in va&uo. The residue is redissolved in 150 ml of ether and dilutPd with 1000 ml of petroleum eth~r and the resulting precipitate collected and vacuum dried to af~ord 3-~ydroxy-1-azabicyclo[2.2.2.Joctan~ borane complex, (m.p. 1 86-8C dec.).

WO 9~ 579 PCT/VS92/01773 ._. 13 210565~ :

EXAMPLE 2 ,;

3-~(4-BromQr~h~nvl)methQX\~ ol2~?~2~}o~t~ne bQran~ cornDlçx ;
To a suspension of 6.24 ~ (156 m mole) of 60% sodiurn hydride, in 70 ml of anhydrous DMF, is added a solution of 22 g(156 m mole) of 3-hydroxy~
azabicyclo[2.2.2.]octane borane complex in 100 ml of anhydrous DMF ~ -dropwise over 35 minutes. Th~ mixture is stirred at room temperature ~or 30 10 minutes and a solution of ~9.0g (156 m mole) of 4-bromobenzyl brornide in 50 m! of DMF added dropwiss over ~0 minutes. The mixtur~ is stirred at room temperature for 18 hours and then dilu~ed with water to the cloudy point. The precipitate which forms is collected and the filter cake washed with w~ter. After drying, the filter cake i5 dissolved in 150 ml of warm ethyl ac~tate and the 15 ~soJution diluted with petroleum ether to give 3-[~4-Bromophenyl)methoxy~
azabicyclo[2.2.2.]octane borane complex, (m.p. 9Q-3C d~c.).

20: ~ 3-F4-(~ çh!~Ebenzovl\~nz loxvl-1-azabicYcloJ2.2 2 ~o~De~dlo~hlol d~

To a;~solution~ of 9.D~g ~29 m mole) of 3-[(4-bromophenyl)methoxy]-1-azabicyclo [2.2.2.] octa~ne borane complex in 80~ml of anhydr~us~ THF cooJed to ;;
-78C is added 11.6 ml ~29~m mole~ of ~a 2.5 M hexane solution of n-2~ ~b~tyllithiurn dropwise over ~ minutes. The mixtLlre is stirred at -78C for 25 minutes and~a solu~ion of 5.79 g (29 m mole) t)~ 4-chloro-N-me~hyl-N-me~h~xybenzamidé~(S. Nahm~ and S.M. Weinrëb, Tet. Letters, 22, 3815(1981)) ~; ~ in 50 ml of THF added ~dropwise over 5 minut~s. The cooling bath ~is remuved and thq imixture stirred for 1~ h~ur and then poured into 150 ml of w~t~r. l~he , - 30 mixture is extracted with 200 rnl of ether. The ether~layer is washed with water `
and dried over magnesium sulfate and filtered.~ The filtrate is evaporated and ths residue redissolved in acetone. The soJu~ion is diluted to~the cJoudy point ,with petroleum ether and the resulting precipitate collected to gi~e a solid m~Jtin~ at 134-6C. fhis solid is suspended in 75 ml of acetone cooled in an 3~ ice bath and 15 ml of 3N HCI is added dropwise over 5 minutes. The cooling ~h is r~moved and the mixture stirred at room temperature for 2.5 hours. The mixture is concentrated ~2 and basified with sodium carbonate and .

WO 92/1~579 PCI`/US92/01773 ~ ,6~ 20 partitioned between 50 rnl of brine and 200 ml of chloroform. The chloro~Qrrn layer is washed with brine and dried over magnesium sulfate and filtered. Th~
fiitrate is evaporatecJ and the residue redissolved in ethanolic HCI. The ' "solution is diluted with e~her and the r~sulting precipitate collected and S recrystallized trom acetonitrile-ether to give 3-[4-(4-chlorobenzoyl)benzyloxy]~
1-azabicyclo[2.2.2.1octane hydrochloride, (m.p. 186-8C dec.) ~,~
;;`~ I' 3-~4:~2-fluoro-~.7-dihYdro-51~:~Qzo~ycloheptene~ nzvloxvk,l~
azabicyclol2.2.2.1octane hvd~chl~ride To a solution of 1.64 g (5.3 molej of 3-1~4-bromophenyl)methoxy]-1-azabicyclo[2.2.2.] octane borane complex in 50 ml of anhydrous THF is added ,~,'~ , 15 2.12 ml (5~3 m mole) of a 2.5 M hexans, solution of n-butyllithium dropwise over "' 5 minut~s at -78G. The; mix~ure is~stirred at -78C for 30 minutes and a ~ ' solution of ~1.0 g (5.6 m~ mole) of 8-fluoro-1-benzQsuberone in 20 ml of THF is ~-added~dropwise over 5 minutes. The,mixture is stirred for 4 hours warming tc room temperature. ~ The;~mixture is poured into 50 ml of water and extracted with 10Q ml of ether. The ether~is washed with water~an~'dried over magnesium sulfate and then fiitered.: ~The filt,rate is ~vaporated~and the rcsidue purified by :~' fiash~Ghromatography~;usi~ng~7~:3 hexane:ethyl acetate~on silica gel. Th~
produ~residue is dissolved in~10;ml of ac~tone and 6 ml of~3N HCI is add~d.
The mixture is then stirred~at r~om temperature for 45~ minutes and ~
5~ concentrated in a rotary~ evaporator. The residue is basified with sQdium carbonate and partitioned between 15 m! of bnne and 75 ml of chloroform. The chloroform iayer is washed` with bnne and drisd over magnesium sulfate then filtered. Jhe filtrate is~evaporated and the residue dissolved in ethanolic HCI. :~
' ` T he' so;lution' is dil~ted~with'~e'the'r and lKe 'precipitate collecte'd and ~, ~ 3 0 recrystaliized ~ro,m acetone-petroleum, ether to give 3-14 (2 fluoro-6,7-dihydro- , ~3~ 5H-benzocycloheptene-9-yl~benzyloxy]-i-azabicyclo[2.2.2.]octane hydrochloride, (m.p. 19~-8C dec.j :-1 ' :
: ~
, ~ :
: ~

,1-.. . ,~.

WO 92/15579 PCI/US~/01773 21056~

EXAMPLE ~ .

3-[2:~z~b~nzvloxvl-1 azabicvçlo~2.2.2.10ctane hvdrochlQride T a suspension of 0.56 g~ ~13.9 m mole~ of 60% sodium hydride in 25 ml of anhydrous DMF is added a solution ot 1.96 g (1309 m mole) of 3-hydroxy~
æabicyclo~2.2.2.]octane borane complex in 25 ml of DMF dropwise over 5 minut~s. The mixture is stirred at r~om temperature for 25 minutes and a 10 solution of 4.0 g (15.3 m mol~) of 2-benzylbenzyl bromid~ in 10 ml of DMF is added dropwise over 5 minu~es. The mixture is stirred at room temperature for 4 hours and is poured into 150 rnl of water and extracted with 100 ml of ~ther.
The sther layer is worked up in the usual way to give 3 [Z-(benzyl)benzyloxy]-1-a~abicy--.10[2.2.2.l0ctane hydroehlonde (m.p. 133-5Gdec.) 3-[4 ~2-( henvl~ethanvl)benzvl~xvl-~l azabicvcl~2.Z.2.]z~

To a suspension ot~0.6 9 (~15 m rn~le) of 60% sodium hydride in 25 ml of anhydrous DMF~is added;a solution of 2.1 g ~15~m mole) of 3-hydroxy~
azabicyclo[2.2.2.]octane borane complex in 25 ml of DMF dropwise over minutes. ~ Th~ mixture is~ stirred at room temperature f~r 30 rninufes and a 25 ~ solution of 4.6 9 (16.7~m moie) of 1~-(4-bromomethyl)phenyl-2-phenylethane in 15 ml of DMF is added dropwise over 5 minutes. ~The mixture is sti~red at room temperature~for 16 hours and is poured into 1~0 ml of water. The mixture is extracted with 100 ml of ether. The ether is dned over magnasium sulfate and the evapora~ed rei~id~e~ is ~uorked up in th~ usual way to give 3-[4-(2 30 (phenyl)ethanyl)benzyloxy]-1-azabicyclo[2.2.2.]octane hydrochloride (m.p.
193-5~C dec.~

,: , : ..

i' .
~ : , . ,, , ~

WO ~2/15579 PCI/VS92/01773 .

:
EXA~JIPLE 7 .
~ 4:l2~hQny!)ethen~ 2~2~tan~ hvdroc~Pride , ',:
To a suspension of 2.0 g ~50 m mole) of 60% sodium hydride in 75 ml of anhydrous DMF is added a solution of 7.05 g (50 m mol~) of 3-hydroxy~
azabicyclo[2.2.2.~octane :borane complex in 50 rnl of DIVIF dropwise over 20 ::
minutes. The rnixture is stirred at room temp~ratur~ for 45 minutes and a 10 solution of 13.9 g (51 m mol~) of 4-brornomethylstilbene (pr0pared from 4-~stilbenemQthanol and brornotrimethyl silane) in 75:ml of ~MF is addod dropwise over 25 mir~u~es. The mixture is stirr~d at room temperature for 16 h~urs and poured into 350 ml of rapidly s~irred water. The solid is collect~d, dried and re~rystallized:from THF-petroleum ether to give 8 g of maierial (-15 ~ 140-3C mp.) This solid is:susp~nded in 50 ml of acetone and 20~ml of 3N HCI
added. The mixture is~stirred~at room temper~ture :~ar 45 minutes and ~worked :up in the u:sual way to giva 3-~4-(2-(phenyl)ethenyl)benzyloxy azabicyclol2 2.2.]~c~ane hxdroohloride, (234-6C: m.p.) 2 0 ~ E X A M P L~ ~

To a~suspension~of 66 mg (~ .66~m:mole):of 60% sodium~hydride in 35 ml ~ .' 25 ~ ~of anhydrous DMF~is:~added~a~solu~ion of 0.23 g (1.66 m~mole) of 3-hydrsxy~
azabicyclo~2~.2.2.]o~ta;ne~:b~rane complex in 1~ ml cf~DMF dropwise~over 3 minutes. The mixture is ~stirred at room tempe~ature fcr 30 minutes~ and a i ~ ~ so!ution ~ff 0.45 g :(:1.66. m: mole) of (4-bromomethylphenylethynyl)phenyl : ' ('prépar'ed by treating''(A-pXenyiethynyl)benzaldehyd'e ~(H.A.'Krick and F.~30 Heck`, J. Organomet. ~f''hem., 93 (2~, 25~-6.3 ~1975)) with sodium borohydride of liowe~: by- bromotrimethylsilane)~ in 1:~0 ml~ of DMF is ~added ~dropwise over 3 '~t~ ; minutes.~ The mixture~ is ~stirred ~at ~room té~mperature ~or 4 hours and poured~ into i~'

7~ ml: o~ watsr. The mixture is extracted with i 00 m! Of ether.~ The ether is dried and wori~ed up in the usual way to give 3-[4-(2-(phenyl)eth:ynyl)-benzyioxy]~
35 ~azabicyclo[2.2.2 ]fofctane hydrochfloriGfe, (223-5G m.p~
f :~
f . :

Wo 92/15579 PCT/US92/01773 21056~
EXAMPLE ~
, 3-(4-(N-~henvlb~n~amide)m~b~LI~zabi~
To a solution of 3.0 g ~9.68 m rnole) of 3-~4-bromophenyl)msthoxy-1-æabicycto[2.2.2.~octane borane comp!ex in 50 ml of anhydrous THF cooled to -78C is added 3.87 ml (9.68 rn moi~) of a 2.5 M h~%ane solution of n-~utyllithium (Aldrich) dropwise over 3 minutes. The mixture is s~irred at -78C
10 for 30 minutes and a solution of 1.3 g (11 m mole~ of phenylisocyanate in 10 ml of THF is added dropwise over 5 minutes. The mixture is stirred for 4 hours warming to room temperature. The rnixture is paurad into 70 ml ot water and is extracted with 100 rnl of ether. The ether is dried over magnesium sulfate and the evaporated residue is worked up in the usual way The hydrochloride salt 15 is recrys~allized fram acetonitrile to afford 70 mg of 3-(4-(N-phenylbenzarnide)me~hyloxy~-1-azabicyclo[Z.2.2.]octane hydrochloride, (206-8G deo.) ; 2 ` 3-(4-(4-chlorQ-a-hvdrQxy~l rQchl~ride To a solution of 1.5 g (4.83 m mole) of 3-(4-bromophenyl)methoxy-1-25 azabicyclo[2.2.2 ]octane borane complex in 35 ~ml of anhydrous THF cooled to -78C is ~dded 1.93 ml ~(4.83 m mole) of a 2.5 M hexane solution of n-butyilithium (Aldrich) dropwise over 3 min~es. The mixture is stirred at -78C
for 30 minutes and a solution of 0.7 g (5.0 m mole) of 4-chlorobenz~ldehyde - (Aldrich) in 10 r~l af THF added~dropwise over 5~min~tes. The mixture is stirred %0 for 3 hours warmin~ to room temperature. The mixture is poured into 75 ml of water and extrac~ed ~ith 10û ml of ether. The mixture is worked up in the usual way to give 3-(4-(4-chloro-a-hydroxybenzyl)benzyloxy)~
..azabicyclol2.2.2.]octane hydrochloride, (70C dec. m.p.) :1 -`
i ,, ~1VO g2/l~S79 ~ PCI/U~i92/01773 ~;,6~ 24 - ~

E~XAMPLE 11 ~ ~:

3-~4~ 4-cklQroph@nvl)~henyl)~enzylQxy]-1-~z~
hvdroçhlQridq.
~:
To a suspension of 0.34 g (8.5 m mole) of 60% sodium hydride in 35 ml o~ anhydrous DMF is added a solution ot 1.2 g (8.5 m mole) of 3-hydroxy~
azabi~yclo[2.2.2.Joctane b~rane cornplex in 15 ml of DMF drop~vise over 5 1 Q minutes. The mixture is stirred at room ternperature for 30 minut~s and a solution of 2.7 g (8.78 m mole) of 1-(4-bromomethyl)phenyl-1-(4-chlorophenyl)ethylene in 10 ml of DMF is added dropwise over 5 minutes. The mixture is stirred at room temperature for 3 hours and is poured into 100 ml of water ancl extracted with 100 ml of ether. The ether is dried over rnagnesium sulfate, filtered and evapo~ated. The residue is~purified by flash chromatography on sili~a gel using 4:1 hexane:ethyl acetate as the eluent.
~; The oil product is converted to its hydrochloride salt in the usual fashion to give 3-[4~ (4-chlorophenyl)ethenyl)benzyloxy]-1-azabicyGlo[2.2.2.~o~tane hydrochloride, (163-5C rn.p.) - EXA_LE 12 ~ `~

~ , 3-~4-(2H-1-be_QDvran~4-vl)benzYloxv~-1-~abicY~!~2~2.2 1O~n~

yd oc Qride To a solution of 0.~ 9 (1.6 m rnole) of 3-(4-bromophenyl)methoxy-1-a~abicyclo[2.2.2.]octane borane complex in 40 ml of anhydrous THF; cooled to - ~ "
78~ is added 0.64 ml (1.6 m mole) of a 2.~ M hexane solution o~ n-butyllithium --Idrich) dropwisel ov;er;~ ~inut~s. The mixture i`s stirred for 5 min~tes ~nd a solution of:û.26 9 (1.8 m mole) o~ 4-chromanone (Aldrich) in 5 ml of TH~ is:
addsd dropwise over 5 minutes. Th mixture is s~irred for 1 hour warming ~o ~t ~ room temperature and poured into 75 ml of water.~ The mixture is extracted with 100 ml of ether, dried and evaporated to dryness and the residue worked up in the usual way to give 3-[4-(2H-1-benzopyran-4-yl)benzyloxy-1-: 3S azabicyclo~2.2~2.]octane hydrochloride, (178-81~C m.p.) : ;~

,' l ~ .

WO 9~/1557~ PCI/US9~/01773 :;
_ 2~;
2 1 0 5 6 ~
,'~' EXAMPLE_~ ;

3-~4-¢?H~ Qn~lhiopvran-4-Yl~b~nzvloxy~ zabi~vçlo~2,~2.~çtane ~ ~
hydr~hlQ~ ~:

To a solution o~ 2.0 g (6.6 m mole) of 3-(4-brornophenyl)methoxy~
azabicyclo~2.2.2.]o~tane borane complex in 40 ml of anhydrous Ti~F c~oled to -78C is added 2.64 ml (6.6 m mol0) o~ a 2.5 M hexane solution of n-butyllithium 10 (AldriGh) dropwi~e over 3 minutes. The mixture is stirred at -78~C lor 30 minutes and a solution of 1.Q8 g (6.6 m mole) of thiochroman-4-one (Aldrich) in 10 ml of THF is added dropwise over 5 minutes. The sollJtion is stirred for 4 -hours warming to room temperature. The mixture is poured into 70 ml of water and extracted with 100 ml of ether. The ether is washed with water and dried 1~ over magnesium sulfate and~ilt0red. The filtrate is eYaporated and the residue re~issolved in 1~ ml of acetone and 7 ml of 3N HCI add~d. The mixture is stirred at room temperature~for 24 hours. The mixture is concentrated in vacuo and basified with sodium carbonate. The.mixture is partitioned betw~en 15 ml of brine ~nd 70 ml of chi~r~form. The chloroform is evaporated and the residue 20 dissol~1ed in ~thanolic HCi and diluted with petroleum ether. The resulting precipi~ate is collected and recrystallized from ethanol ~o give 3-[4-~2H-1-benzothiopyran-4-yl)benzyloxy]-1-azabicyclol2.2.2.]octane hydrochloride, ~ :~
(140C dec.) When the above example is followed but ~he residue which resul~s from -~the ether extrac~ is allowed ~o stand in acetone and 3N HCI for less ~han 1 hour before workup, then the hydrate~ form results which may then be isolated.

. 30~

~then~vlLbenzyloxy~1 -a7abicyclo[~.2 2 loctane .. `.",, hlold~

3~ To a solution of 1.95 g (6.3 m mole) o~ 3-(4-bromophenyl)methoxy-1- ~:
azabicyclo~2.~.2.~octane borane complex in 50 ml of anhydrous THF cooled to -~ 7~C is adde~ 2 52 ml ~6 3 m mole) of a 2 5 M hexane solution of n-butyllithium : `~:' wo 92~ls~7s Pcr/uss2/01773 ~ ' ~ 26 (Aldrich) ~ropwise over 5 minutes. The mixture is stirred at -78C ~or 30 minutes and a solution of 1.0 g (6.57 m mole) of 4-keto-4,5,6,7-tetrahydrothianaphthene in 15 ml of THF is added dropwise over 5 minutes.
The mixture is stirred for 4 hours warming to room temperature and poured into 5 100 ml of water. The mixture is extracted with 100 ml of eth~r and washed withwat~r and dried ov~r magnesium sulfate. The evaporated ether r~sWue is purified by flash chromatography on silica gol using 7:3 hexane:ethyl acetate - ~ ' as the eluent. The product rosidue is dissolved in 10 ml of acetone and 6 ml of '~
3N HCI is added. The mixture is stirred at room temperature for 45 minut~s 1 n and is basified and extracted into chloroform. The evaporated chloroform lay~r is dissolved in ethanolic HCI and the solution is diluted with petroleum ether. ~ ' The resulting precipitate is collected and recrystallized from ethanol/petroleumetherto give 3-[4-(6,7-dihydrothianaphthene-4-yl)benzyloxy]~
azabicyclo[2.2.2.]oetane hydrochloride, (200-3C dec.) ' ' - ' When 3-quinuclidinol in Example 1 is replaced by the amino of Table I
belowj thèn the corresponding products are obtained. ' ~' TABLE l ;

3-quinuclidinthiol 3-N-acetylaminoquinuclidi~ne 3-hydroxymethylquinuclidine ~ '>
; ~ 2-hydroxymethylquinuclidine 5-hydroxy-3-~ceiyl-3,4,5,6-tetrahydropyrimidine 4-hydroxy-(1-azabicyelo[3.3.1.]nonane) ,' 7-hydroxy-(~-oxb-9-methylazabicycio[3.3.1'.]nonanej~
30~ 3-hydroxy-(9-methylazabicyclo[3.3.1.3donane) 7-hydroxy~(3-methylazabicyclo~3.3.1 .]nonane) ~ 'j 1 -azatricyclo[3.3. 1.1 ,3.7]decan-4-ol ~ ~:
..
,~,.
~ .
E~CAMPLE 16 ~ ........ ..... ................................................. ... ... ......................... ..... , 3~ ' ' When 4-bromobenzyl~romide in Example 2 is replaced by the : ' ~ompounds of Table ll ~elow, then the corresponding products are prepared. ~ ' .
'.., 27 210t~6~i5 ~

TAE~LE ll 4-brom3phenethylbromide ~ .
5 2-bromonaphth-1-ylmethylbromide ~-bromonaphth-1-yimethylbromide 2-brorrothien-5-ylmethylbromide 4 bromopyrid-2-ylmethylbromide ~-methyl-4-bromobenzylbromide 10 1 bromonaphth-2-ylrnethylbromide 5-bromonaphth-1-ylmethylbromide 2-bromothien-4-ylmethylbromide 2-bromopyrid-6-ylmethylbromide 2-bromopyrid-5-ylmethylbromide ~:
:: ~ 15 : ;

::
When 4-chloro-N-rnethyl-N-methoxybenzamide in Example 3 is ~: replaced by the compounds of Table lll below, then th~ corresponding products :20 : are obtained ......
TABLE lll N-methyl-N-methoxyn:aphthamid~
4-methoxy-N-methyl-N-m~e~hoxybenzamide 3-~hloro-4-methyl-N-meth~yl-N-methoxybenzamide : ~ :
2-fluoro-N-methyl-N-me~hoxyb~nzamide;
3-fluoro-N-methyl-N-methoxybenzarnide 4-fluoro-N-rnelhyl-N-methoxybenzarnide 4-methyl-N-methyl-N-methoxybenzami~e . ;
4-trifluoromsthyl-N-methyl-N-methoxybenzamide 4-nitro-N-methyl-N-methoxybenzamide - 2-N-methyl-N-methoxyquinolinamide .
~: 4:-chloro.-N-methyl-N-rr e~hoxyphenylacetamide , ~ .
""", `'';;,.

- ~"

WO g2/15579 '~-S PCT/US92/0177~
~6~ 28 '1 EX~
~, When 8-fluoro-1-benzosuberone in i-xample 4 is repiaced by the compounds of Table IV below, then ~he corresponding products are ob~ainad.
~;-TABLE IV ~:

1 -benzosub~rone .;;:
~-t~tralone ;
1 0 cyclohexanone ~:
A-shromanone thiochroman-4-one pyran-4-one 2~cyciopenten-1-one ~
15 5,7-dirnethyl-3,4-dihydronaphth-1-one 5-chi~roindan-1 -one ; ~
2,2-dimethyl-2H-1-~nzopyran-4-one i.
S-methoxy- 1 -inqanone~
6,7-dihydro-5H-benzocyclohepten-g-one . . .
20 3,3-~dimethylindan-1-one EX~eL~

;When 4-bromomethylstilbene in Example 7 is replaced with the 2 5 compounds ~f Table ~V~ below, ~hen the corresponding products are obtained.

TABLE V
: -:
4-bipiienylrnethyl~ bromid~ ' ~
.. .. 30 .. 3-biphenylmethyl bromide ~ :.
2-biphcnylmethyl bromide~
4-slyrylbenzyl bromide~
4-(cyclohexen-1-yl)berlzyi bromide 4-phenylmethoxybenzyl bromide 3-phenoxybenzyl bromide ~ . -3,4-dichlorophenoxy~enzyl bromide 3~4~t-butylphenoxy)benzyl bromide -., , :

WO g2tl5~79 P~/US92/01773 2 9 2 1 0 '? 6 ~) 5 ~ :
; ' 4-(3,3,5,5-tetrame~hylcyclohexen-1-yl)benzyl bromide -~
4-(4,4,6,6-tetramethylcyclohexen-1-yl)benzyl bromide ~:
4-(4,4-dimethylcyclohexen-1-yl)benzyl bromide 4-chlorobenzoylbenzyl bromide 5 4-(1-phenethenyl)benzyl bromide 4-(2-phenylethyl)benzyl bromide 2-benzylbenzyl bromide 3-benzyloxybenzyl bromide 2-phenethylbenzyl bromide 10 4-(2,5-dimethylstyryl)benzyl bromide ~-(3,4-dichlorostyryl)benzyl bromide 4-(4-fluorostyryl)b2nzyl bromide 4-phenoxybenzyl bromide 4~ benzoyl-1-methyl)ethyl)benzyl bromide 15 4-benzoylbenzyl bromide N-methyibenzamidobenzyl br~mide :~~4-phenylethynylbenzyl bromide :- :
4-(1-(4-chl~rophenyl)ethenyl)benzyl bromide 4-(1-(2-chlorophenyl)ethenyl)benzyl bromide 20 4 -(4-methylphenylsul~onyl)benzyl bromide 3-benzoylbenzyl bron~ide ~
4-(benzoxazoi-2-yl)benzy! bromide 4-(naphth-2-yl)benzyl bromide , 25 EXAMPLE ~) 3-(~eQzil-4-vl!rneth~Qx~:~-zabi~vclol2. 2 2!JQçta-ne hydr~chlQride To a suspension of 0.6 g ~15 m mole) of 60% sodium hydride in 2~ ml of 30 anhydrous DMF is added- a solution of 2.1 -g (15 m mole) of 3-hydroxy~
a~abicyclo[2.2.2.~octane borane complex in 2~ ml of DMF dropwise over minutes The mixture is stirred at room temperature tor 30 minutes and a solution of 4.85 9 (16.7 m mole) o~ 4-bromomethylbenzil (B Krieg and G
Manecke, Ber, 101, 1 480-B4 (1963)) in 15~ ml of DMF is added dropwise over 5 -35 minutes The rnixture is stirred at room temperature for 16 hours and is poured into 150 rnl of w~ter The mixture is extracted with 100 ml of ether The ether isdried over magnesium sulfate and the evaporated residue is worked up in ~he WO 92/15579 PCr/llS92/01773 3~ 3~

usual way to give 3-~benzll-4-yl)me~hyloxy)-1-azabicyclo[2.2.2.]octane hydrochloride. ~ ' ''''~",;

3-~4-(styr~icarb~nyl!benz~lQxvl-1-a~a.~clo~.2~]Q~tane hydro~hlorid~

To a solution of 1.5 g ~4.84 rn mole) of 3 (4-bromaph~nyl)methoxy~
azabicyclo[2.2 2.30ctane borane complex in 30 ml of anhydrous THF oooled to -78C is added 1.94 ml (4.84 m mole) of a 2.5 M hexane solution of n-butyllithium ~AIdrich) dropwise over 3 minutes. l~he mixture is stirred at ~78C ' ' f~r 20 minutes and a soiution of 0.~3 9 (4.84 rn mole) of N-methoxy-N-methyl-3 (E)-phenyl-~-propenbenzamide (prepared from trans cinnamoyl chloride and ' ;;' N,Q-dimethylhydroxylamine via the S. Nahm and S.M. Weinreb procedure, Tet. /^~.' ' 1 5 Letters, 22, 3815 (1981 )) in 10 ml of THF is added dropwise over ~ minutes.
The~ cooling bath is removed and the mixture is stirred for 1 hour and is pouredinto 70 ml of;water. The mixture is extracted with ~00 ml of ether. The e~her I
layer is washed with water and is dried oYer magnesium sulfate and filtered.' ;;
T he filtra~s is evaporated and the residue is redissolved in acetone. The ' ~
2 0 solution is diluted to the cloudy point with petroleum ether and the resulting ; " ' precipitate collected to give solid `melting 135-7C. This solid is suspended in '' 0~ ml of acetone and 6 ml of 3N HCI is added. The mixture is stirred at room temperature~for 1.5 hou'rs and is then cooled in ice. The insoluble material is collected, vacuum dried and is reo~stallized from aceto~nitile~o giv~ 0.4 9 of 3- .
[~-(styrylcaibonyl)benzyloxy~ abicyclo[2.2.2.joctane hydrochloride~, (205-

8~C m.p.) (~ ~

EXAMPLE 22 ~ ~ ' : `
: ~ ~ 30 ~ _ _ _d~ ;
hvdr~cbloride kxdro~hloride : ':

WO ~2/15579 PCr/US92/01773 .. 31 2105655 Step A: trimethyl-4-ox~cYcl~hexane-1 .1 .3-~icarboxYl~le To 11.5 g (.5 mole) sodium in 150 ml methanol is added 66 g (.5 mole) of dimethyl rnalonate. This is heated to reflux and th~n methylacrylat~ (86 g, 5 1.0 mole) is added dropwise at a rat0 sufficient ~o maintain reflux. When the addition is complet~d, the reaction is heated in an oil bath at 11 0C for 2 hours.
The reaction is then cooled, diluted with water (about 200 ml) and chilled overnight. The crystalline solid is filtered off, washed with ether and dried, giving crude product as the sodium salt. This is dissolved in wat~r, acidified with concen. HCI to pH2 and the white precipitate filtered and washed with ~ .
water and dried tc~ obtain trimethyl-4-oxocyclohexane-1,1,3-tricarboxylate which is used directly in the next ~tep. ::

, ::
15 Step B: :: me~hy 4 ~y ohal~nll-1 yylat~

: A 55 g (.2 mole)~portion of trimethyl 4-oxocyclohexane-1,1,3-: tricarboxylate is diss~lved in 240 ml DMF and to this is added 2~ 9 (.445 mole) of sodium:chloride and 16 mi (.89 molej of water, under nitrogen. This mix~ure 20 ~ heated~to reflux and maintained for 48 hours,~under nitrogen. The reaction is then stripp~d to dryness~ under re`duced pr~ssure, the residLJe added to water and the crude product extracted into dichloromethane (3x100 ml). The ;:
combined extracts are: dried over MgSO4 and stnpped to:d~ness, ~iving a y~llow oil. This crude produc~ is vacuum-distill:ed ~o obtain methyl 4-:2~ :oxocyclohexane-1-carboxylate (b.p. 8~-108C at 1.0~mm~Hg) which is used ~ .
:; - directly in the next step.~
, ~;;
Step C~

30 ~ - . To a solution of 8 g (0.~1 mole) of methyl 4-oxocyclohexane~
carboxylate in ~0 ml of dry benzene is added 4 9 (.064 mole) of ethylene glycol -~ .
and .10 g of p-toluenesulfanic acid and this mixture is refluxed avernight with a ~Dean-Stark appa~atus.~ The cooled reaction is allowed ta stand and the bottom -:
~: layer (ethylene glycol~ separated and th~ remaining benzene layer wash~d with aqueaus sodium bicarbona~e, dried over MgSO4, and stripped to dryness, ~:
giving m~thyl 1,4~dioxaspiro[4,5~decane-8-carboxylate as a ciear liquid residue This material is used without further purification in the next step WO 92~1~S79 P~/US92/01773 ~ '' 32 Step 1:: 1 4-~iQx~sDir~L4l51decanç-~ç~rb~xamidQ

Sixty rnl of concentratad arnmonium hydroxide is added to 11.9 g (.059 mole) of methyl 1,4-dioxaspiro[4,~]decane-8-carboxylate and stirred at room tempera~ure overnight. The reaction is then chilled in ice and the pre~ipitated solid f~ltered off, giving 4.77 9 of product, m.p. 1 50-6C. A further 1.46 9 product is obtained ~rom the filtrate by stripping to dryness and r~crystallizing : ~;
the residue from ethyl acetate. These two portions are c~rnbined and recrystallized again from ethyl acetate to give 1,4-dioxaspiro[4,5~decane-8-carboxamide (m.p. 167-170C).

Step E: 8-aminomçthvl-1 .4-dioxasDirQ[4.~1decane To 1~.4 g (.037 mole) of lithium aluminum~ hydride in 100 ml dry THF is added, portionwise, 4.9~ g (.026 mole) of 1 ,4-dioxaspiro~4,5Jdecane-8- ~;
~arboxamide over one~half hour. This mixture is theri refluxe~ 2 hours, then ;;:~; ~ allowed to ~ool to room temperature.~ About 5 ml water is added cautiously and ;
then~ stirred 15 minutes. ~C)ichlorome~hane is then addsd and the insolubles 20 ~filtered off. The organic~ layer is dried over MgSO4 and s~ripped to dryness, giving 3.48 9 crude product. ~This material is vacuum-~istilled to ob~iain 8-aminomethyl-1,4-dioxaspiro~4,5]decane ~b.p. 84-101Cat~.7 mm Hg.)~ :

;~ Step F: 1-a2atriÇYClQ~
2~
Paraformaldehyde (2~.2 g), in; 320 ml 2% vtv H2SO4, is heated to boiling and 2.7 g (.016 mole) of 8-aminomethyl-1,4-dioxaspiro[4,5]decane in 20 ml EtOH, is added over 4 hou!s.; This mixture is then heated at ~re~lu~x for 24 hours.
The cooled rea~ion is washed wi~h dichloromethane, ~hen basified with 1 0N
NaC)H and extracted with di~hloromethane. The combined extracts are dried ~ :
over MgSO4 and stripped to dryness, giving 1.6B 9 (69%) of product.
. ~:
~ Step G: 1 -azatricvclo~9~ ~

Sodium borohydride (.7 g) is added to 20 ml of ice-chilled MeOH. Then 1 8~ g (.012 mole) of 1-azatricyclol3.3.1.13,7]decane-4-one, in 20 rnl MeOH, is a~ded dropwis~ o~/er 5 minutes. A further .8 g NaBHd, (total 1.5 g, .04 mole) is ,. , ,,,,, ,,, , . , , , , , .,, . ,, ., ; , -WO 92/1~579 PCr/11!~92/01773 33 2~0.~fi~S

added portionwise over ~ minutes. The reaction is stirred in ice one-half hour more, and then 1 hour at roQrn temperature. The reaction is diluted with 2û ml brine, and extraeted into ~ther. Th~ eth~r is dried over MgSO4 and stripp~d t~
dryness, to give 1-azatricyolo-[3.3.1.13~7]decane-4-ol.
Step H~

To a solution of .93 9 (.0061 mole) of 1-azatricycloE3.3.1.13.7~d~cane-4-ol, in 60 ml of ether-THF (50/50), c~oled in ice, is added 6.1 ml of 1 M BH3-THF1~ dropwise o~er 3 minutes. The ice bath is removed and the reaction stirred 1 ;
hour at room temperature. Water (35 ml3 is added to the reaction and th~
product extr~cted into chlorotorm. The organic layer is dried over MgSO4 and ~ripped to d~ness, giving .~3 9 of residue (52% yield). Crude product is then dissolved in ethyl acetate and passed through silica gel in a 1ritted glass funnel. ;
15 The ethyl ~cetate is stripped to obtain 1-aza~riCyclo[3.3.1.13~7~deCane-4-QI, borane ~ompl~x.
. , ~ ~
; ~ Step I: anti and~is¢~Lo.v-[4-(2-~E~-phenYl~th~nyl-~phenvl:
m h~xy~-~1~ricyclo~3.~.1.1:~

o a suspension~of .134 g bf 60% NaH (.0034 mote) in 10 ml DMF, under N2, is adcted 1-æatricyclo[3.3.1.137]decane~-4-ol~ borane complex (.56 ~ ~ g, .OQ34 mole), in 10 ml DMF, dropwise over 5 minutes. This is stirred 20 minutes~nd~ then the 4-bromomethylstilbene, in 10 ml DMF, is~ add~d dropwise ~-25 o v~r 2 minutes. This is stirred at room température, under~N2, overnight. The reaction is then poured~into 6û ml water and extracted 3 times with ~ther ~500 mt total). The cornbine~d ethe~r layers are w~shed once~with brine, then dried over MgS04 and stripped to dryness. Crude product purified on silica gel 60 column, eluting with~ 5'1~ hexane:ethyl ace~ate. The l~ss `polar isomer ~s the 30 "anti" is~mer and .22 9 of this isomer is iso!ated. The more polar "syn" isomer is isolaled to obtain~.11 g. These are used directly in th~ next step.; ~ -tBp J ~

~: 3~ : -Dissolved .22 g ( 0006 mole) of 4-anti-[4-(2-(E)-phenylsthenyl)-phenylmethoxy}-1-azatricyclo-~3.3 1.13 7Jdecane borane complex in 20 ml , .

Wo 92/1S579 P~r/US92/~1773 ~ 6~ 34 acetone and 10 drops of 3NHGI solution is added and stirred. A white precipitate devclops over an hour. The whit?s solid is ~iltered and rinsed with ~ :~
acetone. Residual solvent is removed under high-vacuum drying at room temparature to obtain 4-anti-i'4-(2-(i )-phenylethenyl)phenylmethoxy]~
~zatricyolo[3.3.1.13~7]decane hydrochloride. ` ;

Step K: 4-~[4-(2-(~)-~henylethenvl~herlylmethoxv~ azatricv~

, ., Dissolved .11 g (.003 mole) of 4-syn-[4-(2-(E)-ph~nyleth?~nyl)~ ;
phenylmethoxy)-1 -azatricyclo[3.3.1.13 7~decane, boran~ complex in 20 ml acetone and 10 drops of 3NHCI solution is added and stirred at room ~ ~;
temperature for 1 1i2 hours. The solid precipitate is filtered off and rinsed with acetone and dried in a high-vacuum at room temperature to obtain 4-syn-[4-(2-15 (E3-phenyle~henyl)phenylm~thoxy3-1-azatricyclo-[3.3.1 13.7]decane hydrochloride.

: EXAMPLE 23 j ., ., , ... ...
20 3~zl2L-2-yl~phenvllmçth~1 aa~ova~l~2.21oc~ane~
~ hvdro~hloride . .. .
To a solution of 1.5 g~(4.84 m mole) of 3-(4-bromophenyl)methoxy-1-~z~bicycloir2.2.2.]Qctane,~ borane complex in 30 ml of anhydrous THF ¢ooled to 2~ -78C is added 1.94 ml~(4.84 m mole) of a 2.5 M hexane solution of n- -butyllithium dropwise over 3 minutes. The mixture is stirred at -78C for 20 . .
minutes and a solution of 0.74 g (4.84 m mole) of 2-chlorobenzoxazole in 10 ml ~-of THF is added dropwise over ~ minutes. The cooling bath is removed and the mixture is slir~d tor 1 hour and is~poured into 70 ml;o~ w`ater. The mixture30 is extracted ?with 100 ml o~ ether. The ether layer is~ washed wi~h watar and i;, ~ried over magnesium sulfate and filtered. The filtrate is diluted to the cloudypoint with petroleum e~her to give solid melting at 1 3~-8C~. This solid is ~;
suspended in 10 ml of acetone and 6 ml of 3N HC! is added. The mixture is stirred at r~om temperature ~or 1.5 hours and worked up in the usual way to 3~ give 3-j4-(benzoxazol-2-yl)phenyl]methoxy-1-azabicyclo[2.2.230ctane hydrochioride as the hydrschloride salt? 263-~C m.p.) -.

WV 92/1~79 PCI/US92/01773 2 1 0 'i 6 ~
.
When 2-chlorobenzoxaæole in the above example is replac~d by 2,5- -dichlorobenzoxazole; 2-chlorobenzotiliazole; 2,~ dichlorobenzolhia~ole and 2-chloro-5-trifluoromethylbenzoxazole th~n th~ produc~s prepared are:

5 3-[4-(S-chlorobenzoxazol-2-yl)phenyl]methoxy-1 azabicyclo-[2.2.2.]octane hydrochloride;

3-~4-1benzothiazol-2-yl)phenyl~methoxy-1-azabicyclo[2.2.2.]oetane hydrochloride;
1 0 '~ ' ' '"' 3-[4-(5-chlorobenzothiazol-2-yl)phenyl]methoxy-1 -azabicyclo-[2.2.2.]oc~ane hydrochloride; and - 3-[4-(5-trifluoromethylbenzoxazol-2-yl)phenyl]methoxy-1-azabicyclo-15 ~ i2.2.2.]o~tane hydrochloride.
- ~ . : ., Following the proc~dures of Examples 1-23, th~ representativ~
20 ~ compo~nds~of Tables VI-lX below-are prepared.
~ .. ..
: ~ : : , ...

. ~

: .

, .
. ~ :

,: .
: ~ ~

: :

WO92/1~7g PCl/VS~2/~1773 . :

~ 36 ,, ,,;
TABLE Vl -:~

where Z is m p~ w~ e. ~ :
_ _ :

~I-Bu 210-212 ¦ ~ 177-179 O~r~::l _ ~ , ~ ~ : ~:)-CH2~ 173-175 0~ : O
: W ~92-l95(~ec) 1 ~C~ 146~1~8 " ~:

H Cl ~ ~80-23 C CH ~ ~ ~
~JJ : 130-133 N~ 204-207 , . . -:: :::`:

W~:) 9~/1557~ PCI`/US92/01773 37 ::
2 1 0 ~ 6 5 ~ ~

o--CH2 ~
N ~ H Cl w~ ~ ','",,' ~0 248-250 ¦Ct~L 210-213 ~: ~
Cl 217-219 ~H=CH~ 247-2 F ,~
. ,,,.", 250-252{:H=CH
Me ~CF3 : .
CH~ 145-149 (dec) ,~

~M ~ 50-1~52 ~ ~ ~ ~ :: ; 162-165 ~:

; ~ : -C~ 177-17~^ ^ .
N JJ ~ I Mq~,~

M ` ~ ; ~ O~
-CH=CIl~ ~ ~ 178-180 ¦ C~3 140-143 ~Me ~ ~ .

w~ 92/1557~ PCT/US92~01773 ~

38 ~;

H Cl where- Z Is m. p C where Z is rn. p. C ~:
_ ~ 186-188 ~ I ~ (dec) - C~ 172-174 ¦ 158-160 o O CH2~ 156-158 ~ ~ 158-170 : - C~ 156-158 ¦ ~C

O~ ~ :
73-'75 ¦ 50~ 171-174 C~: ~: 188-191 :
~L oMe ~ ~ 200-203 175-180 ~ ~ 198-201 .;
CH3 ~ 1 : ~: (dec) -:

~I.~u ~66-~6a ~ ~OM 165-,169 c~z;c~ 1 ~ 170-172 " Me~C C~ 177-179 ¦ ~ 252-255 O - ': ,' ",'.

WO 92/1~579 PCl'/US92tO~1773 . ~
39 ~1056~5 , . .
~ -'~ H2 ~ , ~' ', ' ~J ~L ~
H Cl where: Z is m p C w~

178-19Z~deo) ~3 120 e~ 187-190 1 ~ 178-~81 2ZZ-2Z4 1 ~ 243-Z45 : : OMe Me ~
Me C:

84-~97~dec)~¦ O~
900-90ZI~ec)l CX~ ~ zS-167 Me : ~
263-265 ¦ ~ --C O : ~ : :

O ~ : f' 7~ : 183-186 . -1 40~dec) : ~
: ~ : - . ~ --CH2- C=O ~:
~S~ ~ :;
HO~
r~ r 1l 21~0~203 S~

'~: ' WO 92tl5579 P~r/lJS92/01773 where Z is m- p. C where: is m p C
. . ~ ~ ~ ,:

~CF3 ~C~ 205-208 ~C~0 174-176 /~ 145-14~ ;

O CF3 Me ~ 174-1 76(dec) ~ 230-232 : ~NH2 2 HCI ~ . O ~N ;:

0 Cl ~ ~ I,C~ 197-200 148~-150: O N : 2 HCi I l 177-180(dec) ;~
; ' ~ 203-206; ¦ o :: ~ O c~ ~ ~ 241-243 1g4-197 O

`Br , ~ ¦ --C~L 159-162 c~ 2 17-~ 19 ~ o ,C~3 ~ 147-150 144-147 ~8 o ~/ ~ > 192-200 ~~
.., '-`'':

Wo 9~/15579 P~r/US92/01773 . ~
41 ~` -210S6~i~

~C~t2~ ::
N ~
~ HC!
where: Z ism. p. C where- 2 is Z35-233(dec; 1 X 173-176(dec) O~ 2 HCI N 2 HCI

~N~ 2a3-235 ¦ ~ 258-260 250-252 ¦ ~ 233-Z35(dec1 :: o ~.
~/~ 202 204 1 ~OM~ 256-260 N~ 1260H(Cl C) ~ :
Me ~ ~ ~ ~ ~ 195- 197 ~ Z55-Z58 ~ 3 ~ ~ ~

N ~CI ~ ~;
/O~ 243 246 N ,~ :
Z70~2j2 ~

~ ) ~ ~: ~214-217 N ~ ~ ~

'' ~5~ ~ ~
,;~
~ ` ;

:~ ~ , `' WO 92/1S579 PC~/US92/~1773 r~6~

TABLIE~ Vll .
', '~.' [~Me ~H Cl where ~ is m. p. C
C) , .
~- C-~ 211-213 ~CI ~:

~3~1 285-290 ; .
TABLE~ Vlll Structure m. p. C.
. .-.
,, . -~ ~CH2 ~ ~? 2fi~-270 ~ [ ~
H C I - : :

H2~c ~>_~CI 275 277 H C I
:'~'':
.
~ ~ .
.:' ' -;

Wo 92~15~7g Pcr/US92/01773 :

2 1 0 5 6 ~
TAB LE IX
N

CHz-O~
~ HCI
where:_~ is ~ P ~
,~ :
~~ \~ 267-270(dec) b~--o 4-syn ~~~ 335(dec) ~ ~0 4-anti :: :

~; 4-anti n 323 4-anti 319-3Z1(dec) ~ ~

~;' 5 ~ ''`'"' St~p A~

T~ a solution of 1 Og (58.4 m mole) of 4-bromotoluene in 75 ml of :
a~hydrous THF cooled to -78G is added 23.4ml (58.4 m mole) of a 2.5 M
:

w~ 92/1557~ Pcr/uss~/ol773 36'~ 44 hexane solution of n~butyllithium dropwise over 5 minut~s. The mixture is stirred a~ -70C for 10 minutes and 58.4 ml (5~.4 m mole) of 1 M zinc chloride is added dropwise over 5 minutes. The cooling bath is removed and the mixture stirred for 1.5 hours warming to room temperature. This mixture is then added 5 dropwise oYer 5 minutes to a mixture ot 9g (45m mole) of 4-bromo-1,2-(methylenedioxy)benzene and 0.67~ (0.~8m mol~) o~ tetrakis(triphenyl-phosphine~ palladium (0) in 100 ml of THF. The mixture is heated under reflux for 10 hours. The mixture is cooled and poured into 100 rnl of water and extracted with 200 ml of ether. The ether layer is washed with water and dried 10 over magnesiurn sultate and then filtered. The filtrate is evaporated and theresidue recrystallized from hexane to give 4-methyl-3',4'-methylenedioxy 1,1-biphenyl (m. p. 57-60). ~`

Step B 4-bromomethyl-3'.4'-methvlenedioxy~1.1-biphenvl ~;
A rnixture of 4.6g (21.67m moles) o~ 4-methyl-3',4'-methylenedioxy-1,1- ;
biphenyl and 5.0g (28m mole) of N-bromosuccinimide in 70ml of carbon tetrachioride containing 0.19 of benzoyl pe~ioxide is heated under r~flux for 2.5 hours. The mixture is filtered and the filtrate evaporated. The residue is .
recrystallized ~rom hexane to afford (m.p. 78-81). ;;
. ~
Step C 3~ (1.3-benzodi~xol-~l~ benzvloxv]-l-azabio~Doe2~ ~;
hydro~hloride ~ :~
~ .
2~ To a suspension of 0.14g (3.44m mole) of 60% sodium hydride in 20 mi of anhydrous DMF is added a solution o~ 0.489 (3.44m mole) of 3-quinuclidinol borane complex in 10 ml of DMF dropwise over 3 minutes. The mixture is `.
stirred at room ternpera~ure for 15 minutes and a sQlution of 1.0g (3.44m moles)~ ~
of 4-bromomethyl-3~!4~-methylenedioxy-1,1-biphenyl in 10 m! of I~MF was -added dropwise over 5 minute$. The mixture is stirred at room temp~rature ~or 2 hours and poured into 75 ml of water and extracted with 1~0 ml o~ ether. The Pth~r is washed with~water, dried over m~gnesium sulfa~e and ~iltered. The .
filtrate is evaportaed and the residue purified by flash chromatogr~phy using 4:1 hexane: ethyl acetate to give a solid with 1 00-3mp. This solid is suspended in 10 ml of acetone and ethanolic hydrochloric acid is added io pH1. The mixture is stirred at room temperature for 1~ mintues and then W~ ~/15~79 Pcr/uss2/ol773 .. 45 2 1 0 S ~
.
dilu~ed wi~h ether to precipitat~ 3-[4-(1 ,3-benzodioxol-5-yl) benzyloxy]-1-azabicyclo~2.2.2]octane hydrochloride (m.p. 195-8). ~:

Analysis Calc ~or C21H24CINO3 C: 67.46; H: 6.47; N: 3.75 Found: C: 67.08; H: 6.53;N: 3.53 :.

APL~ 2.6 Following the procedure of Example 25 the following compounds may be prepared.

3-~4-(1,4-benzodi~xan-6-yl)benzyloxy~-1-azabicyclo[2.2.~octane ~ :

3-E4-~2,3-dihydrobenzofuran-5-yl)ben~yloxy-1-azabicyclo: [2.~.2]octane ~:

~ 0--CH ~
~?J ~, ~

~0 3-[4-(benzo~ur~n-:S-yl)benzyloxy~ azabioyclo;[2~2 2]dctane N ~Me 3-~4-(2-rr ethylbenzofuran-5-yl)-1-azabicyclo[2.2.2]o~ane WO 92/1~579 PCl/VS92/01773 46 ~;:
~6~ :
?.~ ~,, ~'0 ~CH2 ~
N J ~M~
~0 Me ;, 3-~4-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyloxy]-1 -azabicy~lo[2.2.230ctane ~':
0 CH2 ~ , . '.

~J b,~ ><Me , ~0 ~',.
3-~4-~2,2-dimethyl-1 ,3-benzodioxol~5-yl]benzyloxy]-1 -azabicyclo~2~2.2]oc~ane , .
,., ., ", 0 ~ Various tests in animals have been carried out to show the ability o~ the compoun~ds;of the present invention to exhibit~pharmacoiogical resporlses that can;be~orr~lated~with a~tivity in~ humans. These t~sts involve su~h fa~tors as .
the effe~t of ~the compounds of Formula I to inhibit squalen~ synthesis. I t has;beén found~ that Gompounds~within the s~ope of ~this`invention when t~sted 15~ ~ ~ using the following pro~edures show a marked activity for the inhibiti~n of - ~ " ...
squalene~ synthetase and hence~ are~ believed :to be useful in~the treatment of cholesterol-related disorders. ~

The squalene synthetase assay used is ~a modification of the procedures !',-..
described by Popjak (196~ and Poulter et al. (1989):

Popjak. G Enzymes of~sterol biosynthesis in liver and:interm~diates~of sterol ` ~ -biosynth~sis Meth Enzymol 15: 393-454, 1969.

,Poulter, C D., Capson, T,L, Thompson, M D. and;~Bard R S. Squalene synthetase Inhibition by ammonium analogu s of carb~cationic intermediates in the ~or~Yersion of pres4ualene diphosphate to squalene. J. Am. Chem. Soc. ~ `
1 1 1, 3734~3739, 1 989 -~
,., ~., ~,.
:, WO 92/lSS7~ P~/lUS92/01773 _.

21~56.5~

1. Ani~l So~rcç and Tissue~hQ~:

Four male Sprague-Dawley rats weighing 100-12~ gms ar~ fed a low cholesterol rodent diet (#5012) obtained from Purina Mills, Inc. in Richmond, 5 Indiana; and housed under reverse-light. Water is given ~ li~. Rats are lightly anesthetized with ether and th~n decapitated. Livers ar~ removed and enzymes are separa~ed by the method dcscribed below ~:, Il. Mat~rials: ~ ~

Ch~mi~als:
All Chemi~als are "A.C.S." in purity or batter unless noted;

AquaSol~-2 scintillation fluid (NEF-952) (Du PonVNEN Research .;.
15 Products, Boston, Mass.); ~ ~ :

:: Anhydrous MgCI2 (M-8266), ~-NADPH tetrasodium salt, reduced form N-t630), BoYine serum~ albumin :~(A-6003), Cholesterol (C-8503);

20 ~ ~qualene (S-3626),:(Sigma Chemlcal Co., St. Louis,:Missouri);

Bio-Rad protein~;assay dye~ concentrate~ (Bio-Rad~Laboratories, ~: -Richmond, CA); ;~

:~ 25 ~ ~ ~ Denatured ethanol,~DMSO, HCI (1 N), KOH, methanol, NaOH ( 1N,1N), petroleum ether ~M-280 grade), po~assium phospha~e dib sic,:2-propanol :; (FisherScientific, Pittsburgh, PA);

Zero grade 'nitrogen gas mixture (cerEified analysis) (Woodla~ncl Oxygen ~: 30 & Supply ~o., Philadelphia, PA) :~

~: Radiochemicals~
[1~3H(N)l-FPP, triammonium salt (NET-1042), (Du PonVNEN, 53oston, .~ ~
: Mass ); ~ ~:
~4,%,12,13,17,21-3H]-Squalene (NET-645) (Du Pont/NEN);

I

~i WO 92/1~7g P~/US92/01773 4~

Non-radioiabeled FPP is prepared in-hous~. The solid FPP is aliquoted and stored a~ -80C. FPP is dissolved in 70% ethanol/30% 0.25 M Nl 14HC03 1 ~:
at the concentration of 10 mM and the solution is aliquot~d ~200 ~,11 each) and . ~:
stored at -80C. ~ ~
.~:
111. PrQ~ratiQn Qf A~a-!L~a~e~

;.
A) Test Solutions:
Test solutiorls are prepar~d fresh in 100% DMSO or dl 120. Subsequent 10 ~ dilutions are made in the same solvent. Compounds ar~ tested initially at: 1 or 10 ~lM (finai ronc~ntrations). 1 . .
....
.,~' B) Assay Buffer~
Potassium Phosphat~ (50 mM, 8.71 g/l) pH 7.5 stock buffer is pr~pared ~:
: 15 and stored~ at~4C unti! use. Anhydrous Mg~!2 is added:to the phosphate . ~:.
buff~r on ~he day of assay for a~final concentratlon of ~OmM (95 mgt100 ml).
; The~ buffer is flushed wlth N2 before use.

C) ;Su~bstrate~
~ Non-radiolabeled~FPP is~diluted to 50 jlM (100 ~1 10 mM cold FPP~+19.9 m~l phosphate bufler). ~Then, 14 ,ul (20 x 106:dpm~ of 3H-FPP (0.5 rnCi/ml, .01 1 mg/ml) is added. 200 ~1 of~this mixture is added per assay tube for a final ....
reaction concentration~ Qf: 10 ~M~ FPP (-200,000 dpm/assay tube). ~ .:

: 2~ D) ~ :B-N~DPH Solution 37.5 mg of B-NADPH ~is added to 9 ml ~assay buffer ~o~r:a~:~ mM~
concentration ~f 13-NADPH. The mixture is vortexed and 100 ~LI of this~solution is added to each tube ~or a final assay concentration of 0.5:mM B-NADPH. . .- .

: . :: 30 ~E) KOH in Ethanot~
~: ~: 7~ gm of KOH is dissolved in 500 ~ml of denatured~ ethanol for a 15%
i : 601ution and stored at:OC until use. 1 ml of this solution is ad~ed per tube to .~
terminate:the reaction. ; : ..

.

9 P~T/US92/01773 2 1 ~ 5 IV. ~: ;

A) Enzyme Pr~paraticn:
immediatcly followîng decapitation, livers ar~ remov~d one at a ~irne 5 from four rats. The livers are combined and weigh~d in a tared beaker. Assay buffer is added equal to three tim~s the liver weight. The liver is first homogenized with a blender for thirty saconds, and then by a motor driven teflon pestle at a speed of 2.5. DuRng homogenization, the liver is kept on ice.When the liver is fully homogenized, th~ homogenate is c~ntrifuged at 10,000 g `:,

10 ~or 30 min at 4QC in 50 ml capacity centrifuge tubes. Th~ mitochondrial pellet is discarded and the supernatant is filtered through a layer of gauze moistened with a littlc buff~r. This superna~ant is recentrifuged at 105,000 g for one hour ~;
at O~C in an ultracentrifuge in 25 ml capacity ultracentrifug~ tubes. ~
.-.
15~ Following centritugation, the supernatant is r2moved and discarded.
The sediment pellet consists~ of ~2 1ayers: a transpa~en~ inner layer of glycogen, surrounded by an opaqu~ brown !ayer of;mlcrosomes. The brown ~uter microsomal~layer is car~fully~removed with a spatula and placed in a beaker on i ce.~ ~Assay~ buffer is added in an amount equal to one half the originai 20~ homogenate volume, and this mixture is poured into ultracentrifuge tub s.
These tubes are recentrifuged at~105,000;g for 1 hour at~4"C. ~

After~this centrifugation~is~complete,~the supernatant~is~again removed and discarded. Fr~sh~ assay ;buffer is added to the combirled pellets to achieve2~ a volume equal to one ~tenth of the original homogenate~volume. The microsomal fraction ;is ;then rehomogenized orl~ a motor driven teflon~ pestle at a speed of 2.5 t~ partially solubilize and make a uniform suspension of the rnicrosomes. The enzyme (~20 ml, ~40 mg protein/ml) is aliquoted (200 1ll) in~o eppendorf plastic tubes, cappéd and stored al -80C~ until use.

B) Assay Proceduré
To begin the assay,~ 20 )11 of the compound of this invention or vehicle ~solution is added to ~ach 16 x 150 screw-cap culture tube on ice. Then 580 ~l , cf N2 flushe~ assay buffer is pipetted into each tube. 100 ,ul of cofactor is next 35 added t~ each tube, followed by 100 ~11 of a dilution o~ microsomal enzyme ~
- (approximately 80 ug protein). The ~ubes ar~ preincubated ~or 10 minutes at 37~C, an~ 200 1ll of the 3H-FPP (200,000 dpm, 10 ~M final conc.) is added to ;~

.
~ .

WO 92/15579 PCr/US92/0~773 ;36~
each tube at two second intervals. The tubes are then incubated ~or exactly 10 minutes, shaking at 150 oscillatisns per minute. After the 10 minute incubation,the reaction is stopped by the addition of 1 ml of 15% KOH in ethanol, and the tubes are incubated ~or 30 minutes in a 65C water bath for saponification of 5 lipids and solubilization of proteins. The tubes are cooled on ice ~or five minutes. The samples are naxt extracted with 5 ml of pf-~trol0um ether by ~ ;
shaking for 10 minutes at ~ow speed on a rnetabolic shakcr. Each lower aqueous layer is frozen in a dry ice/alcohol bath (2-propanol/methanol, 1~
and each organic layer is poured into another set of 16 x 150 screw-top culture 10 ~ubes containing 2 ml of deionized water. Each ether layer is wash~d by vortexing each tube for 5 seconds. The aqueous layers ar~ again frozen in the dry ic~i~lcohol bath, and thc ether is poured into scintillation vials. 10 ml of ;~
AquaSol~ is next added to each vial, and the vials are counted for 5 minutes in a scintilla~ion counter. Percent inhibitions are calculated from the counts ;~
15 obtained.

v. ~e~ ~''`'' '.:' The samples are counted as dpm using a Beckman Scintillation counter (Model LS-9000). Percent inhibition is calculated using a Lotus 1-2-3 program.
The tC50 values are calculated using a linear regression program of Tallarida and Murray (1987). Tallarida, R.J. and Murray, R.B. Manual of pharmacologic calculations with computer programs. Springer-Verlag, 1987.~ ~i ~ In view of the results obtained by the foregoing assay pro~edure, ~ -compounds within the~scope of Formuia i inhibit s~ualene synthetase enzyme , ......
activity and are useful as hypocholesteroiemic or hypolipidemic agents by vir~ue of their ability ~o inhibit the biosynthesis of cholesterol. Having such abiiity, the compounds are incorporated into pharm~ceutically acceptable < 30 carriers and administered ~o a patient in need of such cholesterol biosynthesis inhibition These pharmaceutical formulations contain at least one compound ~;
ac~ording to this invention - ~-, :, ~
In ~heory, treatment with a combination of an HMG-CoA reduotase inhibitor and a squalene synthetase inhibitor could have a synergistic effect oninhibitirlg cholesterol biosynthesis. Inhibiting the squalene synthetase ~nzyme an~ the HMG-CoA reductase enzyme at the same time would most closely WO 92/1557~ P~/US~2/01773 21056.~^~

resemble the physiological conditions of cholesterol homeostasis. A squalene synthetas~ inhibitor could keep cellular concentrations of farnesyl pyrophosphate high cnough for the synthesis of the srnall amounts of dolichol, ubiquinone, and ~he farnesylated proteins required by the cell. This would 5 maintain some feedback regulation of the HMG-CoA reductase enzyme and allow smalier amo~nts of the HMG-CoA reductase inhibitor to be used.
,' ',, ~, . .
The compounds of the present invention can be administered to a mammalian host in a variety of torms adapted to the chosen route of 10 administration, i.e., ~rally, or parentcrally. Parenteral administration in ~his respect includes administration by the following routes: intravenous, ~
intrarnuscular, subcutaneous, intraocular, intrasynovial, transepithelially ;
including transdermal, opthalmic, sublingual and buccal; topically including ;;
opthalmic, dermal, ocJiar rectal and nasal inhalation via insufflation and ~15 aerosol and rectal systemic.~

~: : , ~, .
The aotive compound may be orally administcred, ~or exarnple, with an ` ~ inert diluent or with an assirnilable edible carrierl or it rnay be enclosed in hard ~ or soft shell gelatin capsules~, or it may be compressed into tablets, or it may be 20 ~incorporated directly with the ~ood of the diet. For~oral th~rapeutic administration, the active compound may be incorpo;rated with ex~ipient and ~ used in the form o~ ingestible tablets, buccal tablets, troch~s, capsules, elixirs, `~ suspensions, syrups~ ~wafers, and the like. Such compositlons ~and ~preparàtions~should contain at least~0.1% of active~compound. The 25 ; percen~age of the ~ompQsitions and prepara~ions may, o~ course, be varied and may conveniently~ be between about 2 to about 6% of the weight of ~h~
unit. ~The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred ~;
compositions or preparations according to the ~present invention are prepared ~ so that an oral dosage unit-f~rm contains between about 50 and 300 mg of `
active compound ~h~ tablets, troches, piils, capsules and~the like may also contain the ~ `
following: A binder such as gum tragacanth, acacia, corn starch or gelatin;
excipicnts such as dicalcium phosphate; a disintegrating~ agent such as corn starch, potato slarch, alginic acid and the like; a lubricant such as rnagnesiumstearate; and a sweetening agent such as sucrose, iactose or saccharin may wo 92/1~579 Pcrtuss~/01773 r'3 be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. Wh~n the dosage unit form is a capsule, it may contain, in addition to rnaterials of the above type, a liquid carrier. Various other rnaterials may be present as coatings or to otherwis~ modify the physioal torm of the dosage unit.5 For instance, tablets, pills, or capsules may be coated with shellac, sugar orboth. ~ syrup or elixir may contain the active compound, sucrose as a sweet~ning a~ent, methyl and propylparabens a preservatives, a dye and ~lavoring such as ch~rry or orange flavor. Of course, any material used in .;~
preparing any dosage unit ~orm should be pharmaceutically pure and 10 substantially ncn-toxic in the amounts employed. In addition, the actiYe compound may be incorporated into sustained-reiease preparations and formulations.

The active compound may also be administered parenteraily or ; ~ ~ ~
i ntraperitoneally. Solutions of the active compound as a fre~ base or ~ ~ -pharmacologically acceptabie salt can be prepared in water suitably mixed ~ ~;
with a sur~actant such as hydroxypropylcellulose. Dispersion can also be prepared in~glycerol, liquid`polyethylene gtycols, and mixtures thereot and in oils. Under ordinary conditions of storage and use, these preparations contain 20 - a preservatlve to prevent ths~ growth of microorganisms.

The pharmaceutical forms suitable for injectable~ use inclucie sterile~
aqueous solutions or dispersions and sterile powders~ for the extemporaneous -;~
- preparation ~of steril~ in~ectable~ solutions cr dispersions. In all cases the form '.:
25 ~ must be sterile and must be~fluid to the extent that easy~syringabiiity exists. ~lt may be stable under the conditions of rnanufac:ture and stcrage and must be preser~ed against the contaminating action of mi~roorganisms such as bacteria and fungi. The carrier can be a solvent of dispersion medium containing, for example, watei, ethanol, polyol (for ex'ample, glycerdl,- . . . 30 propylene glycot! and liquid polyethylene glycol, and the like), suitable rnixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the ~requir~d particle si~e in the case of dispersion and by the ~se of surfactants.The prevention of the action of microorganisms can b~ brought about by ~;
35 variuus antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimersal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium ,. :, W~ 92/15~79 Pcr/US92/01773 53 ~ ;:
2 1 ~ 5 6 .~ S

chloride. Prolonged absorption of ~he injectable compositions of agents delaying absorption, for ~xample, aluminum monostearate and gelatin. `; -:
. ~; ~ , ...
Sterile injectable solutions are prepared by incorporating the active ~-cornpound in the required amount in the appropriate solvent with various of the o~her ingredients enum0rated above, as required, ~ollowed by ~ilt~red ; -sterilization. Generally, dispersions are prepared by incorporating the various steriliz@d active ingredi~nt into a sterile vehicle which con~ains the basic dispersion m~dium and the required oth~r ingredients from those enurnerat~d above. In the case of sterile powders for the preparation of st~rile injectable solutions, the prçferred methods of preparation are vacuum drying and the freeze drying technique which yield a powder of th~ active ingradient plus any -additional desired ingredient from previously sterile-filtered solution thereo~. ~
~ ~ ;
- ~ 15~ ~ The therapeutio compounds of this inventi~n may be administered to~a ; mamm~l alone or in combination with pharmaceutically acceptable carners, as no~ed~above~, the prcportion of which is~determined by th~ solubility and ~;
chemical~ nature of lhe ~compo~nd, chosen route of administration and standard - ~ pharmaceutical practice.

The physician will~determi~e the dosage of the present therapeutio;~
agents which~will be most~suitable ~or prophylaxis~or treatment and i~ will~varywith the form~o~ administratio;n ~and the particu!ar compound chosen, and also, -~
- ~ it wiil;:vary with the particular~patient under treatment. ~Hé will generally wish~to -;
~25~ ~ ~initiate treatment with~small~dosages by small increments untii th;e~optimum effect under the circumstances is reachéd. The therap~utic dosa~e will ~;
generally~be from about~0~1 to about 100 mg/kg/dy, and p~referably from about ~.:
10 mg to about 1 00û mg dayl or from about 0 1 mg to about 50~ mg!kg of body weight per day an~l pfeferabiy~from about 0.1 to about~20 mg/kg of body weight - 30 per day and~may be administered in se~/eral different ~osage units. Higher . -dosages on the order of about 2x to about 4x are required for oral ~ ;
~; administra~ion , . ., ~ ~.

~" ....

~ ~ , .' "
".
. ~
~ .;

Claims (32)

We claim:

1. A compound of the formula:

where:
Ar I and Ar II are independently a substituted or unsubstituted mono-, di-or tricyclic ring;
A is , , , , , , , , , , , or ;
where Y is NR', O, or S, Z is NR' O, S or a bond and m is 1-2;
B is CR'R', O, S, NR' SO, SO2, NR'-C=O, O=C-NR', O=C, R'C=CR' or C?C;
D is CR'R', O, S, NR', SO, SO2, NR'-C=O, O=C-NR', O=C, O-C=O, O=C-O, O=C-C=O, O=C-CH=CH, R'C=CR', C?C, C=CHR', C=S, C=NOH or a bond;

R1, R2, R3, R4, R5, R6, R7 and R8 are independently hydrogen or ( CH2 )x-X where x is 0-5 and X is hydrogen, alkyl, alkenyl, aralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, acyloxy, aryl, halo, amino, mono- and di-alkylamino or acylamino;
R1 and R3, together and/or R5 and R7 together may be ( CH2 )n where n is 1-4' geminal R1 and R2, R3 and R4, R5 and R6 or R7 and R8 groups may be ( CH2 )p where p is 2-5;
R' is hydrogen, alkyl or aralkyl;
R is hydrogen, alkyl, aralkyl, hydroxy, alkoxy, aralkoxy, acyloxy, halo, haloalkyl, amino, mono- and di-alkylamino or acylamino; and a, b, d and e are 0-4;or a pharmaceutically acceptable salt or hydroxy borane complex thereof.

2. A compound according to Claim 1 where:
Ar I and Ar II are independently a substituted or unsubstituted mono-, bi or tricyclic system of about 5 to about 14 atoms which may be partially or completely unsaturated carbocylic or heterocyclic and where each ring of said system contains 0 to about 2 hetero atoms selected from N, O and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R;

A is , , , , , or ;
B is CR'R', O, S, NR', SO, SO2, NR'-CO=O, O=C-NR', O-C=O, O=C-O, O=C, R'C=CR' or C?C;
D is CR'R', O, S, NR', SO, SO2, NR'-C=O, O=C-NR', O=C, O-C=O, O=C-O, O=C-C=O, O=C-CH=CH, R'C=CR', C?C, C=CHR', C=S, C=NOH or a bond;
R1, R2, R3, R4, R5, R6, R7 and R8 are independently hydrogen or ( CH2 )x-X where x is 0-5 and X is hydrogen, alkyl, alkenyl, aralkyl, hydroxy, alkoxy, aralkoxy, aryloxy, aralkoxy, aryl, halo, amino, mono- and di-alkylamino or acylamino;
R1 and R3 together and/or R5 and R7 together may be ( CH2 )n where n is 1-4;
geminal R1 and R2, R3 and R4, R5 and R6 or R7 and R8 groups may be ( CH2 )p where p is 2-5;
R' is hydrogen, alkyl or aralkyl;
R is hydrogen, alkyl, aralkyl, hydroxy, alkoxy, aralkoxy, acyloxy, halo, haloalkyl, amino, mono- and di-amino or acylamino; and a, b, d and e are 0-4,

3. A compound according to Claim 2 where:
Ar I is phenyl or naphthyl;

Ar II is phenyl, thienyl, naphthyl, benzoxazolyl, benzothiazolyl, benzofuryl, benzothienyl, benzodioxanyl, benzodihydrofuranyl, benzofuranyl, benzodioxolyl, quinolinyl, indolyl, acenaphthyl or dihydroacenaphthyl;
A is , or ;
B is CR'R', O, S or NR';
D is CR'R', O, S, NR', NR'-C=O, O=C-NR', O-C=O, O=C, R'C=CR', C?C, C=CHR, C=S, C=NOH or a bond;
R1, R2, R3, R4, R5, R6, R7 and R8 are independently hydrogen or ( CH2 )x-X where x is 0-5 and X is hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy or aryl;
R1 and R3 together and/or R5 and R7 together may be ( CH2 )n where n is 1-4;
geminal R1 and R2, R3 and R4, R5 and R6 or R7 and R8 groups may be ( CH2 )p where p is 2-5;
R' is hydrogen, alkyl or aralkyl;
R is hydrogen, alkyl, hydroxy, alkoxy, halo or haloalkyl; and a, b, d and e are 0-4.

4. A compound according to Claim 3 where:
Ar I is phenyl or naphthyl;

Ar II is phenyl, thienyl, naphthyl, benzoxazolyl, benzothiazolyl, benzofuryl, benzothienyl, benzodioxanyl, benzodihydrofuranyl, benzofuranyl, benzodioxolyl, quinolinyl, indolyl, acenaphthyl or dihydroacenaphthyl;
A is or ;
B is CR'R', or O;

D is CR'R', O=C, R'C=CR', C?C, C=CHR' or a bond;
R1, R2, R3, R4, Rs, R67 R7 and R8 are independently hydrogen or ( CH2 )x-X where x is 0-3 and X is hydrogen, alkyl, hydroxy or phenyl;

R' is hydrogen or loweralkyl;
R is hydrogen, loweralkyl, hydroxy, loweralkoxy, halo or trifluoromethyl;
and a, b, d and e are 0-4.

5. A compound according to Claim 4 where:
Ar I and Ar II are phenyl;

6. A compound according to Claim 4 where:
Ar I is phenyl and Ar II is naphthyl.

7. A compound according to Claim 4 where:
Ar I is naphthyl and Ar II is phenyl.

8. A compound according lo Claim 4 where:
Ar I is phenyl and Ar II is benzodihydrofuranyl.

9. A compound according to Claim 4 where:
Ar I is phenyl and Ar II is benzodioxolyl.

10. A compound according to Claim 9 which is 3-[4-(1,3-benzodioxol-5-yl) benzyloxy]-1-azabicyclo[2 2.2]octane

11. A compound according to Claim 4 where:
Ar I is phenyl and Ar II is benzodioxanyl.

12. A compound according to Claim 4 where:
Ar I is phenyl and Ar II is acenaphthyl or dihydroacenaphthyl.

13. A compound according to Claim 1 of the formula, where B is CR'R' or O;
D is CR'R', O=C, R'C=CR', C?C, C=CHR' or a bond;

R is hydrogen, loweralkyl, hydroxy, loweralkoxy, halo or trifluoromethyl;
and a, b, d and e are 0-4.

14. A compound according to Claim 13 where B is O and D is O=C.

15. A compound according to Claim 14 which is 3-[4-(4-chlorobenzoyl)-benzyloxy]-1-azabicyclo[2.2.2.]octane

16. A compound according to Claim 13 where B is O and D is R'C=CR'.

17. A compound according to Claim 16 which is 3-[4-(2-(phenyl)ethenyl)-benzyloxy]-1-azabicyclo[2.2.2]octane.

18. A compound according to Claim 4 where A is and B is CR'R' or O and D is CR'R', O=C, CR'=CR' or a bond.

19. A compound according to Claim 18 which is 4-[4-(2-(E)-phenylethenyl)-benzyloxy]-1-azatricyclo[3.3.1.1 3,7]decane and its anti-and syn-isomers.

20. A compound according to Claim 18 which is 4-[4-(benzoxazol-2-yl)phenyl]methoxy-1-azatricyclo[3.3.1.1 3,7]decane and its anti- and syn-isomers.

21. A compound according to Claim 4 which is 3-[4-(2-methylthien)-5-oyl)benzyloxy]-1-azabicyclo[2.2 2.]octane.

22. A compound according to Claim 4 which is 3-[4-(benzoxazol-2-yl)phenyl]methoxy-1-azabicyclo[2.2.2.]octane.

23. A method of lowering or maintaining reduced cholesterol levels in a patient requiring such treatment which comprises administering to such patient a squalene synthetase inhibitor effective amount of a compound of the formula according to Claim 1.

24. A method for inhibiting cholesterol biosynthesis which comprises administering to a patient in need of such inhibition a squalene synthetase inhibiting effective amount of a compound according to Claim 1.

25. A method according to Claim 24 where the patient is in need of a hypocholesterolemic or hypolipidemic agent.

26. A method according to Claim 25 for treating atherosclerosis

27. A pharmaceutical composition comprising a squalene synthetase inhibitor effective amount of a compound according to Claim 1 in admixture with a pharmaceutical carrier.

28. A pharmaceutical composition according to Claim 27 which further includes an HMG CoA reductase inhibitor.

29. A compound according to Claim 1 which is a borane complex.

30. A compound of the formula where ArI, A, B, R1, R2, R3, R4, R, a and b are as described in Claim 1 and Q is Br, I, Li, Na, K or MgBr.

31. A compound according to Claim 30 of the formula

32. A compound according to Claim 30 of the formula;