Note: Descriptions are shown in the official language in which they were submitted.
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 ~ :~
3 0
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 . ~;
9 2105655
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 )~
E3H3
~( C ),--BH + L-~ Cl)b~ C )d--D--( ~
~(c)~ - u1c)b ~ (C)d--L + HD--(C),~]
EIH3
~(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)~ ~
BH3
: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'
EXAMPLE 4
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
21
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
23
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.)
EXAMPLE 10
; 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.) ' '
- '
EXAMPLE 15
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. ~ '
.
'..,
WO 92/15579 PCI/VS92/01773
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 : ;
EXAMPLE 17
::
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. ~ '
''''~",;
FXAMPLE 21
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
157-15
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
42
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 :
43
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
:: :
237-239
279-231
~; 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
_.
47
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: ~ ~
1 0
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. ; : ..
.
WO 92/15579 P~T/US92/01773
49
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
51
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
, . ., ~ ~.
~" ....
~ ~ , .' "
".
. ~
~ .;
