Note: Descriptions are shown in the official language in which they were submitted.
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
FILM.~.' AND PARTIC_~ ~ ~ S
CROSS-REFERENCE "1'O RELATED APPLIC:.ATIONS
3k?F5 ~rht3.'i~0 .
60. 8,)9,334, f'D.leti i::il NSC3S' 3 ~ 21006, ie7d, U.S. 11ri7visit?#.es .
:':pphi:at.Ãi)Ti :3C:i'i%i. No. 601,'844,, E"
filcd on Sz.~,~3.i::)1ba 33 2,006 ?'S1h#:+::li are botl3
Ã#ic43T'',~:?~.?rw1tc4;: s3eiC:Ã#e by al.,oem;kÃ;i i:1c.il"
entà rL~ty.
,'s.,TATL>ME;.Y.8\ A$3 TO FEDERALLY SPOt vSOR3`:-DRE.3Y:fARe.,I3
i + This :a?v..Ãl-tioa3 03'Ã.#;i made with Gi?v('mnS;)t support u?:.t:t,...
US. Al'?:.ay,'CE`t}pm`Ã:r'o
~~~~ 2-'iJ`r06. 3 iic `3~iYenmiva~Ãf. ~:t t ~~ has ,:~ ~ ~Z,i t tit i~ r~,h2 ~
Ct 3 the ? ~3#~S1.,~ jt-t~f:~~. ~`.
i:,. E. ~ .
ag#i.emG#:x No. 1. No. a~~ ~~D'^F '^\r+...
f'IEL~ OF TIIE .~NVEN'1'.ION
~s,?rr .:: .i C+ c~t::,.i>7'C.i'E'!:. +"i fiTC 4.::: , sYI)kh.` C r Eant~~S r
i11Id p3'ss4s to ptpsir[: pol }m?i:#' bc.S \li
i':.FF'~.i:,.t:s fG>.~, and f, ~ 3x~::t; ~.;~t~;.~l~)S)~i3'~Ã~>Ja~,
t2:t"FC~,t7it~F~.GS~~;~ #~,?#' delivery :S'~.;~3t;.':'.s.
o. . - y.
BACKGROU"Ni3 ormEINVENT10N
N,.c.:I`:cine t,%#~`.~Ãt!#3<3:i3.1+` Ã.Et1li,_.#y.~ or "+i:q,sa,4?.l
i>1.uven¾1Z}:.)s, ft?r
the treat3)?eT.ir of disease. Specific ; s[,;``;tÃ.i2g or localization of
~3,:`,:#3 #1.21i.:.()l~:g.k.~?:: ~)13ti.i<..tgÃO~t#;
agents to d..5;.?cd oi,~:`afs.? and fisstlcL~ is a complex &'allu'1?,~,W.,e, I
W ::hawn?p.i, Q-uwoà .", a
lec..ef?.i7.4 cause of Ci::=<:i~h fim, bot,] mt':i and WE?men lii thÃ. United
States (Jem<?.z et c ..,
.c. . 5)i=
i.Lli.t :i = :>~ j StÃi~e:Ã?t#Ã1 ~.7"tit3.f,)~.:ia6,
c1.I~'5~~.l.~.l.ii,~'?'wi1l at.54'L:tlt?23. : ~ o"lieicii i\S FS I ;.~1# #<.i'
\eat>ce)..~cc\rF.#,enoc $.~Ãndl\)m; sL{E il. va . t.L.e(~tn{ei.tf.i:o7.
4'oni.tA..,az}.`~,'f `s.i;..'ZA1.,rF 4aww4-CtAE-4n mn?<:i?.j
rc.la:#v4l' ,nefft o6ve,
Ot2::t-~r diseases and. madit1oÃ`3s whi4-}e utilize dÃÃ. q, Lac~~am :y
Ã.lL.,#d':'.
w1?#.1Ãic' hct:là n`a..', 3nf+:cdi3:.iJ d??rv).ac., vnmsp:aots,
;1#al~l#~:27i ~ ,
and 1~iI<'~ f.w of vaccines. ~~4Fg~:.t7.t1`r.i~i ~~~ LFg iriai?i3.iLFti?.e8
L)ft.:=:"? ,p? i,.sC'.ilt 4t??il:brlÃ.t+%,:
~` ~#i.~ s) ~riE, a.
::C>? ~ `,.% <:rt)i~ ~~~t.Ai)'tii3~.,~kx:`~ `.`i. 't)~?#.?sFi~.`#'i~tÃ(?:~.4,.
Thus, a,i2i.:f= is a Y s e ', c :'~,#a F '3~i:ÃÃ-
tz*ik:tii.`=d ,nt..els:ista.n.`d del.i4L.`. y of therapeutic iiÃõC:Ã1t.j.
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
~~'eit`i]_i.:?olt'4ti:LÃ`s, poly:.aÃ"bÃ.?maL4, m1d polyarnides are
.;'.`.+fod::grctf,<61G pi?lp7'af;.;.'s
w,i~th lowif?x:eftt G#.i'xd dL.Mmdi:ifi'C`>I1 properties. Such
pt?l472^f..i"'~'+= Wdi:de p\>iv
`aÃ+:3l}`(#e3'd.Io:{ilt~:oriL ), ~~`J S ~~Ã'.371\~I ?.t FaE 'M=<? '??CZnalO
t?L:?y(mnl#.o e:Ei:'.#ds), i33Ea
);`t~ ¾ 34 . #C. :~#:d '7~3l;t(l:i~:=tIt;~ t~Ã:l{~~}#=\Ã~~.,, C?.~s 5
.~ts~=[l.4?`r~[l i:'r
i ~J\. \7¾ \. 44 \: Agrawal . . ,
x ~
~~ss.fÃ~;cl~'~::'3c _.4, S: ~?. 111?., iY2, 1Eii3M; f~i:i.~c3:x[',s: et .ai.,
J. ~~i~>.F3Ãf;t.i. ~k''a.it~',i'. ~til.'i, ~f~. .2-3? t ~ 40.=
t ~kt'#z.~#i3.i'f,~S,
~~,cr~~~es :3~.~~,~ . ~. ~:~_il.<:~.
1995, ~x" !::l.~:r ,~ '+ t~: a ~;. I~, `xi.~~. ~~.~~:i~., ~ '~~= - .. ~~~15--
1~:~,.?~ ~?, _ ~~ ' ik.;i~>
8: 12 9-1 .~ 198 i, at3:#., ALtIan<3tiiC)U. ef a?r., Ai`t. xi"t:i-s4 oj?Z'';
14. 7 1E~ 199 8i.
JI'l0es ~F+'_?t~.?7t t,~ aI\--:.lwt3 >.''z a viinÃ:.y of appil#.:atÃC3i7s
:ÃI?ClL:d1ng the dt,hE +::: y l;-N'_i%i 3.pctafi#:.
phys.{.,.11 p.."'C>;?'l'rfii:.s, of the il~ ilt~'llrL~:ÃE3#l :C~ pi1l}'rnE..?s
i:l.ri: : ftc. l.` .laF>ed
I
1~.,~ ~Iv à at?iltzÃ>.#ca S'.",..eG:i(:}n, p+?lymorÃzatioI1 ted3`Ãiqut.J,
iFtta pt3s:^poly7n+ ÃÃ.c..s?rÃ"r%3
miAi,ficc?t1i7::'t < P. ! Z?pef d:>.`' of 11~terS'.=1Ã ÃnUlÃ.ade thel
f'zF.'t'1:l ~:.~.d`.õià t1.t.2n Wmpt:Ã'ixtili' `x, bulk
aÃ' nz fr: :Ii:YR3Ã~t~irl, Ã'ixi`~~~;`. ~~'igr: dt1t.io'#1, cri'~~affif1aty`,
:i:1d h!'dT'oph+.'.+Ni:.1 Y When,
`Ji#l.~i~i.t<is are iÃt5~~..'~~..:~i it~r ~.YFS~'~~'i~'
~2~~~1l>~,~f.i~'~Ã'~~.~~.t~r i:f.t'~. pi3t''`2~c~:i~i '~~~~~~~~~~i~:.#.~/Z
~J! L'~~e ~~ii:1.4~r..;~`.%:
%
affect host I':,spJ.l:s?. Heni+ww, ai1eL''=d. c:4.ÃstS for pol5'{i"ItiI`s and
d\,.Ã t'ei't scstcn.G wÃffi,
1 v &stÃ"i'.d :w3..= si`.'t. 4f1-i'.i_"fivi for trs:;i3:tiifk11t. <?f dIs
,'.2]Re:i Ã3::3d ~ ):;iLiltlt?Ei4.
SUINIINIARN' OF THE UNVENTION
I.w based, c3~. Icclst in ,~,~ai .. on the dly<.o's'or, t:?iit ?:.umln a t.
dZ='fale~Ã :f~;;`~?s
fide:: c-;#.i b#.: ut~Iifc.t,~i t1,o?i.#pt'.`=utÃcyill}` <?nd/0:` cos;-
rIVt>i.0i:1-y. For c`::c3_n1p.c, many o ihw
;.mL1 }YZ3'r
20 ~`..~23nn`a and particles ti`~\.sLi anl:=dherdn can be #.i..Si::dfo.t."
Ai1o3=i.>ntToii 4s:, li:'sf..r'2l.i.edl, and si3.\:_iÃ:I%::i3
i~efiv exy of vii3 Ãou: agents tC3:: tT'C:i:tx'~~'iuÃ3t of d#,svi:1Sc'~' nd
L,o#:1dr~'iiot:5. InGÃ.i'en are
;~e pa:ic pol~'nlcl' based Ai.:3.iis, paS.tI#,."s.L=s,guls,'.in.Ã rGli.#toi.i
X~~
a t'~<} ~t' ~ . : - = .
t ) ?3;as,.#~.Ã':s, ,~iil~.~t processes fbÃ" i~:4iiYt'.n' of i~~eT~t;~. ri;';
:E:t~'`4~.4..`.1.Fz are p.3C?l\ t;7L.77i: f:1'3iC and
~.t:
p#3a`.1~.~:~i ~~i<f~ :~i à ~`~ LgÃl~ i:"I]`si~f~ ~~Ã3.~~, ~Li~F3 t~ t)Ã7i'`.=
(St #e:Ã3:'`..' `~~1~'a'z~~~Lt~t~: :{Ã~'zaf~s. ~~~t3 a Ei)S
2:3 shL'., w:ii':re il,,~ rd<'.'...~~ ~f fl.10 o1yL'= o" more iÃ.yY:'f.`ai:,
from the fiihI:3 or particle is .iT~nAi.ltt:d by a TAi
~:u~ _~' ' ~,codls~pradal-A#:, pc~lyn1et's.
+,::~t[zt.~, ~ x. Also provided .. ~
~.
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
l.t;: w7e:" <3s3i..~.:.. the Ea3'#1Ã~I~ .~t..Attlk~Gs t?~.i.~.:Ã3#.~#a~s t~r
P<3li.am,', s `~t.#\ #:i'~.*~ i.. ..~~'?~:~:EÃ tl'#1f."
~ .
:nted by Formula XX;
FR2
f+ v.,~ ~
..~.c.-" .\
t;Ãti
"1 .a3M OrP0l~M`.1.;PSs Q i~ :?dCdei3 ,fr'L.3~ m-no?~~0., Sg Sc, NIsa G .~s,i1-
lZ.+==tG~d
u ft:3#n w: on .~~e i?zlo`'i zg > E`u~,:~3.#'L4=
3. y,;
, ~.-=
~~1 t"'~~= , ,~=` 4
R }...\~- ..___ ...~ b~ =~
6 tD
R
R= Spli
~., .
a.=~ 1` ~ , ~. ~~ --Q
. ~r+ 1
jA ~-~~ j` ~=,~,i a r r,~~ ~ti
Rk R;j
f,
.: .: t~: ~
.
R?
= ...._._
~ ~k rt ~~ 13\
;'
i~ R4;,~ ~ I
<3 C~a
., .~ P,tr % =,'4
R^ .s sc:ea`A fr.s92a;r#md}ng h`edz'f.~gG'1: et-t sitI't33wTh[ (?I' br3ncheid
A1', cyWAti i . e:iil EIl,;=fz'#.?.,
1RFl. ,.1~,'a~ r4.lZ'izr~r c <~?k~''~i.~.~~j'E {r ~tw~~1a;~.Gy z~g , . ..
..^,3~~ L..i~a~r~iEa> r ~'~ =c.; . .. :;~~ ti .ih.~e~, or ~~~,
df~.r.~Z4~a~~:sa'}L~.~: ~.~:,..... ,
vx'hcxeis: f af_ii.3lkSA, cyZ.doa.[kyis ~~~yl, L.'rS`.'+fm si#yk
alk)'MyE.aaytd.4i, a{kf~ yl1 a.2wylaFkZ `.
o: fl#`at?aoi..'s?Si?on +,.l-icii#i, i:-, optionally sLi`i-)st#tut(:,d
li"~ternal3y or $e#'Iillnall ::3'v:" iy.:e Oi' mut'e
my' c~~rbo':vl, ctEFboxyC.stZ'.i, t:'cLt=.C;f}'i4'2tmidi., .tl:--ztno, #.nono-
or di-
hyd#o
c +
~'s.li3s:#.ru~ik~ i #,f3~i'li.~, r~~1.iC?4s~~L:~";, 7 .#~fiiF~:',
~3~'1~3sA~,#~3-lw. or halogen
is tiele;.Wcl. froiia aamng hvdrogL~#i, mo-d 3oxyf ot[zoxz' amino, a Stt
a.#g"h; or
~>_.~W.i Lbc]tFr..=~A~Z-'~:~ `ka!x'~ ~ . r~:l~;talk~~`. S,ay1, ~~l~..~a.a.<
Sil~r1. i~l~.ylsil~>,, t2#~~~~sil~~l, :~lY yJ;zy;. or ~:~~~vri~lk~'l
L.. : . . .. . .,. .
.5'
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
` {}: 1 ~5 L;.Rtb433:2:!. R,,v Rz.. mnE? R{, are independently w....iiGfa
&k;n. ..a.3om- a
I l z C?r i~rz::~a_ ~`<.:is~i3`, iy(.lL}<}.l~i~'S5 dli~r1 islL?~~3i tiil~t
c3~~!':J ~.~ 3, i~Lf~sÃ:)''3 aY~~ ~''~>~i 3, ~;r
:~~~~c.,Ik:~l s..,hm:i1; 5>f 10 L:&i'bi7ns, .lI?id R=; i33:?i`i R,~ ai:;e cc3Q
`a i#"tdo?iC.ÃEdei;tl) sc.3:s=L`+cG ftC`d};
MMOD~[~.iy~.tr\~,S'~.'=~2sf.3a +t.it'o::3i o.i s~?~~Siil'~.~~.~=~s Ci1t~.~lf:
i:yC=dl.~ci.i.~Cyk, Gi~i~4~~. rilEi'~rSC,.,'.i; ~.~;.
a,"'.1.ilktil ..,.ail;.ox 1-50 U;=:tbons, whereiti cach &lkyl ::ycl<?.Ãlkt],
a:i-y;. t,1cfd.., .lx, v;.~~ ryl, oi_?
e:l'z'`r iii2lki l Lh._zl.: internally or tei'`zI`s$Ilt$fly l;1y ome or F,3o.
Q ~~c,iv diomF'l,
bvdÃC'Sk>+i..tliir, Caibt`xf'3, cc3rbi.ZE:s:.-Lr., tiatb3x4`?;Sm1dC.=,
iiimii1o, iF.io:"io- or aI?"11tli;, ttiio;, thjoc;+t:'=r, 'wiafiiEtv.
(?htJ`phait; ph~~s'plIo"1at4, or hillo, g4"Il sÃ1b-stztuents<
z~yõ#:..yE`wiil,,~ ;k:iG Foi'fl:?#.lli:#
In s~?.3 ~i?.' i:Tiib3dii,:~,:..t the C, rl,.z},C?#~"'z~:I';~ or ~?L~s <
XX':
R2
# \ s
XK
~tfi.Tis.uÃ:aJ, n is a,l !Ã,, tt4:= [~Lifr31I~ 2 "?i~, i3i1<~ %3r A>
i~1i~7':~1~~ _iF~:= or pt~.~#:~
F:~ ~lls:'~1 ~:}~.~ ~Ã,C A:~ia?
..
xtLn31`n<1: gmlio, the ii:.Ã'la,iÃ`al gS,Lp being, 'aeie..=ted itlTiong
el1oasi
has
aF ~aidis, ~, ~~ z t3:~~ s. s c`. ~tYiki~`?~rÃ~~e,~s,, alkenes, and +.~i3~~'S,
~..~,:~~, 4 s. ~
'w"};ni;eh _.s~.~ect, iliU iiivei~~ion f"c;Itures oligo?.ir.er4 (.rr ~~~~~~-
IA,Ã.rs, OT x>c)rt,o,l.~-
;:`lorcof; ttizii {i,: .epr~,:,svnted by Forniu1t1 XXI, XXII, ~..XIIIY XXIV,
XXV, XXVI, XXVI x
xxviii, xxi.'k = xxx xxxt.;'2.xvSi y XXXF F 9., r}.xxiv, xxt1 vp:1.1R -1, V3
or Xõ~-"".='k 4..n.
4
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
ti .= _~^ ~.. ~- ,. ~ .
~XV~=,=I
~.
~ '~= ` `il ~'~
~ ~.= ~ . . ti ~ ~~~k+~
\Vt),,~
?,'V. \ 't'`,~\ i ~S~-~ ~~ i=?~ .=~ t r y .
, ". ~ 1,= {' ~ =.r ~ ~.~. ~~Ã. ~ r y
X~,1,i :'
..E~.
~,.
; \ v..~ t~,-V i ~+4 Y ft=. ~ ~t.; :.
`= _\` i { }L.4i ^.` i u..~ .\.~ =, ~.~Y.i ::, . ~l .~ \r f,
\'( .
_-4
h r:;
.,.1 i, }. .. ~ ~. . V.~ . _.
xvtN'M
1 = vt
X'KxZ= r..
{ti= `7 ~.
In Gt.cl3 oh~i{Ã;3t-rs or p~,YI--vI"EIcI's, or pt"s2:loy34s, the3'eot Qr is
?tl:keperidlGtl1 'y St.aet;t+.~'~C.: rI'C5nn
~.f., C~:F i~~,4' ~. :3''~~,.~~=i:. ~ .=o,
aaImF'l4F 0, S :s.,, 't?:I' M l S;k' (3;f, and ,, :~7`G. ~.~f~.7 ~ #ils: ~,
~i=i3~. ~ ~ Ie~ ~ ~.~ "t3 ~i <.~731s3f1 ~': t ~
.{-~~~lowing ;~tmd"Ures:
-S
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
o~ IN
:ai:i{I cia ili'G: not the s.:e.i7}i3: 3~F is sC hai:-lI 31:E}FEx
:iFl:Y~3Fi#~? a s:i 'Ã4.ti or bÃ'a3 c,.#ed. :`+lkyEk
cyclcaalk;< aryl, tz1cfin sily`, alk4fls avl, aÃ'y ~lk::I, o: fl:.E.f
.;carlbztrl
V'haÃ#aoi`3 5(_)bar1,7o#2s >ho).c.w5ci-Fcti a`ki~l, cy\.1o(F~kylti = yl..o
e(}n.:Silylr,. Ltikl4l.sÃSL~lq
ES saÃ'yi3Hyl, c? kvdi.s,.1,rE.. au'x.ci.kyl or fli;.oFf3[;.ii'lbt3i7 chain is
:3ptioi':IN i3tern.,lly Ese-
ten;i,..F'Ã.iffly by omo C.?:. 11-mri' hyrArf.#i1.yl. layd'F'ox}`'-
\'.g...f~er, cm-boxZ}'."a Cf~ailboxvZ.steS"
,, : h"~}
:;tii#"bt?xt~.i~ax~t1:, :i.#?.I~..? Ã1i~?Ã~ii; or <~:ixStl~?T~ttu.~.i~
i3~Ila~ii~.i3, ti~Ã(.` ~~2is3~,.;i~:~.F = si.:lf"a , ..; E.~:`,E. ~.~?..~t~:=.
3'^,,'}s,}5> .~~1t:F~lczie, or ,~,Ã?(?<YeÃ.ii~3. tÃiI3['I~rt~; or ~~ zt is
4s.l4l:i.i Z. ~ y3Ã?:: ~}C}>4 (~..}~,Zzci"EZ'
i zt , .-
HlycE}l). poly3o:hylSne t3tSf e; piy;,`'ffiydrfsxi.'i#.c_1d)) a: a,
pIC?Ãi`.Fi'1; a
ptF(yp:pddc, a#l ta,.lair'li:? acid, a I7tade?i acid, a #?uel~.'t'?tÃdo,, a
pol.,v:i7ut:la.,4}aÃdl:=, any DNA C}i
RNA :'sf:jmm<`nl', a lipid, :Ã..?3i<3ly4..icU..>itii"1d`~..'y an
;:1T:1tÃbd}dnr'. a phtin?le.=.s.'(::].tF.ccii iaz,zF.3iY or any
,
~.~13t1?:}'t' 3~~E a :Y`tt~ tZ~;;#C%tf. Ã#,?Ã::i;?Ã~.~'!"; or ~'~l; .1s
~iw~~lS~.k;~_L~i ~..'ti~:3~F~. among i3
33~'}~3~.f;9S.'i~~1';~~f;.~~$1~+'s.~3I%'. t3
A43..11c1l':y crt3sti?1#}ktible gi'i3tap: R,};z iS :se.~ctL-d f;'f"sm
l`i17.~3iIL, I'1, a siI<3ag .t i?i'
bn.in`i la:df.1kS.yr'l., Lyf;lo~ -kyE. aryl, o3.4fim, silyl, tilky35$ly4,
.}ryAsiAyi, alkZ'}:#F==y a.4+ii3ky3:, o.#.
ihwaoatoF~ cht.:n ol. 3 :?:F , atboÃis. L.ach tixkyl cyc.loalk .~ ar, Y.
:,akfin, sfly:, a1k~ sfly=;
lti ~lcll\~ _ ~' > ~. ~ ~.. ~`~, or ~~it.?ii:z:~:{.'~.'{?:a t'. aÃI~' wh Ãia';
.n?i ;Yc 4t
t~Ã.I'~ i~1`~ <#.~ti~:~'s.i ,~'~`~; ~aÃ'õ ~,i or
t<`,nmfnal.) bi` i?>3(.= i:Ã' ;n'lriÃ: h-.drL'r\ v h\d>o4yetbCr, t:?. b431yl<
G.t6m4e:ita;1',
a`?1.:1A Ã27E?i~:~ or ~i Sif~`~~~t:.~u~.tie~ i.$3.'}~.il-ll~:s. l.~aii~?.~v.
t~..`53S s1i.I [2 ~4i~.E Y ~,)a~Ãi4~+p..e.l`~.E`.;
phi3`,'~.pa`età ~ ~te, or hi3.li?g,.-i'.Ã'l zsub4filue31t.`i: x and y a1'o
ez3eli ?,,3dc-pe#?d:.=~~~y -scles..'.,.wa frfzÃ'1-Ã. an
i=',.1toLL?'L`rZ3f 2 '.5is, a is 5e3`i_:tited fr:'DÃl:l an i3}ti.gfeI of ~ 2-
5v b is *e ,eL=t[:d &o#}'. :,#. :atcg ~.i (fi4 I
14 c ?.a an integer of > -14: wEad i;i:l't:b pZ?l1 rIC.riE:. tl.#.na#:ial
,c.;`: #l Fp issel'+`C:t:;t3
fi-Orn an^o:~g aÃ^~~nc.w, thiols, amides, -~~~~~sphates, ,t:iphatz4,
liydso_~ide4, nn.mis, alkumc:<,.
` ~~ ~,ix~'=Y.
a.lkvÃie.`> and
6
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
3.iA aTif.?~~~~3c'.I' iaspi::v, ttai:~ dF,L'i=latityÃ:e :~~i'`~~:.t.li'es
f?l1gC?'I.:as.f>i Z?z ''~3t`lymnw k:a, or jp~:tf Ãions'
:br:a"<.itle, T'C.-pla.s,~nitisd b4 Y ol"#311dia .=`R~t~XVITT:
n~
~~
t= ` ~~v F , ~ 'f ` .f ~.; ' ~ `~.
'
~
4:.
XX~ VIR
Ii3 Siac3; t"slagox'..1i:3':i or paltn3c >õ Or pC3ilIitt1s fl'i(:.=r4d, Q is
:3I.e1f3ng 0, S. Sc. or NH;
F_'r is s::lC:L=t~.~r: t ~~# a i5 1~.~..~::~w.:~ ? `u`- f~'~?d.Z ~ ~ :e~~iC~~i
~ 'S' t~~
.~.: from ~:i~~#5i.iti% F.\~:,=
L#
1..y~-AVA:~b:i.V~Yl.t~d~~iy olefin, st~1 iy tiilk~') i[~~~~~~. aJ~~lst~Yy
=1~5~~ ai yl.
<1:'A.3lkyl, or fluorC`Lat'b%.'iti tflit33ll of 3-50 cil. lbona3 3v'In#:.3tflZ
R:ziL31 3tkyA. xy{'lt`;a3i.yl, w `;i,
~x~ y` ~ ~ ~ :i s r~
:31~.=fi'T1. ~Sisyl, a~i~',: sl,vi, xords:~#yls ;:l~,` ttl.~I~'a, ail `33.:hj
~, l, C3:.` ~~Li:y,}4..c#~`,~,:1 E~~tci`~t :s C3?3~a(+17~:z~,
subgiWtol iÃcWII l3.y or ldVanki:$lly by one or i:I3:CSic hydlIoxyl, h
(s.,<;xw ethos ..=i:ii`buxi`i,
cait?Crx'So"te ., i'ti3i'bt?xy.aTliidc, m11no, a.iliant,aw #1' d1
si.ibsiTtutod ,i.i~ifl".i3; thdÃ3l , .h;t?eSie: ,
he.3~$d?E , ~3 1?3~'; 334+ ;~~'a'33ti~~.~{F3i i~cl, or halogen
substiliu+::.riE5: or R is ;i%luewd l'I;oITl anlJ.Fig
p<ii E #.`t.~s~:Z lent, `;bynCil po.y(tthyle:il& oxide), pof 4
(bj%dIo?i.yr#c:d);, a c.'aTbo;1' d..;.te, a
~c
Fi7`+at6:ti, a ~~t , a.. a,`:'e t~?? ~J~. ~:=, .-, #.i amino acid, a p~A. C:
~`dI i~i{~ pt~-, a :i~..f; l ei~.l.~Ã:~. '<l ~i~,, ~ ~~ ~?; i..lw=`(? , ~I;
a.. tt.., t ` .o-'
~: ~
: ., r
D%A t3rR;ZvA,s:.>~'.t]^:~:C:i'ti, a lipid, a pt)ly4accha3ridC', .ki, antibody,
c1p}i:i?'I',?acÃ:`uÃ1cii:l tfrfi=1.l`c, ar
k ~ selected ir'
any ~.j):~,,;q:?.. .i3.t` a .3ii..x{)} ~ii::~l l~.=tii~~[~3f or ~ ~ ~f is
5t:la~.~..tC~il fr(3ili Ll;.~~t>l~i`~ s i_ ~t1 E i: A..~SG.~.~w=.
or ionically L:ios,fiinkab3:i:' goi.Ã.p; x and y i3Re cxi(t 1nCipoTiZ`i4FaLlti
sC;i+:cte5:1 fimm an idatt;gz:i
i:d 2 '"i: iistilb.c=:i:d 11:'i?I7` an integer of 1 8> and i sakli r2L;li.3li
z`7i ianI'xik:l ;ro 1i:p :s
tiolec`i+.d ft:7m t:Fia Z?:i;ts zir#,:it;"~~`~'. tl.~ii?iS, 't1~3~a.El+.::i. ~
Ya~af)s~~~':atL.s, l1`4 dTi.?.tit~.t: =~J,. metals,
=- r
;:1lka..tcs. iikcnt:s and s; nmcs.
7
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
a.iloffieI aspect, Ãi,e, invention feaÃu3'0s r;]lIgi3nnea's or pobri'az'Fs
having a ;`e.pi.':<1t
unit by F'C3Pi i`.'Lzi#. XX.
ax~~ _
xx
111 `laCl] 'o1#wor pi3.,~;=rT.Fi'=~s G i.?.clud('.s a first group Ãb''sat is
Q~(}3 n.'z' rt.ill:' to a si.`=::.s.'sild
6 t f`Cxafk3 <3s.tftfLfueià Ef'0f73 thL >iaSà ~;I`lyi3:~.;5 at a ~.}~. at or
bf'lLS,,% about 6.0, such <3J :3 0l4fw` abE?ta
1551 or 45' R is '; LieC:Ã:;d Sra a,nfa7ag hyd:`i:_}4?e:i, asà cafghi or
branched .2a H?,'`l,
~ ycloMiky= a=yl, AQW, sdiAw alkylsh)l, ar,lstr)l, a.l.kyl.atyl, arylaikya
ori:ut? :?i<skm
4hi1in 4>:' 1 }ei E.`:aT=.3C3a4. A.2ai::h cEl`,`L\!'# (.yC:Soialkyi, arV`fi.,
ol;,fi#. 4elyl, cE MgyI`'il?`a iy_.i-dyi.
:alky3a:,-Z.:l, drjlaiky~ or fl:#C,i'f;i,tlrbt?r, chain is os?iit.)13c1al',v
siEbst:.Ã4_aEad.Fnte_'F'Iliclly or ti:.3ET.`a,.l1's.~flZ'
by ceo :3r mCiri;~~~krrf,.f'}'x3 ~}~ carU"(1xyB, L:arb(rxyt:"'.:\tF.r, amifao~
rnwvlE}^ or i.s 6ti. tal ;mÃI,i(~> 1:1i:ol, ,j41[)C ii rq 1tlfi:stU.
phi}sphalC, ph<3sp'"i~i n z3ti:. E?.i.
a#:? itiEliL;lr.,-~; and Q f:= se.e`,ti.teLi fir+i1i`a"i :1Tr3i:111g 0. S, S4,
~31 ,Nll .
1.11 z.a$?,a"`>he 'saspf.4L, !.h5 fcawrt:5 pix ÃiC:lCs having a, fi1:Ã.
MCafnt: and.
fnc.liid1;;"", an L`,:.I`oniet' o.having {?a'pLyatiaif.it tL.p1 e5ef`.4ed.?y
'u:"Ãi ,.fla i:.~.:
F=~ ~
1.
tÃ#'? such pw l#.i;:1c4, (,"i ill"Aldes a ldr:it t-~.,,ioup ii1'c.: is
c(?.BlYwL'>`Ãa~."?l2:' frit ., second group diffoa e1iÃ
f'(? n Ãlle fiA ia n:f i`.up at 3 IA'A ia.f frl` bel?:9L3' about 6M, S.a.E,::
<`s bilo';'i c:bi3i3t 5.5Y 5Ø o.,~ 4.5} R??
is solt.cticl .zi:E=:3 among h,ydz;t)g+,::3;, a tiogy, or b1m1ched alkyl,
t,yci.tstaFk~'Yl,
siI}`, a;ky; _ yl., arylsilyl, Ldk;hwv). <~z~vtaIkyl. u:Ã- flworoLarb.>n
chair; of 1-5.; LFaabon:~-
::iliEyS t V:%3oa.i\y~`a Y.'4'l, Z.id~.'.=fin;s tijiyi'., al2' yF4:lyl,
aI'yll'iiÃyi, t3i.kyacarr ciry#a3La_z3_,or
h<<dt'o<<yl hydror. J .<=ffi.. `, ca:boxyI, c,i rbox; csÃer, c.Cz:
bo~xy:Ã.ftdo amino, i;'i{371o- or Ci.3-
8
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
:bs,itwe;d wnum, :~iiol, Ã1hicrosÃei=, sulfate, pAio,~p1:at.e~ ~~~~~sphfn.itc,
or
~
:iubst.ft',ic;.nf =+, aÃnd Q is 4elect`o~i frL3st7. ,ai"i7t1iig 0, S, Se, or
NE';.. Welm, the paz #.ict.; is pl<3f'.:,'f,
ir, an aMv.irOMInen: 11.:ving <i pat :.tt .}r below about 6-0$ the pi=..~~~~le
tt,cr..a.-,.;~ In vx.zlurne
:iv-m the fitsl vE`ll3#:14; to :.- s4=oii12d v~.~lita"1e tb:it is Ti-l(33"e
tlaan tv'o ti.Tm~ theifÃ"st
equiil.>..iut:? s :;~tabl}s`hed,
p(3hn?'1eric, .<.ihn, oa .z3il.z ,.iL~.G~ Lill fTi{~ilC~~' ci11S`
(}K1~>?F3`li:'.=:' or t i'.z' i~o~~`~>'~.~~C~i.~
h0vn'mil. In .toiiE`e+ L.~~\f2A~v4+=.T~.tx3e pLTly.tRi4;5ic particles
lllzlude Ifia>r 3=\*.'l1.i%!l~l.~T at i, fii=.t i}id, <zm?
a se.,oni; vo~urne at a s;.:ct~~id pH, d;:k?it ftt?m the fh~3::n tliw first PI-
1, For C'marnp1c. tli~:.
Vecz fi~ 4 `: vs,:3luiõii:;= i,* IX or mt?;C.' tlii#.n tilC: first r'oewhti.i3
ft%C,' SC,cs3nd pH' ,s i<)w-eE10 ~:'=i~.~ the fin'A a, :iiaL:h cls 4X or n-
,,%3i`c greater t1tal=3 Oh+.' ~:? S. ,=iti3uITa4Wi1:.a: th1 sec.s;~kd p3 a lS
' ':: ..' < c y~::: ~~s~: ~}
lt~vvQi ,~` ;~~::`i the first ~~f:[. or 3 ~X i~:', " ~:r~~r~: w7rt:.~itw.z~
than tIi~: ~:~itit v~~li.,:no ~ ,~s~~.ra. :~ s... ; I I
is lowt;;ri;le, }r,sT PH.
A13,~,' .i:n or pi3:I.1c.10 L=iii: lncll.tde a L]i.~ra:pC.Y.4tlc ci:joi1t,
For ex<3=3..?.e, fl1L. i#..wt.,.lt cii:o
bti= a b:zi;lo M;.c;.illy ...d,.tive agent oC?b3;1pmS;.3'1g one or I1St3i'e of
<I.n x,, i.Ãz.t, il:i~.,unt3'-
sf='~~`
tr i.lÃ'~,'i~~t r~<. .',`i~ Za.:l##:~ <?i a ial agent _. ~E15.,
15 :.~.C `~ l &; an. Lin.,;^'` .~~. A ~~Zi~.;i'~w; ~ = ei3r ~ YcrL=sIC%, an
t: ~ ~i'~:.z. ~. ^~3#~. z.=..
;3't?ua3d hu<l,ng.
For cm:aipxe: ta#e pi.#.il,cles `..il,.a b:: used ft:i` applying to one <S.I'
D'it3ru of .he
' C? r a si~~+s%~:t~l r,=se~.iii;i t,iai'g"~1~, (#l) S=i'Et~ilil.1 f.~ i or
i:~ilt.~.~=c3~~'Ã~ ,t:ai:if3f:
foffla.brl; t`; .
?~
i;iS r y i`a.la3 a tc3.t'~,'L. ~~Ã.tt.. .i~. Ci'.lse.iist: :ls~~~' ~~'t3iTe a
si.#.i;Ff..ncil ilicil"g+:1, :litd (is), a t.a node.
20 ~i ~~1. ~ ~:aS,:F~'.= fs or a~y i~iiZ:<`~:Ia ~ ,~ Y have one or i,iorC
l<i~z.
'~~tax 45:
~zi.~ ~~:u.~~~.. a ~.~`~~.i~tc:t~<r or 1Ã;ti:~ t~3.iri wE.}0 Ã1~~;~c>it~c;t~:'
sa ,t.~c ~~ as less '.:i:in
i?: 1.j'+;~ ti.~.~a ~.0Ã.1 i~;.'..i{Y;~i~#_t:t~.i'S. For C;:1"ti1] slt. tii~'
~:;if~E3~.=,,i~S ~,iiE` :i
2'> i ~~zi~`i<32] ~~..t.~.~ . ~ ,=
. ~:r
clIziI1i4t.Li 3fiF:.E'vve4xn abt?%a I num aa".i{2 2 'Tnicit+i3s.
Any of the particles [:L.: onb3.:d herein can be applied at a iF:it ~ite,
s.d...,,.~ as a
25 surgical 3 nui1"Ãõ~ii .i:.ix ~i~'i`~'.i~z are 5;.<~i.Ti'~7'.(a by the to
tl. ;*4.%.t3~'nf~ 43,4= Ã~ t_st"^.'i >?x]i of .~,L, first
si tL, slac:.7 _'t", a Nip.~1 I1ir(ac. hi zE,3dii it is deS$mbl i.`. thcit
t:he v,.1;t:4ks iha = Ga d1e.0110ze:'
f3f lLsk `ta"1kn about 250 r#il.i7:`..il'a4=ti,:rs.; such as less than 100
nummGEe?".A'i or e!=t ri less +t.ham 5:;
In moF_lto., <t;ipec.i., di:, iitkiontic.}ia ti:attrcy app1vim" any Jelhnn or
pmk.iu:c duJc2 ibeta
w~õ~ 1-w,ei''3 to a 43~; i1sxT4?gST:tllreS 4tap~~.c;+, aI1d./C#i' adIlesiveS,
''s:ii ,.:iio'h+ tI1C, 1i'AVet7.t:Cv" features applying any fist2'i or
qy:iF'tii k f1[;"w,il;Ud
{'~1
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Ili:=r`4'#.;. to t>t.`.iipa1n, ri~ to .iltu hecllÃng m.=.g , to avo1dSSwca2
fs)"`i1.i.tt.i2Il.
Un~ ss, ~:pLc?fic defiÃ.Ãfion`i are pi'i)', tdL,d, E. g, s?s,
aÃ'ii.FÃ.c.3Ee:..~~ below, th4.
':izme?;cht1..'c used in r:{3n.loC:to;.3 with, and tl]'l lkbC?r:itt:: Y
Pd't?'4..t..=itWC', and Io-,.i.l.a::qll,~S of,
's.nG=e; ti?;,.,=ii a,h(.;3F:ti.ry, i.?i13L,'~`'1t::Ã;7zsti'y> synthetic
i?:Ã'fwi3k!Ã~'v obCmÃ.:?f:#"4 u?'zd ,edii<.naE <1nd.
,>~~: art, In Ã~~~:?i ;i=`4:Iii that
i..~l~."i~~'_ ~.i~:'~L,r~i~::~a E1~'?'e.I3 are those known i?a
.,
flac3.. 'ss a LIrafA,~ t3f d + fi..1.:::L3.2s I#:3i tr,rms ltci'e.5r thosc In
th15 ti.'.t.t:i? n pre va`I.
>~_Lt.`t~~ 'I'of;?~. <l.i`#.ei'Ili? a3ct.s, and
As .:si ?d heiemq th~:. ? ab~..~rf`+;`icltil)ITS for any }. r p.i<4 _õt~ ~
ot` t:.=ennpound~s .;funless inÃ...~ilci1iW o:-hÃ..?z.1'1:'se, in accord
w_1tl ;}:Ãcià v<?mmnwFl ti:i go:
ii::t.ed t.ibi}i"1,.viati.~;c.sn or sh>'. ~Et,!PA1r"IUIBOxanni.ison. oi2
BeE.YL,honica.
1I'942-944 (197;~?).
C
r''3.:, ~.;~L~:C ileE:.iF:, Ã:4t; C)f the siea?g3E`tc':' hl4'.$2.d#:.~ tho
Pli:ic3l ..lezC sp`v'clfiu,_ll~'
A4 Fd`?.:d herein, "or" ~ilt ~f3~ 'i#Ã1C~: Cx~tr? Unlt?4s stWtcd
t`..h%=rwsc. ;'urtht.".F~~.li3z"e; u,c;c
of the ti%'run "including" `lr't fl as 4>ti3t:~Ã' fo.?38} such as
"1mliie.ies," i::i;.c
lirdfir:g:
A s used h.i;i?=i, the. terms "treating" or "[roxtiT34nf'
w'I1L`;Ã.?n'3'?,#s': cit.:~er t+l b?ll-i
3 es~.~3?3?itii~'a= 'm1l P#'.3pr1y9c$xiti .-i7ca4Ã;;.i"es,g., dev']gi16l
tt'31`ililbit, :0knv or E'.c oÃAs~er o~N
zI2piu:"f3.i#3 u.?.niScs:sv<?r iIist?#`dvÃ, z:t:hÃL. .vc a .ta:1 or
p,.itO:;..icEl;;i fiS'`:"i of i:~y;;',pZ;:2n1 C>:~
d'": ' s'~:~, ili~vt . i. to ~; $ie, ,a a:~i~.ÃL ~ ~lH+ "`fV. ~~ ~ ;Si:3, i:
Ã" L.~tÃS'i: a z~.4 .:~4a= or a~; ort~cA :?? ;~-~Ã`
.~.. a`;r~.: ~~; ' ~. t ~iz~%
its syn`#pEo?its.
:~I?~ ~f'z`Ct't~T..i~:ti?., of t~SL~ sõ~xl'i~;3[C#3i'i:s i:pfi- particular
d.sE`+z:t." i?
As used .i`,3oa~-.: :,,a b:
<7.d3....I2a`tnat:oÃzi. ol i3 particular t:.(?inapiZl.ind or
phaan1i1CousTL;.?l 4:rlyipi``r`atton refers to a3iv
Y Gi:., ~ie$w~.~:i., ~+ #? w7s~'f, SSi}4~'iIÃg %~ f l3 ( 5:~3 ~ tMÃL~;1, of
<3.Ei ?.1~:~1A
3~hS~;~f~~iw; of r'.~:i~`y delay . . . .
L.:
C
s~iI1g ~jr iI<3n`ii:ai~. t:'t>at c<:i:'3 be 'c.'`sÃ_,b't.ÃtC'zd ito or
3~'3:+..~\ s3L~I~ ~3i.`i.#s Ã}.~ tt:l:i~i~~Ll~.i`4, li]
z:s..o6:ete-.t s,.dini.}.iat..ti:ctii#n rii.-IdIS: oC3m}*.]o:1xT.d or
c`1.,9mpos.ibou.
`~'~6 As used E'1cÃ'e:n, :a1i' `;~i`t7..., ` s1:b`eCÃ" is a }ltii":1i.tn or an
aÃ"1.Ãmdl, f:) 3i.:li.ly c, n]anb31al,
<EaLi3 .a,~ i: cow, h'..~.Fn, dC t;~, Li.t,p1-, 4hE'~ep. monk-C:ys or
i:)tl1i:.i' lixb)iaEto.y or t.t?.I-nt:=st.S..iLiS:i.l
s `
sZ:~:i%~~1i1l. As k.~e`.',i~ ~.?E'a'vil~, ~.i. term "patient" ~ includes '`s'
bÃAXn':.i 'c-1..`. ::i3.~.21zi~. sub)4?s:'ts,,
{
As i.\od hi`,,''ciF3, .:tL' :eÃ`Ã?I i$:=firl's t] a compound thi!.t
fa:.Ili~~te:i :,11.0
.riC:uÃ`p+:?rat?f3:'#: of mitt`itf"' t'f3]?:ipi3-i3i1d Irlti? cells or
tissL7C:=s, For oxi~mpic, d?:nr.; h. i.
f~_~.is'~~~~~ is it:,{?T:i.3i i3?~l; used t~.?'3"~~=I' tbr li',3pT'CSZ?];f
~:"t4izÃÃ?)itt.3: if of t,~.; t~sà f.?'5.'.~l1?::
ci}?'3)po.il ds Lt,.i``s or fi:?s":#e5.
~ ~~
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
y i
As ~],:st =C~ '.,`.Z: tE'I1 ~`3~`'`><?:L'4L#t.i<;e`.il
iL{7`s~1~:3t~~;~a~Ff3:Fr:f refers t<7 a a{#f."f>3#?:.i'3.;
f:C?l]'iv<?i73]d or 5::Ã`1I1p3.?sit::<Jn i:F3p6bic of inducing a desired
;hc#"+:peut:c L..c:i:tsi{ tF:-'>:F.t~~mt.
wni3.hi i.:#7Ihi?f:xJ114i1t'~-r`, a p-hiFm7af'cf3t#L;:3l cC`?:3"1pC3FsÃtioÃr,
ci?nta]t::`, i3;t~ aC,i#vE: qgcx'ai, "O?fC:h #S
ffiFw i-ge;:ts flilF3t 3:{:i:ix'=.`ti t:w dE:sarr:,.f.: :hvfc{p'f-it2C:
e.f{C_ct. P}e .?harmL1w~&.al
0 can co1:tetFil ~a prodrug of the herf'i.{l, Ix3: ct.im3:1:
emb?da1c3+:'.F'tT's, a
'uhi3nmaf'.i:i3###;YFx if~ 3'~?~C`>~1`t~f lr LC3I?.~i11:I ^.I)i3L.+.F1tf'.=
tI1s.I'f"',dxC:fnr.t:;z s;;#s..b as, .:t3F L.xu{a?pley {.mhÃf:fs
and *~.xc.lpiunt:y.
As :,~wd he:i:i`r.'#, tht;li;m`t "thE~#".~.pC?ut?l%%'tl~~ ~f"Te<:;..vÃ;
i#.Falt#'i.#nt" l6as to .ka art"sE{t.23`Fi. of
a ph>z:533a ,~ ..~~ ~ ~~ ~~.I~:s,z cti~r#;"iI.t \ Z ~ ~*~.? {lE:.}ik3:.if.: a
:::f, '~s7if:i: S f~'i..~ r+; ?i.#{'#.:G: e'~.i:= r i~`
41~2{,, ~~ ;~fF~~.s~F<sY.~ f...
As f#`sedl, s eF"C'3'i# t13i`= tem, "~.~I':t3.?'#2'tai.vutct{.~ly
ai.'.cepfablf .efe*;:s f;;) a ~5oiÃ'z~ul<ItiF:Dii of
: f;i~t7~~i5:.i]t.~i i~3:F3. does not s1#rt1#~~4~>:1TFt~'~.~`
c`'~~~af)S.?c.#ti:= t"~?G ~~l#4>lf.~`si:`e{l .~ti.:t#S'#.i\', a
~~Fk.i 17.z%f C 3~3}?~i:l ziC:ilv 'v wad,=?# other properties of 0'lc
`~.'t:3Tt'#:pt3ii71d whi'.=Ã'i "hL so3'1-y:i?.Fl<1tzi'.Cx
cf3n1pi3::nd is tf` a 4:Il~jmt In t:ettdii.T oa"ibf?dii?1at;, a phs.3m 'lx{-
.e,.#..a4::ail`t
c.ica.tptablL fbmwlad4.'s3 F doc;3 >}ot cause s#~,~;ifican'e iFTit<li..-on to
a uFb eC;:
. .. . ~ ; .
r~y used ;?f~'+33.i?F~3~A::f;;2~tlt%CLItt.ull'1' acceptable derivatives
f'~~`i3 ~,:t5?:F?.~~;t.?F'1!~ 1#?c1#.1~:?v _,:;
axti not l#ll t < f~ `~ ..
õ ~: t.# 5, c~C:.f; t.stC:F`s.,
~ 't j;~ salts, asx~~.x~, f:~?#1. '3 eCh'.~.~:i, f:*~ZZ?3 "s. a $<aa.~s,
k~:::'i.. ' 2ls, 3t ~~~~?'~.F~~
r ~w '.
ai:'.ids, bases, solvi:te8, hy&,3ke`t, a'E~~YlaÃif'f#`:, or pr;,3dEftjgs,
t,tf,:a
.
S-iwh cif.fiwitve:: can be readily prwpatsd by t~~~~e of skill in tx?is arl
fisin~ x,?; min n?ut9.Fo;.~s
ffi:- such d,..~iv.btif.aa.-.+m~. The f:cainpoond.s pj(,,slucoP..d ca:i be
<~~~n-fim;;ferud to .F>.,:.naIs or
h# `.?i.tl:k 5>thikin Si1:l;ad,d:i1.:#x=il toxic i'~~f'c4t:i and either are
p}?#ir#:x<l.:=eutIcall~~~' a4tWG or . :;irf?
,?~?t3..~1~~. ~~~1 $1.15af 4F`3L`l:.?ti t.it',a:Qpt<1.?lf' salts 3t1t:lf1de;
but ilY"i; not :li':]Ãt4d to, t:nti.i'.aL S.?l>:<11
sv,,f .? aM bL.f n:v,HFf]'11ti;i e.o, 5:~-d:;ri.?pi;?;..a?nv, f:hPl3.tit.,
~;~` S~#~?411! S ; i i~FY ~:{At t+F:3 ?':?i~ .
i~l~`+~1 ?R ~>F~~f~ ~23i71x~t fi. Ls~~1 t`=tAi>t3{kl?.i#:i1~ ry~
\i.#2'imm"ES t, i3.4~htaFxo1:3#?3#Fac "iIFc.3 other
~`i?~.~~~=.S:tl?it.~?#Fz1F f., g~t';tc1i#?~. ~-'~~;:i3:1,~=z
}~}1f?Y~i',~~'2'~It1~?,#~Fa'. ~-F~3~1F<? ::~~~{3#`-,~"#L~Fif~.
f}1ok4Ylami?ls= and i;+fher altiyl#:mi w-`F, pip.F<--iZiFtf: and
illkah metal ':iS but :.3t?t ll#:i2EtEsi'- to lAtb""I:E.m,
poka-s"'#trii and 1t?d:ui]-iK %Fl[!w[b.in Z-wtii mwta( wl1w,1t.]., lf.tc7.t as
bNCnQ-it S{Eniil.f_, to bt].(`.{1:.#?i 44>.if-'#YFnn
and {71:Fa;T.i.;4.if{~Fa, .. 1.d-1:~#t#f?i`~ a31~.;::~~: .<1lfS. :aLi4.1'I.
as but #1(?t~. l..i?1.i.5:`,<> to :t;#.', .. ~~F.3~:i3 c?th `=s FT3oE.a;
Sk{>t:,.:
sF~,+s,~.'# ~ z$x but ` ^ t~ ~.i;=~t ~'= to sodium ttiT~~i~'C?#~~.# ~ Tr Z ~
~~Y..{,ti,? r t'~li$.<: and ? o .#.~ ~ i~ ~.~ FS..~ ~~ ~3:~Z~.~:r'~. also
~F;~t ..~.:~f~ eY, 'x~#`.-.tt~tl. `1 c3.i~~ #.i..t.
if?LWi.;:;1#;. bf;t not i{m#lfsfa t:?. S-.lt;, of 1'-rdi'1c.{t3.a c3:'l:ida,
~*`.s13Qh LIs b5.1ti3ot 1l1?'1#.trd to
;hy~LÃ"a~~:'z`F~f1F7t~.:k and .xili.3 s<1~t5 t~.~.f?i``~a:i7.tc acids, iu+i7
as but .,#ot l1mtsa:r. ::) 11
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
l:3ct:ates. Inals3 w6, tartrates, citrates, c14ivE5i'i3c3ti3ti, '`.'aucctTls.
tes. ~i e`, I c1::~S t'ale, a;v's ci:1C:~
fu_T+:m:i1tC:S, Ps3wirna:.Ei;:C'Eifii,:al9`v acceptable 4ators include, but
c`~..#'t: :1~.~t aÃT.".(2itiKdw, i:gktl, eifln.c,iyl.
alk`v:1yy 3, c `v:'yli '`i4tfi::oz3r' bly aTc1lk`v'l. 4~ t, "+~'. i.~k "*'
fi;3Eil,"E i ~'l t f.;;~r:iv.+ Cs~w.;~~,: ` `~:~if~:
~7C.~~i~f.v~'i?~#ii~+`3 i:~.~t,: ~?i:`~t{. ,. esters ~ <ai.x
groups, it ciudiiihj.; bu3.:niSt J:a.m,:t5.`d ti9, c~rbo,Xwyl1:c :lt.:id`?,
phosphoric acids, p }t,14c, 31PtiS
4:.dfCkni+:. acids, s&. fimai: acids and bs.?r;'}`.lIc acids. Pharmaceutically
ci4ceptai3,.L . '`~.'~i:.s3l QiI"i.::.'s,
1#.LlÃ.tek~ b1Ft i:Ãm rt3o": l117?3teci to, derivatives of foE'n.i'::#l'rl C
CZOR.r where R is ~3? ~='~ifog~.`Ii, L]lk;Y;,
>c.:r rwt ~\ >~ t ~ ~~{:....~SC?~.
;
cbt~tt.I,~`; i~;~`I?' aryl, }t~.::~>r~?>~~';i''l, cztf3lk'v, h`v~i:3't>aTs:l~~
.s*~~,> i'~~.l~ .~r ak1r .# <,i' ye: ~E>>~~.
~ , t
c~..e4t~tii::#le enol esters IIiL.iI#: , ;,?i#.Ã il.l't:
3?~)t2.#1..3.1~.5:=i~. tC?, ti~t.L~a~<iit~.v4~,`.~?a=..
P~?.O,.I#.~'1'e.~t..4ii t?4;.': :~lly i.1
;, r-mWa C -C(OC(O)R) wbx-e R ig hydrogen, alkyl, a1kenyl Ita~-)I,
heÃz:.r~>A1t7~11,
1i ~ > = `4';-' l~; ,~:,,.~, ~.tac. ,.`~`. ~ j i
~:~ ~.}~i:~~G~.~~:~`i; or 1c~~~~~.s~:~~;1~~;. :~'~r,~.~~~~[3
<~w~.:,.~~~~:t~.t~. ,>~~ wÃ'es
il;3d }1vd#.,..xeA are c,f3I:~~"' >3lt~:4:erof a i:=4,m?,pouT?d Wlth E?iri:,
or f.':'2S)-to4f?kv;le or w,.it:;=T mt..tl'':`.<;iF~C,a, ;iS
i.o about 100, or I to about 10, or one to about 2:t or -`, fiv^,li eÃ?
tt Alkk::;r :a? "<'3x#. >t31.?hafic hydiC?Cw1etxm FF.E>u"#;f wh,.:h. can bi
,.Si'.
a.z.#!'# ag, I i.i? about y`.3'+~a' ~~`~:t'bi?li atonas 1n the i:=hc, i11.,
w]d w1h.2E.h pI"i'.:#L. abli+ .`l, t%e
about 6 to about 50 'L'a1'~.'#t?Ã':ti iTi tt7e chain. ` Lt3wif.? alIfyl"
I'6er_7 to ;Ln atll:.' ` w,:'[3tlp having 1.
4i? Ilm"LIt 8 ci?R'bZ?.t# :1tiF11et, t" ftij?ca iilii\lee refe1' tC? :#t1,
at#kF ~# ti?up having about 10 to al;:>ut
carbon atoms. The .1kyl group mtl be optionally au`t'astimte,,J w=ith, m.% or
more alkyl
group s1,;m5fituunts W#.?;.d'i can be thÃ. S'L?nlk' or s#ffI,A'eI.:,
k}w,lcaf. "s.,3k4"l group ir3c~`a.1G.es x?nF.a7i?.'zI`a'l. } yt ^>o:S'La,
i.liki`x,`r', 'i'3:['ilE??a;.`, a.ki?l+3Li :lk~ltliai?.rZ.~thfi;t,
20 malkylo35.y. GErt-~.lky:i.F.ti[}> carboxy, nikoxyc#.3abt?nvl 'C3xv %',1ttE
t Lyi1tSalky-l i.bw=.if.; can b5:
t?p _io11:?.tly F;3sm;,'d along t:`e <3.lk;)''a chm3:i1 oI?.t:= %iI" more
3x4ra'e.., silicon, 3*:.~i1te`, i?-r
a~`
l~`,"+,.tiu# Z.,~ t #...~l5yes~..tWtt~.~23 # ' ? t'~.i~~x~:~y wherein
t~'#4?ii:tI~~~'~=d~ .naa 4 Ã-~".s~::L`tti~~i. { i.. ~ lf~t=5~~,.
ti\=F-iZi :-~~E ~5n~2~.~,',~~~ L~~s. 'Y L
ti;TF-
ala:yl, taBr3i3'ahL`dtt rLAC1` to an ilk4'3A gTi?1Ep in vwh]tih~ lowct akyl
`;r+.3L3~~~ s`alv..f:i as uactA`y l.
-, include
ithyl, or p'tt nyl. attached o a linear alkyl chain: :x4'1'npli]ri vmmps
m3..ffiyl, A`.'.ix?y.i.; i-prL?~~~.?'yL, n:'.bufyt ~~kftyl: n"'per#tyly
hepLyll, i;c yl. decyl, dode4yy.F.r vr#.i..SoJy.Fy
x g a..,:~ c?,.`'?t ., . . ,
.l~.~t~ .?~a..3~ ~.ibi3. or straight
~3.,~Lri:~iC~b o a` x s~ , ~rir, t~~'Zt~~ . ~ r~.. ~~~.# <~lkV'.[ groups
~#t.~.~..
,.~~a=~v 3.af..'C~3..S,.'i,~~i, ~-~ts~. v õ
~ ~~.~~ '~~~ 1 :~}
l 3, ~. i
ca~~~in.allky; gx.?La), ~ `a L.f 6 to ~ 50 ~:'{:~~?c?~~. and v:~~3 include the
lower .~lky` ~~,F. i. ~.
f~+~?%~~ ~~=F~ 3)~#y t.#lr z~?1~7 t %EE~ L'~ ib~"4`1~3~T:'s of if~~1CsL1~'.
1..' to 4r~.3(.1t 16 v:i~l`i:~,'.?`a.
1s.3l3iw'?ayl" re:var,I'4 to ,".l,Fa alkyl gr(x3'a3 ci7ntc'xli1in4.:.a~ least
i?T.?e R.ai'bt,I? E....`.'bo=3 di,fe,t?:e
.~~.c?nd: `l.':c a;:~,.~myl. grt+.~~~p can be opti.c:}iiully ;,mbsiituFt:.d
.3.i1ai oine or :-nore ;ak_4ri ,~;Aoup
12
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
si:~sfituenL-,~." a ,,,.cmp1,jy xitkenyI groups incitidc: vinyl, t1fly1, i.-
penten,,l, ~~cc,my3,
docleÃ.vriyl, ld-radec:t.d:tnyl, he~.st~adc.c-8-en=-l-yl. and hep.advc- 8.:
:Aak4'n'S r'c -,elk:e13 to ama ixlky`1 gt3up C;onai3:it1#.l"lg a i;.ubon
4.=zex`b<?n i:iple bf3...tS `he
yC3up i.<ln be (;ptio#:?ti;lly sFa~'.?vt3.t1tted with oriu or ;t7od-e
aLa.iiS`;. g`::ft31? ~=~S~1Lxi~:E~~h. <
zlkZils.; g
Erxemp1<3r: a:lkynyl g:~ours include efhy'nyl, pt'op<zr_gyl, a-pmit; tix:1,
dN<3nyx5 and
d;
.?E~C4..L~%~'ii +..~Sw~:E`a;, i$~.~k~`C!3''l groups ai1Glt~(~if.,~ ~}`=
lf}~4G1` i~i3k~raettl groups.
v = /
T;'+,:.lo";Ilkylr> 3'e rtõi'4 to a 31on-,`s?it,~mili.de mi?ni?, or
i23I1lficyw:1c i lt 3;i f':stC'r: of aE3o3:1E 4
to ~~boul 10 ,..:rbc3n aEoms. The cycloalky1 grckup, o4~~i bc :~~~~iont;ll~
pakba:;~y mmwair,xtcd>
Thi', t !'t:l2`c&.kyl group cm>. n s:i:?3:? optionally 4t.kbstit'.1teE.i with
an ilry: group stabstiti.iC:,i1t,
omfs .i'Ttd;ft3r 1,.k1'l'iic.. Representative mZ?i'!<?cyGl3c cy#':lt)eilkyl
ning4 l;i_,cl:adw Lvyi:.zi:2p..`'1ty;,
-L' t.~14x4 =_ t~,t -`:~a cy~ , .~`~.,l x~.~~ty'; '~,.si :11.l?~li~:fl:?~.L't
zJc c.'cl4s.~kyl rings i3'.iS..i.ide adzlrl3ilntv45
i:,E.a,3
octi2hyd,(Ei=?.a1li3131ZJI:~d.Vca""'ii]y cLx:,[}p"nÃii, S,lampha12e., and
iAotsaVC2.f'. -nmaly2.
-.``i.2yl?' ?C.f:+,'=d=s tt,? .xni1mn;t.it: cF.ibocy+.==ilc, radical
containing tibC?i#.t Sj to a:-xwr 10
E'r:nT.b#.}n aWan: I;3't'. E'try) group L.=aii Lil+ ~~~~~ionaxly 4~
bstiLuLt:C3. wiil2 linL i.1:y& g;roi>p
Y~,f L=ti7~{r'~'~.i i ~?~~~ si.'t~::'~bi` i..#w..~i.~L~:vS
1~. ~ } , ~ t ~ ~.~ c ~ixL. , sC3~.nY~.: or ~.~~~3 S~i.~:i~`L_.~t-.
~~f.tz~.3:=f:~ tLt3~~.i", ~
.~~i~i~.~ can
:ky.E 3l8en` 2 :1lk'i2yl4 31'{'>rl} arc~~kV, hyd:I=(:xy. AoxV, ai G'lo:'4:yx
aralkoxy, carboxy, .:fr(3y3
halo 'a>Lr\}+. tl'a.haiomeihyl< c5fbii(oy d.".~kox't'earbC:ny1, ai~~lo-
Nyeafbomyla.
i`Li:y, m4`K aicy?iu?l:11c). an3$`ai.#.rn;ni?; ci.3'~..?ui`[]:C]Yi=
:3:.ik'5lc:'FbamoyL C &;r1C.c: `i?ai ioyF, fS'fth1o.
it.~ky..ttist.` az~ yli;ne; and ..^ NRR`. wl1eT'C' R and WaF"c Z?C:b
c#:C} l, .3:l.~d ai adky: E?S.empl.:ry aryl gg"{_1ups include substituted or
u.:t~.:>l1bSthut...d phonyl .F:i~i
sWbs,aitiÃ:Ãed or un~~~ ~~~~~~~~od n.~~~~~thy1.
"<Yi.cZ.'::, õi.fLi4 :o aii T.'7upy b?b'l'1ciC;in alkyl is as pf;=Lvious.y
dw::iC:r#.i')ed=
ai:yl ;;romps cf?n1j.,yr.se alkyl of I to about 30 carbon atoniv. Exemp1a_q s
c:`s'j
4 t),#p e i?s.Jo i1"#:clI#.d.L- cfiL`,Z lCO'], pr43p+.1noy ,
2^mfi:dhylpfo})aIaZ?yl, bi.Etano'y5, a"iia. pah'n_it#,35,'"=
,f~.~ ` ~~~2a,~;; v) }` ) ry~~ ~ } x~= 9)~2S ~y~a t~ tc [\~ q ~ Y(`' ~}<
t~,`+;
~Z%.=i lii~L~.~~l11.t,'r t2ntYw"t4~`.-~ry.'k.~'- 4.~.rt)li Y
Y'4~.iS.6=L4+12:f1.~ Y~ 3~Lis ~.w~i. t,it.~ )'.'`tdY ~24s~'..1.a~:i.7.a
, 4i:mp~`ri. y aroyl ?4 ~i~ic=i~<~e ~3~'?~.IÃ~~'la and 1- and ..
t t;;
~! ;},!~23SZr ,~~1 C. ~~',..~.s .l 4~2}k~~l.. '" . ~_ p,~3'~~~.~i
~~1~.~:r~:z", alkyl is ~'~~r~;z'ic3:~s.y ~.~s~.aib4~.
,+.w ,.1''i~s.
.i :`c.ori3plarZ ,a.?,kovy' grE?i.lps- ÃI].cIL3iic nwIlhu-3.Z;~ ot'd7oxS`. F,,-
pFopi?xyq i-pÃ`opZ??;:.s, i"? bi7:i.?A1%, a#.~[3
;10~:t<3x s<.
' Arz loxi F` ~c;t-Qrs to an, aryl-0- t:r.3iip, whei-e::n tlic aryl ;~;~~LZu s
is ws ;slvv3fft~~ly
dcs;:nbed. E:.~~in:~lar; aryloxy gro-La7.)5 -includo pher:czxy x-id naphihoxy.
13
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
At.ky1Ã'bk't3'z F.'6c:'s ti, an alkyl-S")- group, whs:;I'..'Itd al.`h'.y3 is
as previously described.
Exemplary al.?~ylthxo, gÃo-u-p4 iriclzÃdc iiiot1iyltliiu ea~lyi~~~io, ~
~rop';=t.~io; and hivy:ul?ic3.
~t''M tis_a?f` 1'cf:.'i's to an a:4:=l--`*-- group, w1lerc1:: the a:1 e'.
gt'i3tap is as PreYit?:.#44y
dL;sc::bed. Exemplary <li'y?th S3 c._%i'oqt3s ?.i1c;.u~e t~~ic-iiyx NC>,;:n#.:
z3a-j?li hy.thÃiE,
AIsllk`u t':#`oNs to awaibiilk>p'! `?=ls`_?~t,"?_W ~.xf%h:dL:i~: i~;~~`3 and
.:lF i. aF4,: as prC v-toi3ti3y
s_i:esc:ribs,d. Exctnplary, t?nal.%.~~l .-~.~:~~?~ ztt:,~u~I~:1~~,Ã~.zt']t
~?liG-t~y~.~.~.~k'l. zi~'i~.~ . i~t-~~~tr~.yIt`~i~Ã}x~:'l.
AAalky,omy` rcf.wrs to an :ri,.1ky: 0-=-= group, wher~~~ii t1he w-a`ky; g:oyÃp
is as
prL.vli::u,s..y (Imsa:..~ib1^`.d, An i':Y.E}Ia:plzt.YS' aTillkyl<7Yt\% group
is bef7:'y1oxv4'.
ie:{ors W tit: arid1kyl==S.,.- f?'f~)q)y vhc..ewn the Leuro4i}RAsLSri
p:t;t'ÃZaus.y de?sLi`Tbed. An 4u:YC.113plc."y aralkylthio gd:}Lip is y?eÃ
?:yllmft3.
r Di.3lk4lC1.rn:no" !.er':i'.Ã`s to F.2i ' N3\1\' group, w_?ier:tà of R
t3.nii. R i"s
indepondor~~ly aÃi alkyl group as prei=iousI ; dea~ilibed. Exen =3la~~y al,. v
lw.uini:< gr.>ujps
inclade ;~:~d d'iet?:lzÃmino:
,,Pdkoxyct~~bony." reItrs tU a.n a~klyl-O__Ct:;Ã.... group. aI .oxycarbz?n;=l
'15 (g{r4tp4 itiUhudl'~. a'rwfh[3xycai'bi?nA 4ffioxYCaÃ'ba1nyl, bF
t?'lÃ?xycarbow f and t-
<
A>I3+~"tiyi~i~"bi~Ã;,`~~;ts refers t~.) `t#.Ii ~.I. ~'l-~~ ~~~:~- group. ..
Zr ~,: b
goups is z.ludle p}:enox:.r wad naphth<:.z:tyre:zÃrboÃ=lyl.
AF`il~kox,f.:=aibC3nYl' refers to a31 :~ra iYc:y~-O '~'l-~ ggrouk~p. An.
f:ktim}YFaiy
wralko;kye,arb,snyi gomup is 'he~'~azy1tAxyi:.azboT1yl.
"ti'[I~lmnloy1 " r;.1eri to an I[ .NWrCO-e gye>~~p=
" 'Jik}q'l{va~'fF1L=~~tl7Zs== '-et~'+r:`i'~i) ~.t F"r=:'~~!V^'^~~~~~
~T:'Cia~.~'4, `'a~.Crtia.:i~. t.i~.t+ ~3~. .~ and :'ci is
à and 3.~~-:_>~c~~ and Ã~~c.~, :>ÃAa..~= f~'Ã'R a:~c: R' is filk~ l a4
Pte}='iousl,= de;;crÃbetl
Ãeiers. to R-'RN--CO-- g~~wp, whemAt~ ~~~ch of R w`td Wis
ind~.~~~emi.~~~~ ly alkyl as ;z~reviz3iÃ;,d3 descifibezl.
>s A4ylt;:~y` res43t`:i to at'k acyl 0 grmlp, .xI1eE'ciÃ"P acyl isas "3.
e~'2~`E~},,~3' t~ai'.=SUIfb~.~E,
,
Sf Aic)'l(Wmfi,.oõ r4.lfVY~,~ boill..2 ck.t;yl NI`3.=.=` group, whe3.4'S.~~w
a4yl is 4~~p.1.`=e ~wi1.`y'+ty
ta~so-ribed,
:A>.o:}'..e.#.~~nÃnf? I6essi.o an aIoy:-N-J'1.. g(,) tFp, vvherC n aroyl is
as, pf.c-v&+:?uslZ'
d:;sc-rÃ~~fed.
14
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
A:kf`le:`3ao c x+~fQ~.s to zl s¾i'a1-:ilt or branched s¾3h'alGnt aliphatic
ll3 i~;:' ~.~~~?Z?:i g~'f?i.-Ip
,
tsZ?.31 : if, about ;.s~? carbon MCims. tIxhe aa~.'ylo33e g:'f)up can bt.
5u"t:7`i.}.,hr, br:...3L=hi;=+.i,
or f..yi:lii;;, '1135.'. .3 Hk~Jene ~""ioLlp '~,`i3I? ht~: also C?pt7:t3nwflly
1.11.>c3wir<.[tod w:ai(3 or substituted w7.m
01W OIr liltir4 ~~a:#k?y'l iIlx~~~e cilll. be opg:t%?I3ally 1_nS~.:B'WEi :
kmti :i1e
3Ikys.:,ii~= group f;:'ie or :n. : ~? i=~1 s?.tlphu:-, or su}DsÃ-Ailkef: or
:.ansub ÃAt#.?wd nitr t~~in
atoms. w~~~rc:i,: rhc. substiÃ-,writ is tx[kvi as prev:v~~~~y dG.sc-tibei:.
Ez>.:.J:11plary
alk , k aw g~i.':sps .#1L-ilEi2c $21f;thi'`Ln' f'lh;.`l`s,:i,iu (-..Cl+ CH{i
), p: t 2ylen:```.
WI E..:r:? " ~ G~Z c:is ~~+.'.X'S':~i.=.+#'`~ ~." ~~r,~`F4fi ,_~~~ ~~~. ~3.'--
~~_~ ~ -~::; ~ ~;.F i." t.*:.E~e ~u~k'3, ~.{S~:F.?..~, _...
f0 `+`t~(Ctfl wbwi,f=m n is m'I lnt1..wfF:r ftom iibi?ut. I to about 50 ianfi
n .>w an iz'.v .~ IRX~I
0 to <3b(? 1t'SOwl":eÃ`l..iIl each :sf '33': wn'=.~. Ii `. 2#+fe4~.'. a3C~~=Ã
;~~' L~1E
:.i~~cgi: from , to b:uk. 50 and R is l~.`~r'd~~?geÃz or all~ys, trtf ~1:~
1c.~~:.~:~~~xy
~1lat f:fllyaehnCi>iC}xt ~? 0..... ). AF3 ilikylE'.ne ;.T,.rt~"e.ip haL`f.
about 2 tC? ~M:33?m 3
ciA 'Don12Comsai14S oYiii fC{.nhor have 6-50 +ruboSdS.' 13z3i.^.' or :
hrlai&i' T# ci: to I311:3r1de, chlor1Lz[;', b?';3n1adc, or li)t.lck~,
The t+,'3-ni t a; fe#.?trr .#1:'f.,ll`a~acS w3thC3Ãlf. lim#~ afiC};t1,
1~`a~=i~:eC ilE~]i fl:~= ~ , .z~a311 a~, mi'mi'i3l
`upplC'ment +..Sub'..=iancC.4 ti4ed 'fc?':' the trf:.'atin'~G'" a..'~t,
~..)rLa-v'o' .tion, iiiaMno'?if',,crtra or nait.~~a~i
~.s.~~a.~ ~ffe4t. [tte 4tr11cE0.rs: or A`LIIiL`tiÃ:iTI of the body, or p?'(t..
of f.lwilw or ffi"~LsS, substances .
t>iu~. ~;s.wa11t,:i i sQco.i7:tL, b1{?:C`,gic:~~ly active i3r:t13f?re ai,'Ãi-
vC. Af[et t teyhaI'e bef.r p4af,t/d i::3 a
p}3'LP.Iite:ii'#?n,p=d phy\:iS,rlo-.~.Ca.[ CII.G'Erf?m-l?.L=nt.20 A tNo:be,.t-
.'v"', :lt,~,Ie't3t" rt..fi:.~rs to <li1 agent ti'ii.~.t is c~sl~.?abic f?f
c:?::cI daxo a biolo:.?IL;:.Il
GffG+:e.Tit vitro andior in l=`tS'o, -11'xc 'x3#i3i.of.?iS:=al eflCrci can be
M As t3s-C'd
herein, rf=fLrs it?so tf? a StAb;~ta1#:4~ that is lv~wd in cC?i3-r#cfi=t.t7Ã~
~vith `um
i~:~l~Ã.~'.8'~.f#, ti.:ii:}~+ l~'s$ ~a~. `~'~.4Ãõ3;.:4 f}.i
appl.lcilt z>t3>"# t. `.3fif~,t~:3`s't,~. ~~i in g nature, 4IE~:li e~ tz in
~?~ i ~ ~'-
~:F3~ is Z~
iEbm4=1wa' of a d.ESLa-so i#.i a ;.?'Lii;nt. Iõt7c bit};?.E`~ive zlgs?ncs, can
bE:'tie1:t?'i4z or pos# ,lvf~ y or
a.~ S= w3:s~~'~~~:i. ..:Z tlc ~~. ~.~ ' Fi~;~I1~ y~13~.'.:'i i3
.c ~+ ~~v~ ~i~~l'~=~ 't4k.Cuiti3ble '?1L.?%1Ct1-v+`.'. ag~ ~v~ 1. i(=~~.#:e<:
I`~
dlu;zs, cells, g:zscs and h`a :=Z?us prec~3isoi s { e;~., ~~ ~r ~#1t~~~~'1 4
Z?: ÃV?.3.~?3:= i~2: .i' . t~E t,
3`lloia;sT.F 4...n<'..'v':iT L'.s, growth fi1.E:toT'S, vitamins, 5tfro1ds:;
pf?lyanio`".y, mtidc? dC:S,
Ã3..#clS:otdt,ti, poka]uGlE.#)l-lfaes, 3nG Z`i,:ig:'tf.}4.1.c awe37.t;t,
`Ea.ci] as contrast agents tf`>r use ?!'>
ct,`>~n.t::tAlf3.i1. 4'w?ill magI?Ud<. = ri:ii?3a3'.it:c ;.mag1'ng',
uitTa4t`i.S.i1Cl, poS1t~.rL3r? 'tl]i5:^'.:f9.i
30 tf; apht , :.:Ã.Jf:i7putid ial nf`>gpph~', or other imaging :-noC .il3ty of
a pttf
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
"G[:31ctit i1:>3it 3'If3ls i.3w`x~E f ~ ~;~t:I2~:ri~llÃ% it?
#':~C3C.~l~.tit.L~t,.;~ 'c3x7~.~ ~~C?~.~'~,f2f.~.L.~~;,t?v,.=t ~Y
tie53x'1'#.;.bi3nuo3czc acid (DNAi :!?`tdi'ibt?i3.Lfi:lo1L~ c`-'~.ciCi (RNA
Ti3G lryf :E? <...tft i.l'lc#~t i'~c#2 cCIIi be
z;ii7ta'~.a by f`i?iotTc :heA`tF.c:3? ,{Ii.t`thf_ 3d'L~logy known to tia?.e
of ordinary skill in the art, or b4
~~iL I t of recombinant te+,..l1txoloÃzyj or by a tt?iTl~')f.Tlat.lof.i of the
,w4,s. Thw :I,NA <1:3d RNA
i:;'asi opt3Ã3.f'f<31lc+ ::07171prfS..= :.#?,111attirxil I]i!4=leofideS
f1.11d. can bC >"It:gIc ordaLFble4t3x3TiÃled.
<Genctic nulti> ia.l" z'i:.fers a1,o to sense ax?d anÃi..Se~~~e D1\1A. and
IP'NA; t:~a> :~,, a nu.:l-e;~?Ãi&
sequef..4=e ffi{.dS: vumplement~e~ryio Gf `peci-fifa sequeni':e of
aucFeoiidesin.DN; A wici.ll?i'
RNA.
The -vohme.`s pI'ci'r'f.d`a'(I hf_'#'e'C,ii. C:an bi:~tti:f3ii
'4G'di.h''u'aape .t.Le.fl~ and:E./L`.}.
For C-xam~~le; thc, poiy?'tien- in any:~orm described hor~:;iii can bca .a,e,t
#o pro#:aoie healing
and/or tFel.. #3-.fh#I73t disCi.je by t'c~.t'~.~x,,o:7i'Eg tIri.fg dt.'~lit
s.ry t*.:1 tt?LWE] e.fF..d f'e<';,tC?Ilt:l caA4;.'Rs. 17ht:
polymers hprL)vI3a`ei`3 hi.s4'h..i.:~a1'.2 also i3e used R)ra wifietV
t3Aai`,lpifL.`t;::ff)f'?s .i;fiQ i.f.3la'f..''`. bLZtnot
li3'Ih4t'.d tt}. :izi?di.,c:1t}n of []:iicY'i)- '3:#1d 1?ai1CiPPuatcle.s,
fihmv, i:.Ã?aiiug`, sf.1t.:e7, and
f:F'thi;pcL1aL :liai.k.r.t;is. S :Ic}i materials kat'f, be used to i`i~~pa;f`
<lt? f. ~jui't.d ;},'ga.i,, b(3:w.
;
i35 tl,i> ?~is4S +..t.~~:~Ã,3.'.= ~'~i3i~=~i??,f<=~'S
pitiZ~y~~'~:.f.~?~s;Ãc:.itl .:1w.z Lido ti:`c.t.'iicai: of 4i.t"l y.
:~
lf... or i1? .'.Z`;kmgly;.>eGe":;d In<llxgi'3aÃ..a.Ãi`s; p:eÃiz:awni:,nt of
mcllignatif'-t~s, or ot:"i:.Ã' :=t)aldildiia
as . Se:]sit..>.'.e:` ti? <1:i1.g3a]e#?: thE:napy of fiItxl`t''m''li.t`
x$4;Lnt atlcl-i as wit.I,#"u~+1..~1i>:1 rt 11,.1~1FC i'~>
avoidance of lt,?Ltf3 :w. Ãt71ii3l t1l`?d:'.= :F:fid.tastis`4=s. Ã$ug?,2-
w:1li3t1o3'T ?f local ,w.EFaE.: .3. c.~.l',:3g
and dd".(.'re<-f3e.ki. Piif~.-`c1.?;;n. ?1#ii.il#pulc;titrn E?f5tru4"t1.f3~..'
aTlct :'6b.7.E}i'1'Iial. se$r foi'.,`.:=at;t#ii. ;1F:43 fCiI=
2,~.,~`r NV tmifvElicait of pC?st"(Yp~.zil.ta re Pai2'f. 111 {,5,.:tc ii`.1
s`:mbotiiiiZ+::,i1.ts., .ti ' 3;?vE#eLx:
i7ef..it? :]t't, tawz to treat t;tizi'3cet'. .`ift` t':ifii3:'Iple, ti1G Pt-
?v27i,ov4 provided ht:t'eii`_ Qcifi bt. i.f;,,c:': to
~rf,at i';:i'.s,l`i.iy s'3~,o`~,~'~f.gnbiT...`fe_dy i'..g, lung, colon,
prf3sifite; pe]n,ca<'..5, or bteastU..Iit,S.:t'= Fo:."
+'.:Y.iai=Fi4`h'. :'.a3el2 #.i filf'i3. carrying i^rIiU o1".i2?f?Ii
flief'api=usic a"CiIta is i.7t1liZeC' E+.t.'f:.'~t ,, L>iYiee::`.
it oan bV iltiaplt`.\T.C ~9'`r[tLir'k_=dS:[2.kl.Of. glued in j.+laLe. e.g_
with 4Stvy.1fou1.+[yl att r4s2[Y..
'F_:e po`3,i'wi'S provided 'h#:`fi;il'l t;ail also be used to {e.i e o:"
w.;.''4' age:I... Tho agL=11``:
4 3#` be in any p1ha#.me:liõouti1:i1liy i;,e4.:cpt's.:C)lQ. J~,=4
lF=elf.fd`:i1g, w'rC ep:.<3ble
st3l J. A la e(; .t.f..-bf., of Ph,..;".'f'i1acLu:1.c.3a agonts are k`?Z3w{:i
in tbe ait e.tid <iy:.' ilil:lena~."+ak; i<?r
~
3;.fs~:= &I1 tlis,_ Pl,:.za-t?.<7.c::i:9l.U;:l c4?#'`.1P+.`~?id3at` t`3fq,,e
pol4'1"i3'Y;=i.c li1ata..Ail.i described hC'rC'.3m
Acceptable agents include, but ari Eif1t 11i7'i:Ybi'.d to,
4hemt?{he'apow,r:(..t`ef.t_, .:Ãrch a:+
f'>ldIiJsS'.=ns.tiif;`r4, ie''.f:~~~tor Mh1b.'iO1s and a,t~01.:3i~ .lt: t;
Iz#lt7:ian<.
~
:~i~?tjsul'si'f~zi i and ~i:t~izict i'~ iiM:l?~iS, as C4fE~Ihlili ,,
;~~{3~*~'~a ~~1.t)i'>5 or ?:<'Ã~~>CIi ~,ViL~f <,i'
1.Ã?
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
without the co-inC3;3Ipt3, aIok~ of tumor or pathogen t1t1t-i-gG'nFi to
zF'#.i,',recFsL tlaa tlF1.t,-;1vi7ph3st.10
response o..1 a Ãnewi:i of vacE:F.?<= devC.lt3.llmC'F3.t., IC;+L;a.1.l
c.#.Ili,.8tbC;di: aE?#::nt,a, an~ib.,t>Ii`v:'s, tÃ"'
a3,.EaleFi.= <iL3ds as c? niG4F?S of lc.3;,a~ ge1:ie 131eF`i1py,
thllt.~~s od.eni iSe dS.'.fFÃieds o L?. . as abova:, all tC.'~~,lhn:O%il "Fnd
` .t.Ãf#i.':L. terFa:s used
1-wF'i :FF `ilat e. `^-ii s.3mi: Ã?ci$ii i11g as Ct3IT1.iF.7otlly understood
by f3iw of S3T"dfF':i~li `r skill in .i"Fi:: a1~'T.
Ii"? i~'hicb z,:là n 3:nZ eT:=1wn b0o 3g3. Although methi)ds wad
.`:1ax,.=rAi:Fl`:+ NÃ.mffl.:P_d' or k.qi.:ivc..YIEa=.t, tf's
. Y=~ a be ~='~z., C al~. the a > r' .fi t~ ~ the a' ;fia. .?~: i::ÃA ~ aÃÃ<
those z~~:~t~F`Ã~i#E~Z~ :`3~F`::1, can ~?~ E1Si;~ ~i~:',~I~~. *,~~FI2~; i3.
,:~.t~-s;~~.l...~a',
~# . zi})`e methods w1d materials are described below, AU pa:?F1{vat#Ã?Ã S.
patent
iappl.FC;:itlÃ'+Ã,~, pat>.3=it:^s and t7th[ Ã' references m','li:tloI7cti.
Fi'FZ:i`a:Fn ..Fm= #rii..oF,~.~i}'.cltL.d by ..L :(.'=a"~C>.nc*w=
?1-3 their L.ÃFi ai`.~ty -undess noted ot3 C'.F :vlsv, tFl case of
i:3:Ifl7G>t? the i:'usint s`t~~tiSõ'.lfficalio`a`f,
fflc.udF3t,`, i i%fimF#.5ons, will Lo$3tÃ's.)3. Fn addition, the I7.latcÃi<.F
y.."Ãt.hoL%s. and .;}isa""ip4es
on1h' and m~~ intended Ii) bi: IiF l11n:;.
~~ .Ie:S;` la io=F1Z.e is i:i.c3E~.~t`:= to a URL or other suLll ldenfiÃ.ier
or iFddrcss. it
;.#Tld#. .F'Sw(?d f-a3:3~ suf h #deF:ti':1t Fc`,. can change iln.d
paFTt.cE3:aF' #:nxt? Int:.tFoIi on tl}o #.-'}.ti:Ãn;t.t. c:aF:3
i),, btiE i;qui= t:lcÃ_t:. F: FfS3nF7F3.tir3n can be R) iFÃ3d b-',
s4a.itrblrt"3r: tl3c
oF?3c and
~~efe1'"a Ã~~#:cc. thordez u~~='~#.i3e.F1i.:eti the availability and pLibl3t
4'.el.ssi'=Ã11Ãlti'::FoF
Fi R?rn.la`Ft?;:;.
tiL'E1nknui:Ci can be t7s`.=.~~ doi L~3iaFFIÃE:F~: "'zp:Fd-ww.,,
c:F'zi.:F2i:C>%Fl ctÃt'k:'i`i.':>,
phvF?'Iat3.+'..i..Ft.t_,.a, 2TI'vpi.#.Fi.1t#.o1, formulation &n.d delivery,
:#.Ãed, x1'i.c3t'.1`#ei3t :o-I= s-.tbj+.cts.
Standard :.o?:.:?~"#:F;.ÃqL#i.:s L.ctÃ: :: .FsotF -fi3r ii;=coTY1b3.F"#.<:=`o-
:i. ''s~NA, t1~~Ãr.3Ã.EFI~:i<3~ 1+ 4' .?fl3.i.'9 a, and
(Issu :` C1.#l.u3"e ;iI2d OL=ct3C:tpCk3"c``: ..Ff?" R4:i i a.i}.Fls and
Elu3`IficeA:Fon fci:=hnÃq`i.Fes cwi be pC3itbr%]'t`~.'l, t ,., using kits
a{,',cv;di;EaÃY to :E:i3sF..#fat':'F.R.Ff.F'~.'
" s ~C.'+,.:F~;~cf~,a~1:`s or c3:i i',=(~.I~'1I133:Ti~' FIC:n,'.oF~i~.~9]
ÃS~'~i'=C% 7]1 i`Ã~5,5 :a or as described herein. ~~Yhe
foregoing techniques :1.id prCr.edlll t..`i ;"f.-'.='I2'LL .'alt\' are
pe'fi3:7':r.ed zI.".:QC} d1;.a;:. to ct;IYvi.`.Ã"#hoÃFk.:3
mett,ods well 'known. in the ut aiid as described in various >,õerieF`a: axd
moÃ.. specific
1'cfGIvÃzi i^thw are cited and dF4i=Ee3'wd ihT()u ~?i4~iC=7:t ~3E i l~t 4
a:l?)..?. S'i '.g.
Swmbrook F.t F: , Molecular Clonangt A Laboratory M;wual (2~.i e,]. Cold
Sp.ÃFig Ha.F~boÃ'
Laboratory Pross, Cold Spr;iig Harbor, N.Y. (1989).
Other :uatt:#res an~d advantar;4s. of the ~n.vc;n#i:r,<: will bc: appa:c..~:
from Ohe
~~ following da;:,led wid ftom the clai:iris.
~ "f:,
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
BRIEF FIGU RE DESCRU"11O'~
FIG. 1. is.: :xa.' ~;~=~~~~~:~ ::~~<.~~~~i~~Yw t1~:~. ntÃiiib~.r of
~:~~.lIs..~t;:cr 4r~:~Ã~tyi?~:1?: vv#t~~ Ã)--
iyd#Z??%' c3"Ã#pti;tht i-Ãi3 loaded fi%:i71s, control fili?tS Svit'It3it ~
i.i i7`ri~Ã`i:3:S yC it:I?~~ J. ?4.ii1. ~~i:
~ IG. ~,' is a bzir graph shmving the nur:~bei o1"cclis Ã;eat.-~icritw:fli 1Ã3-
cfaded aihns, i;c3n.tz'f?1 ffiltnti witffiowt 10-hyd::oxvamp#othec~r,.
b'hm~.ik
a~l#?~~s, wic~. ,~~--h,~~~oxyc<3:uptotla
FIG. 3 is a >3ar sÃz1px# Sz?cm-ing ehe cyl+_](E=:gxi.C.ity of
a?E`?ly(`'a.~i:cÃ,~l f:=(? L.p:";31..sclo;ieI
111G 4 ik .i :)cir gÃ`a.q~)}1 haiii.]~A."1#3g ti?.c cytt'~toxÃ4ity of
nulnE>iluti+.-.C,` vv?ffi 10% paclitaxel.
FIG. 5 i:... bar ~,'~rap}i :=hi>wÃ~~~ the c~~tot:oxii:ity of poa~Q.l~sw>
iui?'Ã4]pi.:F"t2LlL's, W11,11 P~`ES ri.:fylati3Xt3l.
~ . ~. ;5 is a ~~i',3q?x? 4x]Etfi #1 g the release of
10~}p5'E~;t?hyi~c?#2;~3:i?~?#~.1Ã:
Iv 'p3J3yilau1 u. myÃ'Ã>itÃo, p$lmitac, or stearic ms,LcZ.=wl
1~1(_3. .77 .,a a ~i't1~3}l S}lOlWÃrlg _0-
hyiitCt:tiLYf:'mTttAollacc:nti,lw<Isi:= flt?n] poi.S{tite;1.rii=
gftlc>ol "A~`i.?:iT:es on pS.YiE.ari:muÃi.i "itrIps.
~ IGS, 8ai. and `~3'B, t1T:. '3+,:u1di.37g clectI'liÃ"~a m.t;ri}g.iph5 of I
lti~ded poly{st4a:ii, glx cea'.?l TF1G. 8A u1,ow-. Ãil~~
sug ~~~c:.~~ of the fi.m {su~le bL}r 3 -rniw:rc?vs), and 1`1G, SB shows ffic
fiAl:~~ in
(sccile :.3<`*i^ - I Oi3iAi. t'i3mS):
Ã'iijs:i ;drit3wt?g IvarbiE+le .`iwr^llÃFig 'si;.L wlai<,:3'uS pl-P:e.
h I\ , 9 i$: g
1 5G:10 is a gmphs}?l?wSng Si.ie do].TA~'L]'~~.'i~tY~.~l~.[ \}bsi.3..4~+.~..~
l)\t .v~7.4\~a [.fC>51.'~+ C.~7i~.ihy *t _ Ct
E~. i~ . v .s 1..~E:ckÃ~". :"viõ]~'`jy -at a ~Z t~~ 4a.S..'i~iss4'tA] S`.]a
?~12 t~~].
.
~~.` }' IG, l I is , "'zarm:,ng 41ectÃ;?n mac.raasc;?p<' (SA" M) of
FIG. 12 3.<? g?"ap of the d3.i.li2wtu of st,#:9i`~I' derived TnEÃ"o4phci'i==4
at viu'Ã.#:3uJ r:3ll:?;
Ã"aG . L? is it bc3Ã' g3'~pla 4i-if1wiJlg ti.#AI?or rttt]lÃ,121iC: in
2'^t'=.4'pon;iO ti? th#:;':I.oÃh41`F#.py-.
?otWkA 11z1110piia ].clf':5.
FIG, 14 is c3 beÃr z>'si`'~3,:1 Sl3t?w]I:g i'i1LC'i:#r Li"tlE1m- in response
Ii3 .si:ia]4Ã.a cs#`aci]us
2zoryri,c: ~~lm Ãn]p`,;yirttalion.
is
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
FIG. 15 t` iz R,3tiir gmph showing tlt<. percentage of hum1 s,.sps;3T.isG=
Ti7
;i? ad::f:i R04-1('PT aand uffle.?aded fil:~~?s.
k?:3~' '~il~>rh s~'a)~1'~Tl'~ G aa7~:L'caIICC1` activity of riiEa.l ~`s~: l I
.ra<$<>`~
~ I Ci. 16 ,4
c.. ~ ~ } r ,.
pa.;tc:os wzffi UrC (lun F ieinwGÃ') GC7al,? 'L'3.I'T'i).
nr3nE5
J'a~~. ~~; i3 i^a: i~ÃA. g3i~~~l': }}~f)s al~fS ~~aC t9 ti~'Ftb of
i~c.~G~.lti~.,.ysvt loaded 2]l'~~'2i?~)c?Iw~t ~'.~ :
s?:3cti.?thehomi# ciol;.5 in vitro,
FIG. 18 is z; bar gmpl: sh.~wnn;; tliic wita-caz~cet activity usf pac1:>axe:
I:4ad4r:
s><mopamiclt:~ ~~ ~ ~-., A459 Minn= hang cancer col1s in vitro.
DETAILED DESCRIPTION
Pl"tt4'1dQt> .1e1'i.'ii? %'.Teci7mp:3uS1dJ at.22d pd't?cG>scS to pr~par-'
b~mt;d fl3Yli:i.
paIEi.:la;',3, f;ld:;r ,A.xd :~lw teCi co;.11p(?s`fit331`'a, c3.I1d
~'`.riZ3C.E..S4ct fioF." d`l.l iv`r.'.i`n3 I'ki:.'=
following de;>c3.i~.~c~" 1i'3~ sy'nfhcsi;' of M3'f'fotnter units aiid the
pOcynmc?1:'si6i.l`: of Lhtsst'
_ <
i~lÃf nffi~~:G:~ z.1~13~.ti. Also ~;4tis~,'I'L~c'..La is ~~lL : ~ a1.~.t'~YS
of Pt`1:vi31Z:3"#:G S.`{'uL%3..E1L..y <hs.i a.Ici.''qvx:tto
t } .hef~. -} <
1a5z3`lS~? diIr1~Z~35.1~.#~Fl~#.s to '4L~':~:~t ~'i~'~'i?3~'I`<
Z3isi`~`~.tsC'.S a.::xL";
a }f1~a<)¾vt:xt{.]Z. i~~ ,s,>r 2s :A ~t t~:fG. y~`~ 5.A. V"t~1r>d4 :.?f C:.~
~c.=i.?L . . . . . . .
dis(?'k'd4 rs.
WL will first describe i 1t.1ya n1?no271Lr:S that a'an be i3sed. in .ia
ak#.ng ':~~E:= .w~:~w
z~.~olti`t]'.ers, as well as ?i1etlious of synthesizing the
s.3'?+:?t:?c?..7iens. Wev: i1l then (#t;,,i-c,'ibz'
.x?e~a`~~3;~s ~} ,~~~ 3 a.r ~~g and ~~:;r~x,F the pc?i>~~~ers. ~i:~?,~~ ~:
will describe Ã:?~: ~~: ~:~<~~if:tÃ~. of
fiflms and q<3C:f3 il's, as wi til. vs fliv i11i o3~P~:~T':.~~tli?Ta`~ of
agents 1:i1t(~ r]t}lfK:3~= :C: N~,`#..+`'a7xGs.
Finally, .~~ will di,;c~~~ the applic:~fic?ns c?.~~the po1yrn::~s and
ps:?lymer-ager:F
4.=oiv2ib}A. Viia~ I Monomcr Unitg
~~~:.$: As shown below, va?'lC?us vii?vl .ni)1?o1i1Gr units are disclosed
(ae?"i'i`.i.
t?JaZ?:3~`~'r %#.i7.Fts i#.Y'." l;1tiE:d to p'op:iTe pi3l~7T1i,'.i's5 a's
>Ct. . .~. 11 fiu'thLr dc`a"r,:l. buji3"t, V;~ik'i
t?nz>tnor ,,inits include cÃsrnpow:,dy of Fs?m-1111;1 1, lib ~1r~Q III.:
19
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
R,,
.~~
Q
QG r'e..
iv'h@.~~cadl Q wS >~Idk.'-'A~cn{.cn.tlv sS,iFi~,cted fTt3m wwonYti0, S. S{. or
NHr
C7 or 0 In{: $~ t g;:'=thS..:, ~.~.{'o st:lt,~`cted.ft't?fii among:
..r
~~~~`~-= ~,1~'~.
R,
R< \m i\ o
~ is, sc,e:.~ed frona amÃ.atig a Sar~i.~,Eit or bt=us .hod alkyl, evotoalk`
a'`yl, o,e ~.in.,
tizlrl, ,<l. yl, ]Y?, at slszlyl, alkyl~ry1 ary:Ialk} l, or'fhotocax-bc?>
chaÃ~i of - 5:_ car.~)c?ns,
wx`{eri:.$n L4E4 zi ;1~~Y `{<< t3c:E!.. W~ 1~v ~, i33i.v1s3T4r~.,
a.E,1~~:~5..-1.
or fl;.Io?:E3aYtli'bi.`.ia cha'erf is 3,?pt1on`2'.liy substituted iI1tC:mi::li
j' or ti.nninal ;.5' by o-tlw' {3r;I1C?I't;
hydt'oxyl i`y{ i{3 Sy''v'tfief , {=aeb<)a y'. l:a{'b55'S. "Un.I di.j .::k3hao;
m(.>uio 5;F (az^
libGtdb3ted .liu..i3t,, tthiC;l, th?tt{.4toI; sWfi?.+. phi.1sphat{'=,
pa'1i34pha{1 1t:{d, i3r f1{ o, u?"#.
I1awit's; or
R~, i; S..tC,dcd fi-t3a;I wn"zi?ny p3ly(S,. hti C:at', ~r?.ly;i3l)
l.aibE1hydratt:, a protein, polypC,pt1f1C.:, an 's.:T:l1Alo acid, a
t:ll:ck:1+:
~0
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
'c+;oli:, i:i>al].La%'.oF'.fdi4'., a ,"t3olyi2u`t'ieC3ti+;..~ie~ an't%. .'s.-
a,f'.1]eÃ:Ii::: material, such as a DNA +_i .~IN'A
5i= '71w:nÃ:, a .:p3:d, a :?[?lysacch<1Fide, ziFi :?t.tfit?ody, a
ph.intAcl:'.cutFc-ai agent, or any cp.itt)x3i;
1{)# a ``F#i3: t~,~-,Ff:i.ii receptor; or
R. `.~ vQ-k...Ã',~:d flam. a.tmo.-aÃ? i.: P~IC5Ã:t?E;I7)s5ltl7kciblt? or
ii:;n1E,a I.I ;y= c}c;~~N I : ?kah, I % gZ3up;
~ or
Fi.\, comprises a first ~.,f,.Fi:i..t) that i.s f;=o.F3,-vi:Ftlbl`s:., Ãfi a
second >i,[ap 3.1affF...i Fit ffo~;:~i the
a..Ãrià ~?~"(31t~? ,1; :a pfI a-à oTi3e`ow about (),0;
R.; i'~ ~&`vtÃ;d ITt)iF'i .{niE3ng hydrogen, a straight or :7.F":md:+:<d
a'kyl., {:y4.;loÃ1l-kyl . :3i'g'i,
{alC,fm,,, s>ly.Er aY ~~'il~S`t a13k~`~ls$iZ+l, e33~~:'.~ca~.~iY'.~ l')I~.
~3s~*i-~t3Ãi?~,.:FI~~.`~E?4~ i.:tÃ:~ C~. 1-50
' . . J . d .. ..
~y c"~. .v~~FL.>.~:;n ~~yc Cd`kZi ,~lq cy~., ~)i~b~Cy., ~~ryl., ~. 1l~:~~F~.,
~Flk~lh,i ~' ~~~l, ~~r>15i1 t ~tn~,yit~~~~f2,
FF~ en~. . ~ '~ _ ~
<a"+-l`lkyl 3f flÃat?ioz:ari10I, is optionally :ia.li7st#Ãtaod
Fnti`.F`'.,ali;}' or :on:l.ldwi.:y ~y +)ne f?`:
nao,FE: `;'}~'~F+3,{Z`~. ~?ii~Itia =Z't'':tCF ~.i1:i~?i 4"v x i
ill":`!s`~?~}`~'"itC':', Ed'FaF"btiyZ'i3~F'la~~`~, i3iTFi]~Fi)K ~:aFi.F#:f?
4:;i
iiF :~,,1>)s.#. F.tÃed amino, thiol, Th2oiaie.:', SiFlfaÃe.pj:){)sp,'3<"F:Ã<',
ph,.~owp:"FoF'1:,;Ã~.', or hka o:.Fi=I3
#;", efi..?i,A.ÃGiFt }Fol-r1 ayTai'}l.lg :.?.'.'tFi'.31; l`a,, or branched
alky, s :'Z.`.lo.lkyi <lrS'l, C3lZ:fin
sÃ:[~I, <~I~ ~r~~ia} l> ~.~ l~ilzr, i~lrtr~~~~~ l, ~r~,~I~3Ik~~l, or
~~Ã~.i?~~t~~.ar~)~.~~~ ~:l~.~..~ii of ~.~-:?,j i,~~Ã~-~r~)~~~,
3~,rhc.o-:<in alkyl, c4'`ioi$lkyl, a.I=Z%l.; olefin, 4alyf. alkyl;?S yl-
z).r\ l>.ilyi, .~ask'i'lary,, :1:Iy~llk;",J.
E3F r~E'xi?;.t?f ~F~'3<.3ai cha#r, is apt1oI1allJ' slabsÃ1t4.Fti;i~3
#IIter4iu"Hy or tf.vtlin.:3clyby- o#.ati= m' l.'FC3i'C'.=
ar:ydrC3i':'l 1{'f.~roxv'dhC'r, c<~Ã'bi5xyi, G.FTboxye5iea ',
{.t3.1'boxyF.#m:id(:, a.1F-n;i1:?.. ;'#1C,n{?- or di-
\ubst#t1:1:sta a#:r:ali.;. ffiFo..~ thioesÃa, s1FifaÃ4, p~'sf~:9sphate,
phti3splaf4nt`3.Ã<', or l.4iliL>,'=;kn~
I1, F,ciÃ.: 3? a i:=LA#^t-3poi321d t}fFonnF=;F~a 11 is sE..zei :ezt fti)F*.'~
e:lfEat3"!g a
cC)Imi,i?imi.. 4EatiwÃi i7el(?i`r:
.'~:~
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
R R"?
SG
=~ S :3 N
-;
V 'Y
U Ni ;
t3 Hi
NG
ly
=
; i` ix s x eiE3 ~:3 k ~`'H
.a`hoai R's and 6 1'#:'f? :iiad'L'pGadl'.Ã`itly Sf:3,i'={.ieCa. :i4 deflllfi.d
}1ere1.a:
lu i.C;naal? :":mbc`d.l3-i'=~?.~lts, ~~-ie compound of Fti#.Ãlzi?ila Ia is z,
of FCZrf:nu.lc.i
IVt wzlf i'L Q ls oxygen. 11.1 4:>a#'lFÃ.tl3 C;ilibC>dII~.1t;Ã?t:i, the
i;mnp(~,E..`eI`.t`e o:..FCZII1'2alz. 11 is a
i'O;:~ pC`.ul.:. l:? FE7a7m; a V i?.''hC:t'~~ Q ii 81:i:fiiÃ'. I.['~.,
t,.eTt:'a'.8i cmboa.rr,l'.nti., ti:Fe mn'{:oE.F.d i,'A'
Fommla 11 3: a 'S ::fl7iP:'>u1le`: of F"L?rmL3l'il F't''!, where Q is St,`_ In
1..<;F"ti:ÃlI. C,FI`.b<.xt.~..,a~:v.'+i ve tht:
::_io~~-ipm:nd wa l?ftn-nula If is a compound of Ftx;-~~~~~, VII. where Q is
Nil;I:.
In ,rà h.er ca-ii;?oslim4nt>, a cz?mpf~undcz lffz3rmu1a I1 I is s, le~ ~~;d
rrcz:;. xnomg a
C<]mp3oun.i ;k.l'mul's? VIII,, tx X., o1' X.1, as show2i ill)oLC:. 13i_
c5,rt.3liri :..inbt3d.m+,:nt'+, t~'.e
30 ct;zrtpC~u41.3: t`+?: Fi`+i'in ula e11 &s 'c1::Ã)inpi3uI.d of `'3mufla
'L'11.1 txdht.'IÃ:` Q Ioxj'.SS'I^, b t;t:i:ili.Ã1.
4;m,boc~iimeÃ,Us, the conapc>~~~d ot'Fomuala II.( is a co.Ãllpound of 1"Onnula
IX, wljc;re Q ~~
sL~lftir. In ceat.ain ::Mlib:yd;:Ãni..nt4. the ct~~~ipound of FormuIa 1.1-1.
is a 4ompo,>nd of Formula
~õ ,, ,
;15. '4~.3i:'~'U ~ ~ 14 :~o. lÃc :~"~7.~~ttiMlil~L,tts. Ã~Ili i,t3mpÃ?u.F7d
of Forimifict I3I ts a L.mr;.pou#1d
iss Xa w;:`>4;ro Q 3s N11 1'1.
[z# C3#ti'r eI1~boteln',ti;3]ts, a C:=t.'?mpi.,~'u11d of Ff.'sr'i-mi:a It 1s
4t,.;ec .c;=.d firom a{:';o71g a
compound Ft?nmta~a Xi1, XilI, or XIV, as shown belc:sw:
?7
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
R"
i.. ;~\!2
SG OG
"Y y
~1.1 p ~~I11 ~ ~,
1b.
f iv
~Q`'z
H H
H
SG OG
xv 0 s
XVl 1. NH
where R' > ;tnid Zf wre :i?de:?enc.~ent`~ sclc>E:.ie41;~~ defined l.z.:rdn.
c?1?b>d.1i1"?Gnt5, ti-?.c ia`~mpfx?.IÃ"d of Formula I I i'sa wYin:'.+tiund of
:?
XII,
Xil 3. it? ci.A:,$i:ti ..I'? biy(,smU'#?ts. 1l3ccon'~pÃti3.,,?dofi ,,)I"Ã?-
iLIl.allis ~i 4.~?A:"tlTL?f?a?ci~.)..'' l`(srt??U.l:}
xiv.
A cf,rnpound o: Form~.~la III cm also ~.~~.: indepcm-donÃly wle;tw, `f: s3ri-
n, among a
conipf?und c?f;-omnalF~ XVY XVl;,. or XVlI, ,~~ ~hown above.
`j? >,:C..rwin t.`.l?~'"~7Cdl;'~3Y'i tC, each G F:rC?up is..clecieL% fr+.2-
m.amoi?,~~_, :.i ;;ilZti:p slwfivn
bC':1{:sw,
2 s
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
. :
R3R2
~ r u
~ /t l
.,....,.~x y...._.,\
f i
:"43 Rt
,r'_:-~= -' ~"'~=.,
t,t \fj A~ `f+
R:
Q
`4-R
i r
R`
~
whE.=p; Ã:::ath `tQ is i:1depenÃ;i<:i3dy selected #.oni a:'~luilg 0, S, Si.,
or Nii;
[1 s~:=?c~,::,: ~..E?k"1:~ i~.i"~~(?~i9 ~]'s'I'o;F~::O. m~tht3x4'',
ethC's:`s.y, `IEAI-4 (), c3. 'sti-a ~",ht or
btwicbM .~~kyl cytic3 lky=I., aryl, ~~lcfin; s<ly1, aMyhi~~~L aqAty:,
a'~~l4aiy , < raryta,kaiE
chWu of 4 `C: Qarbo-ns:;
R4 Llild R a.,i'C' ccit.:i ~.I'$~~~~ :I'L~i I:~~?v st~~=~~C~~
i:"~'=t1naI1It$ng a s;3" mt E}r br:3:zica1F'd
aI~~l~ c3:.lod:ko aryl, ~~iefhi, i;yl, alkzrlkl,z, aFyiSi:~14, Ay-,<uyl, t?t
;~ryla,ky t?
c=;arbÃ?ns; t:~ld
R, i i :idf.4ted f1";3sn among hs'de'3;yf.-n, a 4(raI4.~l;Ti or branched al
'p'l-
&i.:3 i:yL=zC?aailyrl, aryl, ol<:f#rl, i3lkfl`s3?'y3, i.'s~uyA<3.Fkyl m:iaaI-n
of 1-50 c..sidbÃ1ns, wherein kl;S::
24
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
<;,k~), ~:}~c~+_Ltlkyyiryk, olc.ttn, aI.k-,`1aAyl, or ,~it~yfialkcQl uh<~Iii
is op:'t\?nal^y subk:tt-0iec?
:n...rna:EA4 o:ermbnl:ly by afzc o-rmore:(lydr;zxyi, hyd-myeffier, cai-
bz}tiyl,
a'ar'#3CZxyLstC':i,, iwrbFxy':i:lid~.^', amino, mono- or di-substituted
a'lll:#o Ã.#Fol.
tl~loGst:er, suI1aw, phosphaai.<., ~~~izosphonats;, or halogen .~.5 h3 cutaln
i'.:`>lb(ri:lnwnts, Ã'=<,lS. F3 G f.;T'oE1p is sCõleeiLld ..1'~^~m
i?.llJi*il~? a gi(ii.ip
shown bi.1t,w:
Q ~.;R.
~ty F= .
c.-Iq
~\r ~ky
=~-f'J .Y~.rr
ll 1
~
~~.''`= '.,,~:_._~~i;;
tir
where ~~.>Cx~.'~~ ~. R~ ; ;ml ~ ,, ;3:~~ ~.<~~ ~ ~dL=` - ~:tlcit:~1t,; ; ~i
]l~, .~Ã.c,t~~i:5 <. .~s.'~,E'~~'e~. ~
ct~~7 >
IIl sso~~'tiliti. <?"I7.~.~+t1dim(.'? is, ea4dil G g;r#?EFp j:a
sG;lE~.'~ctC'.d fTs.`3m x3i2-3.i3Ã 1 $ ~gn,)up shC>vJI`~
~ 0 b0m3':
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
ti F
-' :
- ti_~ .._;_ ~~-r=;
~.~= ~..
~..
R,
\ t
p-=. (.Y.r l~ ~~ ==~.v. -_-" \\
f~'f ! \
~.~ ~~ ~ ~ =~.
~.:
fu
.jl
. =
........ _ s:f i
}=-" ~ ,,\ .
F: \
R` R:, R. w ). 't337.C~ ~'i %#id ~~?s f rf <~ i ~ i~f i1[iF ~~ ~a~ ?t::`='t>
K
I rtii g~~'<2. i t '~;L~c .3 ^`~ ri t M siÃI.,
~~{{y ~, :~;~....~.,:..~. ~.s.3~?~::17t~f3.~.+'~'3 ~~:f`ik:. ~
~.~~~~3`~;.is.'d Z 's ~~iJ .. ~'~~4.~'~4 c~:.'~~, Cl ~.
si}; , t~lkyNi z'~ ~rylz Iy .aak~la:yl zxa`aÃyl alkyl Ch{ziya of I N10
w'af;roms: zand
4 :.1cUta'Ã~ S k .~ zat ~ll t~al~ ?~? {g x~i4~r~ ,.t`~~~C:n, :k#, : fE~: t ,
' riÃl.czlt`t:. L:i. R~5
., cv~-le~r:lk1`l, '_~t?':'
i~., ~~ :'? !,
ohA#?'d, i3lkL'li .F"yL it' ar4`IalkL cha:#.n t?f 1..50 d,:wbi>w, ry:ht=IvIn
t.heillk4l, incloslz?ivt alZ'ly
olZ.i'li3, tilkyli.t`yl i,i' anli#lk",': chain is optionally substituted Il1
,eY#:?:.dllR% c,a Ãt.F>?d::Gtlly.: R~
mw or Tnis,c IiVdi\,j'./,li hJ"dto^f,\f..:hi.)1 UGlrifo?}Y=i.
Z.^{YrV`\xyosCGD, ctArboTya:itzd\>> amino,
r
mt?`lo- :;i darsubsi::uwd alz`]lnw, i:L 3.C3l, :h1+L.titmq 5ulfa[S, p
f's5pt`.3W, pla4;3spy3t3l1ca:4, s.)r
,exl Ont S
czg
I.~ ce.i.t~in s:,m}?C?dim-tenÃ4, c.3::h G {3I'a`}1.i~3 i5 s( l?~t;.t~.~~
:~I~fTl ~:t:`~iÃ?l~,it a FE>~I,~~ :lzlL~~z
~ xv:
~r~lt~ _
26
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Q`
it i~
.... ~~ 1,
+ . ,
R4
".. t~
~!. ..........
a xQ
R~ R,,
<'i'I7l.~To cm.dl1. Qj R^, R4, RZ 5 as dot#.n'd hUree.11.
In ccm:i$t R, of F<3m1#.Zlil I gN sC:lwed fiC?F13. al:nt1.sg b'tdio',';f i7.
allk,vi, cZ=dl43<I=.kt 3, alkvic, dc`c2lk1; f:Ã yl, md hLt`'.IL?ar:4''l. h1.
:.e:ftc3.;1.: e?nbod::mt~ nts, R of
Fonurfla I :s s;:Icetid fr.?M rIMOV-9 Ct C2r3 alkyl, vv,=cloaikyl'., :_~ryl,
and In
~~rtum, embod'nie.. .s, ttts: ~~, ofForana3a, I is selcewd.faom am..a <w w;tiy
gso,,up :~1Aowr`
b~
df?w:
~~-
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
m~thyl
ethyl
~..__.
Ãsso p r<?py f
..\ :.~
. .. ., ~. ~=.,-r
~.
\,=. =,~'v . ~,lt:~~. ..'= . " _. ..
. _ '`.:\ .!"= i'\,= `
,.. .. .. . \.. . 'a: ..
y=~r.'4,~V ~==~ ~.:'~\\ : .
\=
i'\.= ~\= ='i-~.~
. v =\\.r~ . "v ==\_=r' .
"=. =,.. y . 4`l r ~` \~i =\
_" :~.\ :=\= .~'~ /~." -~-'~, e.'"+..=_
` =\:"\+,! ="\r_~~ ="`:': \.....:'~r . . If~ ~,~'. =.~~,. .-\,.
~ `\.~;, '~\.~;.. "\.~:-r \-..: =\,...r"l -!"\...::.r ==\:f . =`\:~r'. =,
~.:
}'. - . ,...,
~ \ti
: 1.=. y,.' r\.~' ., _
- _ ,.~:. f=="._
,: ==.\. ..,. = / J~`'~.
f =
\=s..
~
~_..... ~
iJ3C.
nY
...~ = =F1T~.i.
~
=~\:..: . ~~\
; \ \\\`="\~ ,.~^ +~~~
. ..Y r~....
r~ ..
ti~.~'
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
In curÃxair, 4m:sodirm-mts. R, of I{+}miila I is sclected fruÃYx aal<xn9,
all1,
i:aloaiky , 3.:eÃc.~rontl.(;:s 1c<<z>loalkil, zAlkylc.4'ckmtky=., tura=` and
'acÃoroaà yi, w:l::Ã`ein
::li: aliay, ha:[e,~ Jzks ;alkva, tvc1c?{iiky1. .~lky1c, ca~~~ ~lkyt, ~ y"k,
and h,.wawiryl axL.
ty,~~iona1h.,~u:nsfi'Wied, In oxqa:i-n miabodimmts, R, of Fo>~~iu1a -1 is
sclic~~d frÃ3a.n ~unEs:x
~ C# L ,~lkyl., wz.zn:in fl:ev;lk>>1 is <rpÃi4}nA}=su1~stittttod with ~~ ~lo,
01: NH ~'~TIÃz HA,
s37 (=001'1. ...7 csw`.F'tal.n iat"ibod1:r.t3eJTt;i, the Ru ; . : m..1d<Z. I
Fs Seemtee.l ffiri~m at~"loI1A,
?: .
my' W i:up Slii? w" bi ;low:
a,
29
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
t?#4 .
: r. Ni-i.
. . .~
~OOH
~ ~~, r +-Y=`'~..
=/
,..c:
. \;;'' . . . ~ .
L) 0j
0+ ry~
V+
~.......~''~~.
1 s ~s;~ r
~ hte
~' ~. .. 2
NH
.=,~~^,,..
\
j
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
B. MeÃhod* of Syn#.hesdAng Nlavl '~~onomer Uitit~
~~ shoml i?eaf3w, ihZ. vinyl Y3:C?hTi?iT1eT tJ:niv descT`#bed }l..F's3.FI'
can, 4b'tlvhe;iz~~L by TC .=i3ctiIli.3. a cof31p-ox`:nCi of.FtJi1'1a[! 1Ftf?
pIf?v.dv a ct?'.'2pLrlsa'#E3 of i'oIalidli# I:
. ~.
I~
~.3 ~
...R.----------- -,_.._....~.__~._ .i =
\ ~\.
at ~l i l
Z..
`A,FL.: Gts
`11w. S,'. ~. " . ~ r~ ti>x jl.,eLe =~'~L''=~` and IZ? i~I~:=1'fs,C~ , ~~ ~tlt
s'`.=:s`~f: i IC:<_ "~ as i
c~~` ~, ~~j., f #, or ~'} :3Eiix ~f v4~{.=e~.~ C:l t:fi;"ied.
he:': w'a}.
and 1.6 is i:l lC av, gyo'i as --e
~,l or Br-
n a cc?mpound of F~.3rn-mla E~Q0, wI~crj`` Qand 6 .;rQ as deffi-;ed
h.feiTl, is d:,;:,L3lv+`.'<i:. in a s?lvs:ilt: tiucl? 41.s h.~.Z-aIlc,
bc..t~zt-?ea tE.3lllt.nc> diei'la~l ctK~er.
k_f:iayl ,.cetatc: ~~iddcf.i'ott,Ã:thanc. 1;4-d.ioxome, tolÃ4tffy~,.~rofar;m
(x`HF% acGtonc,
acotoaÃt-ndc (MoCN), (DNIF), z~irnet.hyl. sulto?ti'ideti oc:..fic acid, n-
t ,
~~L~t:3~f1f'~l. .SC)a;i~;:f>~`~i.~.InÃ}l. I~.~~".x'[:>-~~3c.i.l~.l.'+3,
:.`=~hi.EtE:1l= I138.-:ll#t.#.17.ol oT.6=atL:'.r. tE3'~~E:Iti:?.1#.:
S:i7,,bodl,.'}onx:~, a
Qompourid of Forn?ub.i l-lQG is ;:ii<:~~~lvi:.d in THF. To tffiis solution is
s~dd<. si t: l a. A yltjyl
haltda, suda k h:orde. En 4c.'tain crnbtizdynaen[s .: lsasc as a ti,x:kyi.
amine (e.g. lt: te`hy:al-tx,t1: ), is added to the I'e:i0toF: 1:F1:i?...tir4.
The rLyu . wih; product 'is, a
cCE-y3pi?;3i3d of FoF'3:3't3la i.
I'`., atnotheE' i'.m-bC5dimint, a ci"31pt.'su? id of Formula I is ~~
ies3:ored b4`n ac}i.ing %>
z:omn?:sb}~Ind o~.':Ffst::-lu[a s~~~QGJ. w~:czc Q and C3 are i.lefined: zt-i
ttbove;; with at ac.ry1
aI.h't'dn"dL;, `utfh as m4#h::t4;I'yl1k3 anhydride, en tiae pr4=>i=.Tii:~t: of
i3'3%;SLY s;.td'.= as tI'?ictiI'v[
m1%31e.
C. Me-th{sds of Poiym~.xrazing, V ~~~l IN'lonomer Units
As sbt;~.sn :)cI}.w, a t ..mpd1und c?i"Fc?a-niuls~ I can be pol,metizwd' to v
.e;d U>
comp.~~~nd{ & Fonnl~~ a XK
~:1
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
~ i ..~`.
.~ =~; =~ r~~ + ~~... ~
X X 1>Y s1'op} 6~=
XXI pitti#ac :
hs+rt?phH:zÃs
l` . Y
.~"~.~.
\t::4. ~~`! `~ ?~ f{
, .. = . ;~
?~FL, - ------------r~'. 0~'
fr` . ...
-
{,)!-i vi-i
}~~~`'.C>F'fit:
lvhÃlv eaca, (2, (3, or (3 and tugz?lher; and ~~~ Mmo indt:~.~Ã;ndentl N
selected as defined
and r is ati ix~tc >e: from 2-750:an(I
~ 5.,:3ch p3 eL''113Lr1c tt.: il b143A i,fi~C?up is 4C'1cb'rwd #i'T'o:'f1
a:nJn`f wnmni:4. `,:b.iobõ i%:n1dZ`\.so
ph l.spa3atei hyd:t'oxi&,, a:kof1eSv and zflkya3.G:5.
A. iy .:iYE..thodi o. Z ;nyl p13%yrni...-ri: 1a-iion Ssnmvn i>.a. diC' arL Can
be,..:\'~,'d i or Lhis
#'L c c:7.i3Ã1, Fo> ,:~mwitpl a cun-ip{ ''14.`~ t?f Fon3-i4.1lt1 I i ari bL`>
F`cai:=tf-A wÃtt2 a ftt. .. '.".>lisc'sil
mit~<l~i~.a~. ;nC:lude ha3cF4en mo#ixutGL., Nucha4 C1.2, alCi eompownCfs~,
st,c.t .a4 2 , 2 ar:cxbini3 Ã:aetb:~lpaoyiioDibilc) {)VlBIN)> and org<Tn,c
puc?aidcs, ;;wh di 4-=
buty,pw:roxiz2o, Th;c> polyitkettzation canaIso be ~iu.:uced by !:ght an\~ a
ph.}.,zin:ifi: =oÃ';
,,-i one cn.t?i7Ã~imer:t, -a compound of Formula I is di;:4c}:vcd i.~ a
solvcnt:, so...l-; as
13_`x'.iT,o~ i>Ci'1cfiL. to1Cze.,a.:: ta3efl'-iyl Lti#.i:z, C:hlCiTC3fl)C=m,
tfiyl c;c;ft:3tF;;, dachlo>l>Ii C.'thc]Ido, 4r.
dho<3Nw>4 tt.v&hydr(~furf.Y.tA S=iiSBIZLicW.w1L2e, aAreto)fitl=L.t4' (MeCN)
\~+3~I~~~lPJ.'.~\1(~x~i~Y:fJ.6{i.='
.~,
7 2
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
(f)'~4F'), or dÃk~iofli,:1 s=.a't:3xicie, and re:actcd wiÃli A [BN to ~ri..'..
.-a u-sm~.~c>.und of Formula
xx.
In cca'ta.l3.Yn `~:'3:nbi1di.i`$ 'L':nts. the z?('bl:1`mf:3' of Formula XX is
hyCsai'ph~'~~.?a.c and i;=C)rmul:t:`s
P.H n3il:ve group. Cl grf~ups that mz> pF~ sunsitrve can besc1e::.iefl.frc?.in
aai:z?n~ ~.lr~:>
xYt'irraps dcsi:ribed he.rcxn. As ah.ow,~~ above, ~.,t?l.rnc.v~ of
Ft~rnn..ala:XMI 4.~m bw= Omaip6d lt:
a ~ ir~ ,~ ~~l:l , .r;=.~:zsc
group. A".3y- ?n;C'fla+3d aff acid ca4,,fly~,,t:d hydrolysis kais?wIn in 1hf'
art can be uSed, f6r this
Ãõt`I.ns~i?rÃnataE?i2.. For ctx<mapae, the 2irpdrf33Zs#s can E7e
r1.c1.a.zi.:d bv :a3:lia.irsi:ng ehe p;?l~'ant,.`:I~ of
Formula XX ~rac? a htitfi-c?w:h..aric aczd solution. The pti of ~he scAuÃion
be between
,~tifsr:, is ~:~~~~..c.a~ I ~ z~5. 3- >i.~c`
a
'1 ~)c and ` f 0 t~.l and `3.5. ~ .~, ;.t=i~:t~ G~~ ;~Ã.s~ii~~~~.nts, :1-~~.
pl-1 of ~.~n~. s<~1 (
Q~t:7npic. Ã'~c rsi-z can be b;::;<3vv about 6.0, A .5; 5 0, 4.5 oi: 4Ø In
c:ortmii Ãhe,
PIJ 4. >.? :5t.3L=.k' ~.:.11'.a,bod.II1-l<;nt5,~ thevIll sensitive group viln
bC: r'c.;aTlf?vZ.i:.i 1:::;.dS...r busi::
conditions Flnd'Err L=iin b:: cleta-vod +,a ry-m 3fical`i,%.
As shfl;.vn kt3ve, the hyz~~~~~Iffiffic poiymcr of Formula XXI czir, :ncroa>~
1113 SÃ21':e f11S
i'oT?lparod, tt> the Il~vdtoph$3i1#t. pi.)l~mncr of Ft:.1n13Li.G<a X-X. JRb:G
1.7:;f't'i:sL,d z*,i t'. (S;;) S,:.n1ib+:'.-
:7etw,ei:'n. L 5 :mtb `:'..0 or 2:'tt3a':: tll1'lc=`~^' [i3t'. C}i1,I3Lil
Slz`4.. (S 1). [n certain L.t..bs:`d amesIt~, One
Z.~ .. C aig' 1n ;1ity` L ? to S2 is L 'j~. ; '~: ~rvlirw'~~ ~ ~~" ~^....a{ ~+
~ ~~.~~.~iL~, ~.a.'g.,z., ~ ~., t i` =1 '' f';e and 3~~
,t+ a. i'.~.~ 3~! . ~~ . ~. ~~. _..:;y :a~n~.. , t'~ ~a~~4 ~~:- ~=1~ 5 ~.~\:
:E.
2 ,ind4., or 8 s.:n6.F 10 times, ffic origaana} size.
E Addi#~~~nal Y9='~uv~ ~~ioncsmiers,F Polyma:rizations,and Hydrolys.as,
CÃang~idorts
As ~hin~m below, a .:.on~po md_. ~.r., cotnpom.,d J., 21, 3. 4, 5, 6, 7, 8e 9,
10, 11, 12,
13, 14~ 15, i;r 16, 1spt> y7r.A.eil.' :4~i;~~: alone or in
C:.oml:sÃa'ltat.o1'l w,`.:h ians`_idaB,I Fa:{3#`to#:'aer, to fC7rm,
a po1"vnier, e:A, . cz.impound Ia. 2a, 3a, 4daa -5a, 6a, 7a, U, 9a, 10a, I I
a, 12a, 13a, 14ag
'=
1>.."+a, or 1~3 ra. Aa> KVtY i~3~>i#a~{`4rv~ti of ~?YF rl~c'~.~i,iiJ:' 7 S { t
i ,{ l~,a:xE;' .n s`,,. f>c~in bf:. > iÃNw,) e `e
,= r1.t~43'~~ described l~ ~tJa~ ~.~fK
tr_.nsft:rmatitan. For exaryiple, compf3fi~id 1, 2, 3, 4. 5, 6, 7, 8, 9, 10r
11. t ~ 13, 14, 15, mr
e ,. . . . ,
.~~? be r~.:~:0-'~.u(~s t='~~a~.A a 3:reo-~izdkal. 3lni.~F3its~~ 4ilt h as
(AMN ). I ~io rw.ardfi~g c;.}nnpound Ia, 2a, 3a, 4a, 5a, 6a, 7a, 8a, 9a, 10a,
11aQ 12a, 13a,
14¾a. I 5-a, (:~ 16a is sts ric-rally a hyc;roj~h;:3bic poI~iner wl Ãh a p:+
szr:Ãmi,ive t a;?up. 1kily
AnofE-iod of acid c<a:wd'tr~c~f hydrolysis loi-[42wn i_rn t}3cm: cw xb% t3sLd.
to cleave Ã:3o pl-.
3C. ;>ta:isa[: vk g.r[3up, as d<.,st,ri:7ed ht?.i'k'tIl. Ea1zpm<3t1C Ivyd3
:alLs:r:4 ulo.ilt;., or i"n
For r~?:4:Fui'iple, compound
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
2a, 3a, 4a, 5a, 61a, t a., 8aa, 9a, 10xi, 1 Lt. 12a, l3a, 1.4a. 15a, or 16a
Qwi ,3:. ir:n,nc.=.;;ed
in t~ h-,"._{rodh1oric. a:;ic~ so~~~tiorr. 11c resulting ccwmpowid lb. 2b. 3b,
4b, 5b, ~ib. 9b, VAa
11b, 12b, ~ 3b, 14b, 15b, ai 16b is a hzrdmp~~lfic po1~lncr wani can increase
Ari si:r:
bt.:weei .i 1 .5 wA1d or mor(;~ li2?'1es fl3'l'% L7F'3r:iY3Ld size of
w?npo`ttnG I il. 2a, 3a. 4,i, 5a, 6a,
7a, 8a, 9a, 10a, I I a,'12atY ~3a, 14a, -1 5a, or 16a, respectAve] y. For
cxx~~-npl w., compound
I ~i, 1,i. 3a, 4a. 5a, 6a, 7u, 8a, 9a, I Wt, Ila, l2a, 13a, 14it, 15a, ft:-
16a can bG ~~)
mn _E..ldii'. ~,t~iuÃloÃ: f+3" wH,.Ãt?us pÃ'rI.od;4 of t1Ã&ie. Longer
p;I'Ãcids t)f exposure ca:'i kad to
itZ.#.'.`{t.well:fig A~te1'3'de`:bfiw methods of ziC:hTevivq; gi-f..el.oF"
g.+.;`i4't!'a.,l1L:.=31AQ aiiw,51ng :h
:oi 3:.1arc?.i..t'Z' ,ir'ec lCõk>e=.:-nG; thc ~T1-1 . `~.~~1L~ tl~9t'L'~. to
1'~i"ti'i.'.I'.1~1: ~.;."sil,t~: sti~~:~l`;~ i.~:,Ã be tt~.~-.i'~'~~<i
by =.Idd#.3'3f.; diff:3z3ctioni:~l czaf~~~ink~.?rs. Di1E3Flcl:aE1..3z cI'ossl1-
rkkt.'.?'s it3i:h3x.:i'. &11--<m:yliiW 4pe: =fLs-
<li"3d p`t?i td~~ et':?ash.Al x,` be-tweet-i =?iC3yinc;.t` chains fluil
fuabi:; 7e5E.7dl thi ;~#n s.3f i.i;o
p.:.EitzCli` t.`?t?-n Q." ::~an'sif?E:.
1, 2, 3, .i?ld 4 111d1vIdwilY i2te p(3lv123cd.izGii to fot'Ãn :%po ly i 7ie#
t? c~
e
e.o m p () u i ^d I a, 2 a , 3 a, :i n d- 4 11Y ws sho w n b c l(.) w:
v,T~4
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
f,.,~ R ~.:
..
QH QH
~> ,~,.=C}
la lb
~=ri
,..
R; 2 R:` R.
2a 2b
~
I` = "'`\ ~3 ~. E #Y
~s'rt,~.~= w.''-.,i` ~~t _.{'~ 3a ,~E~
~ `::
H. 43
R2
4a
15hcre each Q ,n;, R? R;, I)t". '`'`I.~.d tennmal ht:Ip zIie k:}dC3p~~n{ji.a.'
.' 4i teif:>:. as t;:~eft
(~ i',;i ~:=3Ã1..
C.:1F3# oui.i.` 5 and 6 are "B1ilivIdu3lly poliI3'wx`.i:r od tEs 1i`I,in :Ãpo~
i`#.1 LI', e.g,,
c
~ c~}it~,a?5311'{.I~~ 5a~ c3nE~ ~811, iti s.~3\"Ys~1 ~.~~.SC`1S':
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
r R,
, ..
a lo
:x---~~= y /, ~
;~l_-~Y~ / lw_:/~ ~^ri.
~ i ati3 5b
r
~,
R2
, ,
s ~ F HQ
i P 6 6a. H.~ 6b
P14
L?.'`leI k',. c.'dh Q<'{ R:?, R4. R. ~Etli{ t4=1ÃZdiIa.&I ;;,Ei':>l.p 3Ie
.i#,idC'pondGÃiil`T \(.lcf~:t4d as de.anS>i~.
Y
CCa2a'?p<a:l.tad 7 and 8 m4= Ã.ild1vidui1lly pC3ly#'a1i .S'"s'c't'd to ft3am a
po.yi23im t -g",
L+E,'s3`Ia.~`'J{)a.l`.ad 7a and 8a.~, as shown bo3.LJw.
R'!.
~ -Y~t -~.~ f,2=.
~ ~l = ' ~ /= ~ !~-... +f ~ ~"-, 4i
R4 H-/
Qf R
A R4
.~---~ `.,'~,=
=~
R,.
7
7a
Ã~-
~`}~_-
~~_ =~ ,'=~~~~
`~ ,.~....__~..
41,
i;. =:4~~'
8a
36
CA 02653811 2008-11-27
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~~ herc. cac:;Ii Q n, ~'~ , R<:_R;. and :.:nninal ~~~~ip :u~ ~~~depcadc. t`y
sel~.~;.ted as t1..fined
~~.~=r~::~~.
~'t.'f?anpC`und;g 9 <:illia 10 al''L'Y i1id;vldL1a(ly por'v:T3leTizt;c-I to fa
l~`na a ~]C~.~!`S~~a't, c w:.;
,:
com;?i3,3nd 9a and Itia, as shown Mowc
a f'~ i J \~F ;
rw ,
t
~ tc y ~
{ -- ta
V ~~ k~=Y'`G . \ ~i~..
-~ .. . ~.<.
~c3
t "~ \ ' . ,=v,. :^j 1..~. r
~ =
` .=G~. '.
_------ -- A.
r.=`~ ` ~C~ t,Yk~,#?P
R,,-
143
~NvhL.Ic eac:i ai, :.'~>.?, KI> R5. ;.3ndi tiyr#3i1rlial gt}t.~.~.;~ %11`i;.
11~.~kS.::3`t~n~`' ~t,?.+.',f~f~'.f~ as ~..c,iÃ;.if.'~'~~
Corripoul~~~ ~ I -ii1 i 12 we .In~~iv'1d;.I<ill-vpt,fyZ14t,dir:ei; Ef't ii?I'm
:s polSni:."r. O.g,;
_ ~..
co~~~pounL3.8..3 a and .1.2a, as sliow.~i beFms'.
-,:
,,
?i
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Jti`\o --------~ ,
{ Fiv
`{f
~ ~ ..' .
-.: ~ Cv a f.j: 2 17.
~~a {
-12b. i'.
where each t' R:., R4, Rr, R,~.ania t~rminal gmup a.?c se;e :ed s~s d.
fincol..
C._nipz?um1S 13 and 14 a,G: R-iÃ~ivzdua1ly pt31~raerizc:d to aimn a p:r~~~
rier. c.Ã_,.-
: s)i?lpomnd 13dl tznd .1.41t, as shown belC3w:
~
3
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Ã~=:
f... ~
R':
=,..-r
M ~r ~; s\
= - -- ---- ~.e õ~
,a
;\
R
R5
13 Q
R' 13b
, ~
i ._ i.t u ta
<Z.ts R.
+f~fi
f*Y!
R
" 14a 14b
wh,e1t!. each ~,,' z3 R-i, ;.~w4z ::~- med t1:17n-ii1:al gx't)tip aI'e,
Fz`t~lepond4'.¾-l'd sLI.ci4d a.~ d0fined
}:is`.'1'c:if.t,
;:'orzypounds 15 and 16 are In<lÃ3Fidua1ly poly~an~.1ri,xet1 to rann a pfr`
t1z:a, e.r;..
c#3mpi?faa?(i .~~a aa7Ca 4.6a, as shown tk;low;
39
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
t'; ,'~ ~, r \~ ,f,? ------`A- ;it~
D 1 -- \. =s.;,~.
it;, Rs 3 ~r rZ
i_ .L:~ ~~3 lw6?
15b
P. 15sa
i _......y,. ,~.. .~..,, . ; ; .,
. ~3 . =.`:,,..
~G 1~~ ~~b
wa]ew eac3i Q Ia R^w R3t IR+., R., R . R,.aF?ci td;:~~I'nAt":ii:#l gt'43up
E 'i'inyl:~omÃ~~~~~y-me~s and Copolymers
a i'odt..d I3n are p?,'paretl bv p:;::v.T?C.? S!i'I?g a vi3`_?1pi_?E:nd c,,f
I~z}rzY~~~la I. In sonw c.rl-ib<.:?di ment=, compounds of Fonuu1a I car-L bc
cc>,=~~lyn"w:t:lzcd ~,.J;h.
.~.i?I
flÃ~~` vinyl ?~i3it~"#.i11.3i::f described ~"3<:Ã'E'i.Y7. or `t, ~'~':el in
~'~1::,~, c`~'. For +`.=?S:i~IIi~.~lC;, C,ripolli:.i I ciu:
be Umpi?l.t?2d 2, Compound 3 S.,<a.zi be L..{?'-p(>lp2:C.1'`.'iCet3 witÃi w?Zr
}via?i`.5known i'{?th ai"=t. orL'.:`ia?"npEZ.'.nn+alhyl.mC:dhav>vS'lat{ `.
Ir, t<thÃ,i +, .F=zlhi>diI7.?ents., any 5'E5mpoL.aid5 of Fo~`a`~~.L3l< I cwi
be i:<?-pt?lyflz't;lizoie ;? :ch
r, ~, t'l i Z e= s ~~ w ci to tt ~
xI7?' ~`1Ã ~~ i3.Z.'xll.Ã~ .?::'Ã~7E;t~ iit3e'11s ~3~ ~ 1#irlti%I3 in the
c.~~. ~f. ~?T"...+.~f'sff.` a .::s:fC~i?I~ E:i`~?Z~.l,i'7~ati;1'.
%i block 'ti>~~f?:~ 4I.~.Z~.`, a_lltC:~I1zi~:F]c, ,.opi3lynlG:1, or 'i
"1'<3.ft C.op..iy-nor wslng any mellt?dti
kilownÃI=` ?lla< Llr'..
hi iidd?i.ioa]itl t'.I'fAi.'~4:'3dTlz3eI3I4, c1.i'y' compound of I'i1i`'-
rII.El23 I L:;;Ã. ..tF :E3 ~?~?{.4".tFt ,~,;~=~:
w1thi :t27y- V:?'lYl nC?Ili?a:iC:.t" described hS:.Y'cISl or ~ti;,~Cywn in the
arE'i+? Y"4.ld :`~ lidwc3'`
h#ur; or Ut3?,":3i~ ~.?i?ain~?t3 ~t;;Ii^~õ i~.Tly' methods ,~.ili:~ '#i Pi~.t
s31~.
Any2<,Z?i5 of a Sli ~~.,lo mo:flt>E"Y3er ?'c(atFv4~ to 'sllxs.3dw;
2]'iC)ni?.I7?eT= cw1 bc t3sed W -fi.ti?'1:i3. w.
ffp.?lym...r< Difxue11t aatioS of Ã:-ic1iol3'?ei= fsntts i.?iipaT't
d?ffert.nE. pz'7:Lait.az w1d i'henÃcal
x t
~:3"'~37~7i;3'"~.ie`?'L43 the i~xl3'i~lE:]', ~~::'L?~~i.~~'~#~;'.s of
}zil:cros~i~ include, aiut :3~o ?~L?t :`.l: I,`~'[' ES`.~ ~il~:~l~;,iil.k
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
t~an.sitiot~ ~om ~~~..t~:t~~Ãe, ~~a::l~E st>-~;~~Ã~~#Ia, s rt` t<~lIiji~:~,r,
flexi~iait~ ~:r ast ~~ ~ ti ~~l
hydf,'t?p.iio:,tcli'y, Y11us, by Ga.:'S:iiig Ã1101?0Td3.C:1:' ratios, it is
Pos+i:'~le :Cr c.iff<}rd i copt~lyrnei'
wiÃ~*i f1o4i.etfc'=>~racÃc:.-Hst.ics. For G~ample, introcaui,tion. (?f a
bul:4y hyd.o;Yhob1G side
:~~'t)i7p will. ako flIL ptYl'r.1n4i more hydq'tsphobÃC cEiii3 Ã4G.uivt the
rat: hy-df`i7lys1s.
GF, Additional Polvnug=~ ~~~~~~ as Polyc;sters, 1Poly~lthcc`s,
and:polvearbonaws
Ie
i1~1Ã~ ~3i3llc~ilai if? acids can be prepared ~~:4cf11'e~ÃI~y; ii? the
C~4suIi~1ti+J~1 ~~13 ~iji~tS~. 1~'~<t.4'. a' ,~St.
viAn be used to õ3'.iake ti153 filn3s, A:3i3I't7ik,,.sT r 'Lasõ and related
dLticrl.bL.d 3.'tc3"5..ix3p aÃ:d can be usvd e.g., iCS Ci`4'l2v41`\'<1Cio..z:
i{4õf ,>v4; g bitK3u li`i... cli;t:nt:i,
As ti~:E~sZ I.'i bf.ltJw, ffis. %hcrnF<:iÃ:x :: i.?"l,ietutE.S of :.?Yi.3Es
ÃleZv poly~.:iLg s ,m3.,Ã;:3g
F f;3-~nuhws XX r. XXH, 'iX; If, and XX iV:
f~,=
' r ~~ ~_ ~ .=~~~_ x?
`.~
XX I
4..: `
k'!~='~'+i~, r'``=~ r~,.uf,. ~.t~1'\. .r~> .
.. '{ ,'\ r. \. = ~'`l` ~rt ~'1.~~ ~ti~.:r'~ ~\'~ k~,
a:1 rtr ?,,
:.?ixIt
f; rl' fy'.?
I'v' .r .
r"~ .. . ,Y`1.F`= = '~ ,,,i d.i~' `'.,\,. "r ~~.~ .i r ` 7~ ~r
xxit5 !? ;
L=i,
c+,
~V
r ~ ~ r
: ~.:.~ + '~=v .r..=n~..~ : ~ ~. .~,-'.
`--4-~.,,.
1 '~ ~M.+ 4 ~ ti.~~f '..:r=' ~-.~ ..i,.
x: aiv ; i
41
CA 02653811 2008-11-27
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w;iG;Ii:: ci.ch Q fS iF3dZ''pC'.ndiilil;' s~dccti::d from 's$ma.31?Ã:. (). Sõ
` )'i:., or N14:.
GY Z3i% and 62 arG l:~GIch indi.:p[`ndendy4iw,leS.:ti'.d fr<,`ii1 i:i:.no37&
or R.who'whi G:,' und Gi_, &-ro not ~~~c
" sa
Ri.' is :eclC:oti.'t. fi`{_}i~n among a sUil.lgalt or bI :I11d~ied M\%
L'y<,.toaa`4l cli' % _ <?ie'ik.z,,
A yi, t~lk)ds;Ial_ mry,sfl yl. alky'<ixyl, a:-y1alkzf) or flzxo>-txct~~bon
dhain of 3v50,
, t~. ....
tVhereÃi; t.is;.. alkyl, c~ ~:I~.~i~.lkyl, :x~?~ 1, c?lt;~ii~ :~~:'~, k~11~
I~i1~~I, . j l:~ilyl tl:~>~.~~I a~,.~-1, ;~r.'~~ilr~ :i
~ yl
hy(f-3.o,~~yl,, hyd oxyeth'4r,, ca.wbo~~yf ~,4i~~boxy1+::jE-cr,
carESoxya~~~~1.~iitioa2 Xint!, n.ono_ or i~:,,
`r1i,-)StÃt17ted 3a:~~irlEST thiol, thii>t..5:~.; sulfate, pa:C?Gph3n.A`:v,
oor ;1,'01o#r;o$]
3rfieili: i:S: cs:'
R,, ' is sZlZ'i:;ti;'.d fI'l?i?3 cxY3:3ng pC?ly(~thyii'.lle g.ity-col),
p53ly1c~~.~:y1a;'I,;' ox1dc3;
polrr~(hys?wotiykicizi)); a c,:rbohYdraw, a pri,?win, a polypoptli&~ an am;no
nid, a Pudci::
ac.d; ..~~~~ eofide, a pc?~yi.,mclcr?iidi, t3iiy DNA or RNA si~t~~un~i:t$ a
lipid,
~
p<~lys#?t.cha.i'i3'e, an fli:tibofsy, a phc3.i'rmaoci1tAC;i3.l c2vt:I3I, or
any vtiittt?~.3t. r.fi` a ~~li<;li)g14:.i7.l
A
.~5\.`\.~=~~i~?y, or
R~ is :tit 3o::E i3vd frolyi .iFru?7ig p1ht3tC}cross11nk-c1blC' or
1o1iicall`0 4Ã oswIinkableg-r.3lp;
t>:`
R, coIlipr,,:iZ:s a first group that is L`l)I1~;'~`(.ii`xlvic to, i`s
s't':l.t}nd ~i'i.'+%.ip the
fin4 group at a pa.s os or below about 6,0;
`c a` lw W'.4;.tcd fiau1-n a`il.bL}n' hydroge.n; a straight o.i~~ branched
alkyl Ut''Z'lIialkyl>
art1 oa fia., si,yl, adk aii.yi, arv'i:sily1õ adkj`xaryl, aryla~k)-=l; o.,
Al..ion)c<irt.ois chain of carbons. 1,11Z a.kyl~ cycxoalky'1, a.23.>, ~lt.
izv; silyl_ aikylsil}'1 aiy'ssilzl, a;ks atyx
:uy.ta3,tO"lt, t?.i' ::bcw3"i:1ccl::?ola chain is optionally 7ub.`a'+;i:n.itod
n:ntomad_5Z' f)a WT-i-ti,10.~~aly by s:1:'3C.'.=
cw mai`Z 3L'ilii;~~S53, h,`,rd13:;S:yChe-#'. ct.B.t'bt3xyl,
c.?E'btl?:y~.aS1iT, :%<libi:;L'G'ai'..Iide, n'loA3C3- i~FÃ'
di-;it3l,"Lfib,i~od ann`>nor }hatxl, thlt?L'.stc T, .: _e: <õtc,
j3hl3~plh:3ES;, 131it3sphi?I1.3tZ, (;: .3.ih~3gc'ii
412
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
;S and v are t.."at.e}: selected fro.ITi m fntegE .I of a '>'`4~` and
wL.~#.`. ~'~,~i~~~~~.L=~:~% tor#:~:ii-n[kl 4fi;'ou-p isse3.ecl~~ froiii
aynovig an-fi:.e , i.#.nZ.~do;:
ph<yspbat4v. v~:phate5 xv; il~~~~~Ide,,,, noaIs, a1knos, alkenes, wad :lk.Ms.
A:.so prowis:=ed are wm~.~<?unds of Fo.rrÃaula XXV and XXVI. as belt?w,:
G{
~ ~~~~~, ~=
.i;~~`i` ~t ~=
G'
~j 'txvi
i .
:~}:tr u<#c~` Q. :} , S; !'q itl~~ .e#'#.7111^~i_~ ~.?Ã"~3.~p are
#is~:pi`,1~L3~:T~~E~;~ ~~a:?4~;~.~.d ~~~ ...l,3e~~~` ,1~:2~.':it2.
A >io provided are oompowids, of Fz?rmuia XXV11, XXVT,i, XXIX, and X-X'X a,,
.
; bozvii bek3~N-
4 -3
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
, %;2. ~~i ~ <S. : L~.=k~\ ~ f
l \ ~ L, f./` ~\,\ ~~~
i l.
MAI
~;'~ ,=;'.%r`~
= ~ ,.. ~.~:
``~-~~~ =:;=- =~= ~ ,
r ~
l1 f \ +'"~`
S ~ ~`=.F' x !
:KXX
iixix
Ladh Q% il.id teÃ`m.iwii v #'~~LF~~ Fi[i indt pe1xd4Y)tlSs .t C:i ;C: ~l
dÃ.:~fmwd
t ,-d;..h= ~=
3zt;
r3Ã:~ t=nd
3 ik suhk{:'iQd &'tTm an ÃntÃ:f?.er E?f 1-25:
Aas{? piovi6M ai'c cc?mpi3und.S of Formu1.i =KL XXXI 1, XXX . XXXIt='; and
XXXV. as show.n. btlcn.':
44
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Q'
XXX:t
~ ! ]
}
~ Ft ~ ~\ r~ ~\ r~n #p: G> :\ f t\ {,,
~R ~ `~i. ~ ;,! =,..-~` \~ ~"' ~`~, I ~,K .~{ ,,. ~ +~ ~ ''FF y
~' J~ ~...~~ ~}= ~, ~r ~.,A',
;K
~ ~~TV.. -~h, r{~~~~~-4 . .f~'~ ~~'~~ f'~~~'~. .,,..'`= ~.at~~'~ ~t~,.r
xA
( l~r
r
r.~.,'`3~'.. ~=r'`~.~ ~.,t~'~ y'`~ C~ ~~
b: 1`_a~ ~i.
X~ ...`~ . . -~, . 7,1. i.
~S_~s..~
r r+.- ,
L'K` G~'.' ~p?
'.E I;:,'t` v; and Wunini~l group aCC', IÃ1depe~.~dently scli,L.tQd as
de:.7.u.ti; and
b is Yo ccwts II'"oni ai-i Un:eget' of 1-14.
Also provkdef~ are compounds of Formula XXXVI and :C-*,,XZ'H, as s1::oNvai b;
lf?w:
XXXVÃ
.. .-. .r}~r
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
whoae cac : Q, (33`, R x, i', ytlici Ã'o nslinlal --yc};.tp aro as d;,'fim~~;
wid U is >oiQc:Ãed ali :ia:i~gcr of 1 -14:
l?i c::na;:n embod:mf:.~rzts, [Eic. (:3' of ['(:xmud<: XXI.-XXXVat is
sUlec>Ã.ci fii}orn
any group sI7vvk''~i b5:low;
vz`~~~~4 oaci: and R :' ati ii:i~a'~~~3~c~e~z~~~' as aefi2:ei1 Iwrd:~~.
\ f t ? " i ~
In i~'t:}~ ~~3".? X.;5.I.,
~XXVIa .s, inciop4n -izmt1;' sÃ.~ec~od fflo:7i aa-nc,qga ,.~'fpt?p shÃaw b
low:
46
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
methy l
e:"yl
~.......~
Es>r.3; ;"opy?
..- \\~~J .. =;, ~.. ,\'\ ~ \\'\
\\
-~,~ .. ='\\
= ~_rf'l ~. ~ . . =\~\!tr \ \1J . \\v ~\.~_ ~ \.
r~=\~ \ j-~` .. . I'.-'-..\\\ \\ %r\:` `f ""\\ .-`~\.\ .
...\\.r` ...'` `~
rr=i - ~i
,
.. _ . . ~ - . \ ,
- \. -=.\~ ~ .~.1 \~ .l-'
<,-
. st.\. .. . r-'
\.......~
I . ~le
~\f khe
LLL \, tG;~ r ~J\
In i'3 i.<33Fi C::i7:lbt?d:?-lent::?, ti.'=aL'h:R;', Q', G-+`, and G'
rsF<5?i,3 of c. tly of ~ ~ \1Cf. ~ C~ ) ,C
:`f.~.<~~`~i >~ i~:za~~;.~.Ã:t~..~ ~,. ~,~.~~r~, ~'t~~z~ r~a~~~a~~N a ,r~a~p
shown l~~;lz.~<~:
4"
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
~ Cl
"~.
O ~r
,~ ~ '~~`~.~%`~`~-,. -'``~,.= ,. <....-.' `` ,
= _ ~ . ~ ~.
NRC
_ ``~...- :_=,~=- ~..f `~ ~:,?- ~. ~=:
...=r''-~~`~. i,: ~~`.,%~~~~ti:.;-' -. r ..'=s` . . ~ = ~'~ = `-`l1 =`'. ~~
~'
`~~ l; .=~`~ .i-..~~ !'~; v
~_:l)oi-i
0
7 ~~=
~ ~.;~}~`~~ ,"'~``5.F='"i ~ `~,
~OOH
's
0 0
1 j
; ' f?
~....... f
M~ NH^ -
``~~-''=~``~'rS~~~,.9~ ~
r-.
"~<:' =~;, ;
i ;~1 '~=~~.~Y~~rr ~`Yt~J ~~r-~'L~{.
\ 1" `~= _ ~ ~
s
~~H
4 S
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
I ,`, t,i~t:a`n ti=irabaztsj?liE.a1t`. oach R;' Gs;`<G at:cA Gr' isFf3t.1p of
x3.T ?S' i?: I'i?3'3-t71..I ,i xx ::.
4
XXXVII is i:=.idelmliai lfliv :aC.lt.cted fi'(y2`t7 a?-nt3n~g a group as
5ho,~xa
..\
?=~~ ~"~r
~I.. K
Q,
',t'. r `=,.- r.\r= . ~`,,.. `~'=`r
~r
+`,. := ~ ~'r~~.~
.. Yi ~ -=.~\ ' . . . ,~ . ~~'~;:~,` -,>~: - ,
~=
~t .... ,~
\
~
(=J
. 4~.,? =,..~ '}`~
Me
r
n1.` i ~1\ p
Q }
\~ ~J' =,` l ~
#k ~ ~ 0111
~...~--='`~,
vwberc eadx ~~.~` is ~:~C~~~~~=.t#~~ ,~~.~}'' ss.=1ecied ftom aniong 0, S; SQ,
or N111".
49
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
~.~ S L~ dl~l ~:133~7E7Ea1.:l;t i1~3y each R. (',', G~'y and G4:aTM'C3L1pi?fmy-
of Fi?:'il:mlc.. X.X3-
XX'XVU is Indà peridently :wlected.firom ttziioiig ~t ~~.Foup tts beIow.
+^t? k:
~i: ~...
r'\
' ~..='f~~. ' ~..
\Fi C, H
L~r
-.2
-~r
. .. ~~,..:. 4~f1
\.~
~t.
zJ
~,i {wY `~ r
'`.
tmch Q' is a:;idipenda ntAy wixlc~~ from amoiig 0, S. Sc, or Ni-l.
Iil cCrta1I-: S:,znbZ3dÃr::wrYt4, S;E{E:.h Rj`. G. and G' g>t?up t?fa,:ny c?.
1";?r;x~ZEEl._l XXIv
G
X?SY XVI. is ia dE?px'nb~~~ ~ly aLls S tCd ftEjal3 :I37 oIlys a group a.-s,
slli.`w-n "!elE),,:i',
()
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
~ ~. =\1~ r;,
~ . . ~a1 \ =\_ \ ~ .'t. .: \. .!\,.. .
Y~.
. : ?.:,. \ ~= ~ \. . . . ~, .
~r} ~!=1\. . ~`"\ :\..~. ~~
=`t~ .\,` "~.`.. .==\..\
\K, . l~va~}.~` ,.=\ . _
f ~ _.r . - -4Y v \\. , -~:\!=
. . - - ..;~}=.
f1' ,.-c:'=
1
Sai
..'v:i~~.\ %`=\:\
:. Y, r 'Y':=~. . \~,\...
.,' .
`~ . . .. ~\.\l
S i.a:= each Q 3s fiidwpor''C}.C.nO t .S'd'.i:ct~`.`.~.~d from among 0. S,
Se, f3i- ~'~iii:
fr ~r; 2 cJ t ` r :2r>l~$ } {r r ~ t ~ a> ~2= ~ ~= 1S( ( t CC Y>](t2i. i w ~-
V;_ayy.~ A 2 k.i~Yyt i~~fl}.n~:4.~~~~ r~ \.~4a~i..~.S ~~'r~ ~ *~hj,s.:~~~
Ci.ai\~ ~3 ~y ia~-} l C.}.~, i[iiY~\~~ 5~2.2.i-.. XX>
5.`^
XX_,'~ Y' II ?J :.i~.~E# .~ Irist I't~~Lr ~~ ~ti.~: ..~ : '~Ti3~1: s~'Jl
t3`lg a g~l.~,`, as shown ~~G..<3tr,~=':
51
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
CvH,
Q,
~. . ... . ,.
~'.K,4. .~..~ . .. ,~ p .~.
tiv:+
C'~--~'..~iH
"'Ãu
mE:
wh1.~~~.~ > ~' 3~ :~~ ~~{~l1.~.>o3~Cf3 ; Zrt ~ ft~ ~`'3~; or ~, .
each 2,~~ <...~'~ ~~.r ~.'f-~t~>:` L~ f~~i.'Fii~,~`~.~~1 among .. ;~;,
1lz i?.~<`F,` ,,~ of A.? #~~i :'S.~'i..l
-
~,;.~. R ~:rR ~3 ry.~a~^r 4~~~\ C.~' F-,r", a + . i
Ir, 1f.ova x ~~ .~l bL.>~ and ~Ã.i.~~.:c~~5:~. 4:~
XXXVf. .5 :.I#dt pi=#.^>iently' ~t= tv~ ~ ~. from aT?-T11:4: a g;0R.ip 'a"
shf3'4v3 bC S(t:t=`;
5 22
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
;??ethv;
~_.... . ..
., ,\_~ .. .
-~.
...~y
~,-
. \'. A\ , +'\~==`+,\~`-. ~.
. . . ~..~.:''~
~ .. ~ \.. ~.,`
.. \;.+ \
=\l =\` \.\ ~_ ~\
\
~ \....... d
~'~C` .y ......
~47V
Y ~ \~v
..: '.
iL;,o pto\'idti, Iw C:s#;'.,#pf:wnd l)f Foii3el7h X~~XVH5, ils ;,f35'i
3be?f3'.4.:
5i
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
;..~
.~~~.
' '~, ~,,`~ ~, = ~` ` t..
;=~>
u XXXs II.I
. f
`~ r~~ ~i~? ~ i' , , ;~ S and Ã~'.3"Iix7.~.~~, g~')E;:'3 s .< =~ ;aw e.z ,
~õ~
~ ~.~.`+,;~av ~ C ~ ~. ` ~: llrLai=~~?~Ã :41~.~~t `
..i..,i. a.. ..~ = ~.:...~~.,.L..C. ta.~ w~~.~F~t..~ E,c ei: _
aad i> i4 t!l~i:t. ~~ ~i'i;~~: 'c11'# r31t ~,~;~1' 5f 8,
IF.: v~iiinfta;~ embodiments, to i::(7.i.71pi?wds i,& Fz3t'awla XDXA`#rI3a
i:=a?, b(: a r~.Y;.k:m1;.
a block >_.t5pf#Iymer, aliem;:tting cc)z,E~ly'mer.:sr, a rfratlctrpacyme:
ai.:fm ~=,bC?d?i?1i9.n1, the t;=f?f?ym"Fid [}fFL:EiT-nl;.a? XXXVIII is a
c:?mp.?-ul#d of
:=o r3=3#e <a X:,~,-X2 X, es`
_~E.=
ta
~~i1 ..` .r=1 ;1'i r=. ...~.2~ r=~ ;<1
- ~ ~~..='~ `~-.;,-`='f i`.~. ` ~ +.`~~~. ..`ly}~r ``~~r...:<...1 `'~:.
1J-ti r
t i ~
Vi3.w "i: wi#w'h Q, O. X. y< ~I.I#'.; lS:t=:d'n:nal g#'tafsp ai`i.:
indC;pt;ndZ:nI.L tio_ReGtet ;::5 defined hi:n~m1.
i~ :n w.'erta:Ii-; umflb(sdltncÃ.`3~ flw cm=~.~ptnitli, of FE`õ$.Tl u,?~'t
XXXVIII :~: wiA:s.:ti'd
nor":~ 'I f}
i.. ~ a.
G~?~ f f~~Ã
rii ~~ '~I_., ~:~1, X1:1I, i >~' +. ~'LIhl. ii L s s ,z,3~bG;,._3<.~~~_
r r ~ i
54
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
XL
b
r }} }] i
{ rr # _
s ~.~ll~;= t
`L ti:Y. f
='r
i x '
t 3 + i =,~
x> il1 ~Q'v
~l -
' ~, e ~' = `
N
:~~_:~i: , = ~~ ~:
> hc :t`L~ c,..ch C: x: v. <.,nd te-m.in.:;l t à oÃ;p:) an xndopi'Ã:d~.'11t;y
stewied as +::t.f.n4J.
a.i ce?':'.3:1.1 ;mb+`iiT.t-&t.3t4, a compound of Fwniw...:sX;`5X%`a11 s .
.3cbvS:ted 3.if$i~~l
w.n~`.3T]g a ct;'?1?:.FL i~?kE~3 of ~"~ 1T~;a:f~ X ~rz'liE Ir ~~~ is (~xy
~.~'~, In :<Ã~i~I~? i I1?:?~.C~.~sl1,' n`~.s, a
==.y, t rr..~`Il is ?C. -.7~xS;>;~i~~ <a a lS_rf.s~3 rs'?LFf. ~' Ã r i~~z._ Y
F`~ ~~z~s+~3~~:~~~z. i?~ ., vs?M' ~~.>wz~ ~1~.~~'Y3 ~i~ 'c#~T~`?3~~ ia ~
i3:w ~~Il t:h~~za ::
wF , in c -r ~ 1 ic <> ~# < ,{ ,{ n e(:r;.:~~r.~.. a. ~ E ~
...4_'L.', ~ 4 tia~~~~~a:~ certain ``e';'3x~~ts+~h~,.""'...C`n .`~~i zx
<._.~ ~tz?%F i.`~ 3. XXXV :~:; F is .o31..t{.',d
=-~}.r -e s r c ciata~a= =rdn:~li~ Xa. ~1 r.:.~ i= ~ :'
~.1, ~; a L:~:iT~~??E.Ii~'t~ of Formula s~'~a4.:i'~.=" ~ is 4, ha
O:1#.c3d::
r mPoL>1ii1 of a > : ?lt.ta 4 ~X'Vlll is ~O ,. d c'Cs1u. amEmÃ, a ci
I;':pi3.#.I`t of Forn.wha X1:.1a..
4,~
)Y ~f `'`. { ~r 4 .: `i .i :
~~hA 4'VZ~vt-~A?t e~~~2C2\`$..fine.Skti,ti5v.., compound o~". FL,[Snuta:~
~XXVI+I. j,~ Lihi.,lt.ctGV\,e )]ona
,k 'r ~;f t ~. i~ ~;i:.
.~ ~l7g i CS.i. ~. ~%t !r :~~3~ 3 :~ ~ of ~ i. ,7 1~3,.~c i~ :S ~rLV~r, 7T
XLVI, L?I,~ ci5 J~'' at. v4sa1 s ,
. ` 3. ~. .+i'YZ C
<l r.C
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
fi ~'~`Rf,t ti.~=.r ` ~1r'' ~ ` i.~~,( ``ti=~ ~..~,: ' ~.
S
X: `
3i
0 : ~: ~`~. = ' `:. ~ .~ ~~
` =r~,~i ;'v
Ni#-}
3 $ ~
;:S> .4~..';:3:-<. Y X. s L:Ãf . it:t~ < !are z.E~{.~.iN~)v5Y'tli.i#~ >.~v ~
.L[~.4..~.L 2 as Ei'ai~1~va..3.i6,I=.S :~'Ã.
c..#Ãi3S)daauÃ`',~, a cf11 Ilp(1uTÃd i.+-rFd?n'iw~ aXXXV 1.1; is \e. E .L~.
3konrl
Ã~2,.E}e~lS a,.i i~,:;~t~?Il?.d of .~'i~;":E~~t.c; X~.:~3'. I.i C`~';:"~ti1#;
i:a3.-iFi;~~.l>`..ti, a v<,3 -2-1~~);~..~3t' S?.. ~ai,rÃ`Fnule3.
~T
XXXVIII . si.,?.,t;l:E:d ft?b3Ã k3a~loF~g a i:oli1poÃ3n#:a E?f.Ff#3anÃ.23a
XLV. .i^ c.._E.,,?,:Ã'1
4mlbt?d:+ w.#t`:. .co1'Ã:poulld f;f.1,01."e nuaa:XXXV1.111. is ~:s=i" f.ikin
LEÃz3Ã}i:h:. t,5.:3~ ttS~
FL1I j~ X,., V :.
11. ~~~~th~~~s of:~~~~~~~~ers of Fo~~~~~~~las ~.,t'~.J - XI=NI
A-faSe #.,~a\:vh(id of pi?.t4`n icriza4a.ion. 4aii tFC:i,isx'd to pnmiLa..e tE-
:ic poh'E`a4; ` ,, aM1Fi?~~~~ula.~~
XX1: . XI,.VI. ; or õxanap~e, polp-n;,r` of ! ox=mulus, XX1 ,XI_ Vl can bz,
prcp,.wc~ ~ ~ .at~: -p-
l7# F;-k?t)i'Ãl#.n- pt.tlymt'rF1<3.Iion, or 3~E.1i5?i
by
I
As Sho':=k'n belC3%,-, a polymer of FZ?nitl.`ix_. XXXVIII s.wi Jx;
pr3:.'.p.3.IE:d by
r . ~.
#i <]iZtZÃ`.:Ci< 33E;
~~:~iSf~~nt,.~'Ã~t~#.~tÃV?> t3. ;:: ~.c.EE,:#;t~~ .i7.?t?i~it>.o~' -.~ E~`. a
?d;"~3t?f3:?:Ie ,:.
=. 4~ ' . . . .
~~.,~.Lto~7 *:Ã1.-.E ~f ~- `'i)`. ry.Y\l\ 2 '~ es Ci s p1~MnPr !R>f...A ~(]~ i
3` ~''#.~i~E31e1 ~t.~'i~A''~~.kl~~~.fit.'I~`~.~~ ~.?. L:#~E12L.f, #.'.1.'
,. `~. ~..~. ~~'..f:.'Ly2 1. x ~~ . . . .
~ 4r
56
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
,,..
0 \S`...
. ~ ! p
r~~`
~ ~
i1
fJ O.ii 3 'I
t'4$id termna: gà 'oi1p 0.r~:= iI3tiL pendetarly :1el.'JL:tcd as (ac t1.3C:d
;`E 3.,2n.
Any :ani t}.iS1d of a:n`, z5pC .mi.ilg potymo{',}lataC3n can bo ;..~sedi for
th9;^ .. t..:aio#.; For
ox>.:l1v.Ã. `he ;,;1~ ffp~1I3I1~ pol`{E";:zz.iizt3dl:t'm iTla"S .7w
i.13:duc:,; ;3-v H
~?t%%l he Ãvth~ iÃE$~1. xIs O t
or2~ibt1d1l,u`_iit, t..e roacfiom zs t a..:ivot b:r a :llt:tal a=~~lalytiC,
Ã.t lF. 'Ms ` ;lG= , t.. ick.lt?l]
~
c..n be ?er:i$,"i-ned m,Ãt, i?i- 1..} dw pacsLF:ii~ of -a solvent, sliC>~'~a
as t5:ixt3e.
fj] di;..'tf, il E..dhe1, :12.~i rCSta:.= lif VL<i(V4' use@.s, iKor
w.}'tC2,?;i.pli., =}i4'r.\2~ic, \`t caA\Y\}aSat4'
al#olri.>z.~:~ar `,o, >2#irtc3l1<:. i.l`l?nf1me. (:;a . bG, I.1. .~;.
~....~.~. ~..~Yv I ."~y 1 ,~3K E 7~ ~.S. `~ :3; e. 1 `.~.
. . .. . . . , .. . . . . . . .
i#1y;w.onit' cc:nbfv used iz;Ã' the polymerization shÃ:>'rdi'3 abt~ve. As
s.aow'#1 b~ loi:t,
Eli,,. ..:i::mw c=::i3? J : a ,k f;riFive? six, or 2ifa'e'eFz m,..'1:E3bi;Ã;id
d'i'x'3g:
~",
_. ,
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
., ~.~
~= r : : _. .. ~
:\\ ':-, . .. -------_.W..W~,. ~j~,.., f=-f` .`ti. .=`'1,1 ~~'. f'~J...
`r~'~. .~;'; .
\ . '~ ` ~ ~:Lnf' \ .=t! . . ~.~.r v
i? ~7 F 7
r=~
\'.r..
~. _
~ ; r ./~ ~',..f . ~~ ,. i ,..~~ ~ .t ~...
,~,.. . . r ~
-........,. ~ , :
~'=~ ~4 t r:'~;.
-3-
='\`ti
rr,1 f
.,~
fE . ...............__-----3Ps~'
i~ =f= '~\-~,
r)
A~,
~i ' '~. r,^'~: . f`\, r=L?.{ + ~<-= r . ..... +,~. ..i~~ ==_~. . . -r`
.~`.`.`^''' + `'`. ..,~`, e,.~~ `~~~ ~
~ tt.~=~ c
~v",:Ã: ~ z=~ are tt: .i=. ~.. re ,~ i= e, ,.tii ,r.~1~..3. ~Ei. :~~~ :Ã#'~=
iÃFt ~_~f'1'1i:~Griit1~' w+..4+,:.L..t ,,z, dofiu:c?+:i ,
.t ;'..ii:,
As dzown %Ãbfj5tfi,'.. Compound 17 fti prepared by '.?E?lj`Ãrlet,;l: Ãg a
'bi.li`:%li?xt L?le'Ã....AZ?:
curbfyi-wZ. %'Wh oxt.:u.:", 2:-onw. CmT3t7C>1ti1i~ 18 ~~ ~~rep37cf b-,, .-
p:?l:ymci.z:l.n 2 be'n?t C.xy
L}.~~~L3 ii~r} 7 ~¾ p '~ as r
t`...i~ ~ ~_ :~~:?~3di1~tc ~~.~i~i ~.~~~.~~
~;r `.:'lr, Est x .. . } r.. ~~~,^ ~ i i ~^~.,=~:'G. ~,.\. L~.L3 A:. a },
o.~~:~4~.~c1,:by
tfxo..S l:'.3 t >.Atw; 'sà b;F.1't ~ 1o`4` ?,ly e e:Ã3l carbonate E=6'ilb tC
'#"ah4`dl +_, ? 1'~.~~1
L.yz ~r 5ili~.~ ~~~ ~~. ~`i ~~ . b3 ~ a ~ R bE.t ! e; l.. i~ s,
~ F :'~I~~~_. t ~Ã:i by F i ~;<"t'~iC=Ã'3~:I1~ a 't~ ~;E~~~ ~ .`su~ aÃ~?~
~..~~. ~<2aa<.. ~;_~~~, t. 3~LA;3al1-
}"Ã;nfi:;.
L C-he.~~-i"- ~ ~~ckifficatio~~~ of ~~lviners of Ft~rmulas XXI - XLVI
a ol..>:Lrs i3;' Formulas XXI`.13.3,.VI, W;:3erei21 C1r 14 a protecting
~g*:'oup, can be
i
.i".F .i`~.:.1~:`sÃ'Ci t"} ~#
4t.il:zsiii Ã'l~?it; `<[~3i:; e~;.Mof1'?s ala:~~ p(:I3i.a"?i For t. tarn'~ic,
G' cea;-,
be wa,v p5+.`.tei;:``, g,?ii'ol,Ep known 11:i o-t7.; ail: hrl :tis1mC .
e:x3b'eDd:i]~ents.. f_3 is a Q[hcr or
~ rotL%ctII7 ` fyrC31ep, Any method knC1i3 n'#.?1 the art of sa?~'#.ing a
~4dc: i'<hc31l: 01"
pe >.Z{hf~a g~$.-}; to a ~2. p3.d.S 2w~c:~.=~' 7~.f~d~2 }=~~=~,, L:Z. > used
~~.a.'~r:.='l~ p k,~ f)=~ ~~~'q q S2~~,~.~ll.~,k ' ¾j~ V ~T~) =5=y ~c~~ of
.~X.i.
!\s S~`3=~ ~2k ~.y=~ ` =~4. N~_ I~Y. ~ZiLi~~. X.L;.J j,
e'F?.
~~~
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
t6r example, a #3f3hyz>.L.'F"= of Fi7i`Ã-ni:la5 :''i.xI Xj,VL bt.`= ~-
iiCjdÃfit;i~ to ?Ã~,. .. s'fd< ,tY?.EÃ
l ..f,`?;i am]of?g a straTg~~':~ 4)#'bI'a.~'.3chwd 's:lh.Gl, ~:=;iCle.""alk2 :
%E.i'y olGfin >3lky~sÃ.y:,
<3Tyl\dy . .Ãaii 4 li ~?l, Ã?`4ii~.lk~~-.~ CiI .~l,.[i~I`~~L"-.Ã~'}?i?F:1
~:~~.i2111 of ~j-5~i:wcÃ~`~`,'~,.,.,s, ~~ ~~:.. ~.. _ "'.~~ i:~~. ? l~i`,~~
_ =...
t yC.aoCnc3<yl, i.~.iyl,. Z?.Fn3FÃ`, sdyla ~~lkF i+1~,4. ,Ãyl41..0
alkd:.31'yl, arj'lalkli or f.uoF"ol,ubf)n
;~. . . ,F.i . . .
.'~. a.,~3.1I.:~ is ~?a~?`3C~Ic3#:?~' SwE:~`w'FÃF~t.:'t. ~#F:`~..#:'F.?+.3li~~
or t~:1'tI':i'#is'lll4' by i;.ne or .#3,m
h:~Ã1i.~~yr.Li=a~_Z.,}r ~..f~.i(~'{ `},,f.jS~'~. y
t- :~, >,~r~, ~'i2Y'~~.r`.lci. amino, mono- 3:3}.d~ sui,fJtÃaacuf
>I131#io, 3.hYE ' .33F.3eswt, `;i?i. aEi;'., pilt#s??h4itG`, phL? ..
y~~laÃ3'~ ,I~~., . ! s~. ' h{Ã,t3` ~~, _ ~` ~ > }._
Other ..ÃÃ~._ ;:1tà .. t Ãe'lIp` ccÃ#-, be >Lis ~._A fta?m a. +1-F.iJnt3
z.Flv`"E.l 'yiÃ.o'no gj3`C;+..31,j.
ioly(eth},e:xS,.o.K.d%);7oly(3~ydrox)'i?S,`.id), :~ C:=aI'bi:?h~t~i3.t~3., a
~~1+:tt~'d` a ;~f~ Z`~T{~,~~l~`i~~v, ~:t?.
õ
+.1'#Ã1:i7.`l. ,.16;a_ a F?Fkdc.ÃQ :Ãi:id i.l.i+ ...ot3df:q a any DNA or RNA
~~ 3 ?1CA3
' a
.#p:t3,
lzit31uggical i:_s;.op.ur_ Adia:FtÃ:>pm1lv', a haÃ;c;F.clnas 5idt: chaÃn cap,
be A~ac-orpo.atest into a
polZ~~'`meà of any one of ::oE'I'..3lrxh )Vys.i"..~i=.LVI. '."~F.t'L:h i s a
phC,:<3lni?tiskn,ÃC:bh~ {3i' ÃL?ni..c3.l;~.y
aos;ifiI:kcab3Ã:= Maemp,
i.l?i]e F:14ii:~(:sd of I:lZ:'dÃf' :I?.,',, a poly1:23'u``r f3f Foa~3~>nl.tl.~
XXXVIII below. Ta3o
beÃi.:;y: otl..er can ix L_lS..w i'ed tf) iÃ.ffi5?'d a hydroxyl ga .Zup, AaiZ
izF.i t~iod o% 4 f...ctv-lng a bcn1 S'l
ether kà i57}'i,, in t,w art i.'=ar, ?e F.1,`'s^d '~.i}Ã` "`.~.#J
ts'~.iS'~ti~t"# :'~Ã~sil. Ff'EÃ' v;~.a~.Ã, ~# the ~` `+. Ã
~ F:iI"ic i :7.~4., ~c~.t: a;3^`;:Ã'
Cm be ~ by ~%i~#g S
cleaved ~~c.l~~~:14:'. ~`3i''+arl:tso3 yo~~2ti `~wi >lm.r ..~'~v~uYC.tF,~`~
~..iL nt [pT ; qy`r{ t~: x:.t~~ c}~Vt. ' A~4=SY [)e}4~~.~f~ Y
J .+ JA_q~ 26~~2.iY~~a r1Z~_ ti:~. ~"~-~.,'z a i,}LwIffi #'i;actFiun l?,
;C:='il,t,i..n,s ft3 ari',dl#i;e the polymer of FC`.+I`.ln.ilc3
X<`i,5>.~~~'ill with a f:nt1"b'z-
'r..'.01 Za.~r\~w~=i~ ~,:r ..} ra~s~p Any Ã~,iet:.is}f.E C~...#`ei~.~i.tFl~.~.
[Ãn alcohol k~ Z~+'~` i: i' ? can a '+s<:~.Ã ~ .
. ~ t= ~:L ~{'Ã t,,:,3: ~.,~. ~t 3t.}.
Chi .uL<ll1i\1r2>. }ni:\)n.
1~.. {~ \~,... .\t
~ . i
w. \}
l&XC';
..........................'~p, ,
=~ `Y.
=~ .'~Y:;\C' ~1
M, Ã:#::' ci .~.poz,.n& shown a:.~ove ri y, i=, and the ternl:Fral. group,
arc. Ã .idc<pcnd:;s~~~~ Selected
s'. s >~~ <3> wd hczeFÃa.
59
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
, ...
. -.
>~5 shown 33C`.lE?~,~'õ ~~l. p<?l4:3S .l` ?:~. ~.'L~.'311"alcà XXXVIII
mZflt=i <'
i_
c(2 n, b~ Y ii~.`:> ~ tF. 3 ~ ~ y.~L 3 . ~ a ~. f.w 5le~W r with
vi:Ii'1.'1kl;i ~ ; \? is: 3_E f?' .~:~r1 '}'3~i Zr. ~,~.L :~; 1_- {.. k ~.
t~:,~`l
~: ~,3.~..~,,. x \= ,#:.I" E#~ r~~: ~
bi.my.iS.:Ãed s., %,':irboxt ixti~ ai~,tL such as ; EcF3ri: 3c:d, o:ec aei",
or t2 ae;ia: I3':
Z?:hLn n':=3t3d:#:ieI t , bw c13ii3ho; ds, IGELti d with 6 b<.1`l! 'lo?t.y-
.,e?zcl.:].?Fc c?cF:Ã, }wxc.t.na=fi14?de
L`tiF:oe,, C?F' ala~} .-:)v2~3~~3?ti}-~~~ 5<f~~Ã53 aGlC.. ~.11
t2l"f.t}`a.3S ÃtiT.*
i';%":3up ?~sa, ci?rb<?n< c+'>, ali? ester, Ã3T al CI1u.
~ _.=i
rxr =~;~.?' r
f;~' ~ -w ' ti`l ` `4 = ..
:ti
~ ~ ~ =~ ~ ,;
-.:i ~?=.Y" ,... 'Y-=.- ~=:` '~ +,,^~t
~ tl
.. t ~..c: .si..
`~=
..>~tj.,~~Yx,3i'lfi:. =~.
.4'i" t~'}-..r'.y` ~~ _'~. '= =
n ~=
, I F ~ .=`, i .
vn~
:~ ~.`.1`: ~ . ... .. .
1;i1 f.le ::d:?nwt?.7mh- . inf}w.,? ::bÃ}ve .',.. t e; and. tht~
tC".E'F3::3t..zl group are i1.,d5,:pcltle..it:> >t l;C;Eed
3 wLwi~~~ aLh+~~ h.~~. i.~..i4~ tf. is .~4%c4~~l.~cZ1 from ibii Sli~:s~~yYsa
of t'~i.t.~,
'.i
As >ht`iF:3 below, a p+?lS``:ai:i' o4:Sl1t<.#itiz7lg }..lydrom-4 }F +aAS'
i,a3: be n.,;,d#fie'Zi to
p.'dilce a po3yirwIw.i}?':t}i'I> l~ : :m1p;i, For exaiTmple: the aloti`h:?:
L'w] bQ, I:=,mi`.d ?i,ffi. a
s ,..bw'.YhY x3uf~ such as `'tea.l."#i, acid, ?lC:ÃG acid, or InyFitiuc
n;Ã.Ã. ?.l? o.hcw
.:~'t t ~4 5` ~ ~Z ~ .r2 '~ ~,
.,.a~ with ~rn ~~ i iz,t ~it3~Y~ 3 ~~, Ã ?c~, a u~ i ; ~i=fÃ: i?~(?i~iE>~f+
.,.t`3 i . Ã: .~E a?: a
w.:~:.}a`. !w ;LÃ
pIm4_...., ae.Ãd. ri;e bc'.r"t1'.yii}'S.y,?:'37:i5ni3"3C:?'Zx4vl, and h%ios:
p:'C,tCctaf:g r'"x3up"s
R 5 v:.ln be ml3wv `iA E3y' 3.r,LIhodti known in wi-f.t: art to pr>d:x: an
izlwhol, a Ã:'afbo} Z'be acid, Ex:`
~3:? unn1ÃiL ;isp L'QA .='0,y:
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
p fi
F:i:.ti_ - = .: ` : :YZ:i
:,.
=~~
1L
.n ti1S:;. 027. 3}:i)..tnd:i :i=1own %ib(3 ve x, Y'. 4} ~ and fl':c tc:i
i11al
wlvcLf:d a~'i %si '.#n;<3 h%iweiaI.
~ I M~~~~~ods of ~ ori-i$~~~g Particles aud.Fil.ms
v:?'{'ttzus :-ypi.y oI flm: e~f:f> pa1'fides can be ;.C3#1ned firf)m
pt#lpa:?C'.Ãs of Ft3.in.tahFs
h.X~XLVf. Astiht?;' :1 below, various t~pe;5 of fibus and p'i3wF.cl{'.s,
s`i.lchws m::ei0- (?.i'
.=iailt.'i'+''i?TtiS ~t:s. ~+ ~- ~+ ~.,{~ a . ~.i~i~ be #.71^.{~S 7?T3'
l+`$1~.+:.l~;o of "`l?IFT3`3~t~` .. ~X and ~k~N e 1, ~ f ~:I'3t;~
~. r .~:~~? ,3
. }'.II~.C.Ts,.. a~il:i`..4 .,:i3~ ~~a.It::I(:~lG.".s Cif Jv:~."3`t,.':C~
~:`t'.ii2 i:~'t~."#~ ~~?~,. '#lai.li~~, `L? #:.~'L`'d~.?i};: :i..4 ~`:C;i
iwt.~'
~'+i~ c, C.. f'
< i
t1`3;.~3mltc4, agma_s fh*>, polymt:rsll"1.:C:tEa'Ã; t(? j`)TFdCFI:e a
7NCZ'i2#L :'i:3S.'f.'nt i:3mnsE.EC,-'.X.
:l iy''mlvthod :-uw,ivn in ih3:aft can 'bi.; usi:d tf, {i3 w y=.<~,t [.t..~:.~
~r~~ L.n 3.~ } r. ~ ,. . 3.~~~ 't~ }~Ltarii..1~ ~i.,t.~-:. r~>. ~lu:.-
p
.~~~s;~.{~~.i'~'s;~+~:~.2$. ~
L=l~v~la~~;;~~L.3'l:i7.Ma~,4~r~if.,=..~`L.g~~~~~.
~I'S
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
i~,..
~ti ) .....__ M.i?.,nii~~i~i.~s#~.+.~.:
~;~' __:~= ~ ~' `
x ~ l
Q
s~XXVI I1
-.
1i1.~1i,'.~ L~.3~#1#At{3F.F.ii~:4s~']<3~~C~:1 iFi~~.3~,'L~, i;:F.L~~3~ Q.
~~', ~..F'. U. n R?; y, t=; ,AFId tQ_U:>,.}nid .~~~4.?ur? <EF';
1a,i.dÃpC:n<.:e1>t:y si,'lC`c$.:.d as dÃ:l7F"ifsd h3rrw.la3.
i'3iSth43ds of Mil.~F}:hx3Li
,>?cpo,.y"#ilc.F., described h,Q-iein can be [F4oC`~'e:fr peti.?dlFce,.
õ3.?.i4.i E.`=t:i`g tt-.;hn#.ques
LnL?wF:F ,n tl:.; art. Foà om3:npze, aus sh,?wn Li:.fE~ve, a p3;41#?er of
F:>> *?ur.: XX ~:= .:~XXV'I;
` dl stolveL; .h <da? {SÃ ` x.i# }c~l~ #:3~. ~~?F.c~1~<?Tl~ Fli~ y~~~~ `c
Ex4lL> ;
. ~ . .L)S 42#~4'~. L4~kz ~Vr {~:=; .<)::
{
.,,q.:1E',`+`3Lt4 SO..#,.:ii7;.1 iE2i, dct?L?sF'.ed i.?i3:i3 a solid surface,
such as a glass sufacii:, 4FF .ei:iF#:Fn
ithZ? ~.<<?tyme:F #s d`eSsolbM in 3 :iolve`: ukC)ng !.#`.'h ..<:F ;gf_l1f, `
?ch ?s 10=
i3:?d depp<FSItQd onto o, solid sL?rfsl+-t.., w.-#b:3.e as i4dc:Vs .#:#i E o,
l,"lf't
~
st_.1.'~.#'~'14 t}a~:,F# ~.~f' 3 3 ;i??Y~S.:~;1 i.i. c~b ~~Fy~:?f i.=.i~: to '
~~ ~ ~'~ .'< t,zi~ a ~.Z,~`ci'#~;~ '~#l~. F a L:e~~i~.t :~ 3
t .F#.F; iÃ~:;'1Ã~
tl.mpS:.na;l.F.i \ or pr't'.wuo, o# <li .l'i' vc#.t~'f~ or ~"t'(.~#.lL.~`C~
Z+? a .~;' ' ' j . ;
~. ~#I~LF'~3~' _~?rok s~:.:`.s, .:#.:
certain unboi`aimleIlà <. "h::= h'Fol\met {,i#li1ta43T1 is deposited t) 3t >
the so.1#.{ s::Ef,.Fy.L: -ws#ii,~ :3
# iQ.>?3 i.]?:="s}~ xt~3 i:. 1-i'~otheI 412t.i ilt~g~~'1r7 tLm.s, ) ~ .; G `,
>.
b~,yxF'c>
~ f~~ ~"=- . ~' ;}c}~tiÃ:~t ~.
onto `c}Fa. 4=diii ~mmk3s'::; ~::g., gls3M>. #`.lk:l, pL)l-vIlder.
c<)flaH;'.i>l,f p46:C;a'3'dh.#:-I.> . tt"L
llF+,.t,::l :Fa~`:e#a u.fla? 4cd.F~txid.. or :~#:: f:4..iE~sq .L~Ã#~e}~., a
J~~.i~i~ tffF õ ' ~f.cZ.FL:C?, 4L,i.~# #'Zs .} # xF~.'.EC, ~1~3' ~.
~'.
&vfcc, Fo#' w`1...?mplc, films E;=CIiÃ.ci1nw::;:3 polyuF3eF' 3;F
Fi.fi`?#Wul..XX or ;'S.XXVIII can i'Fx.
3i)FF:3'~.`~.i ioL t#' k32Nl,.?t:-r in <3F~i t3? Fl11ic i}:` aqueous
4<?lLsil7FS, i1`z
ijfgi3#.1.1c w:L; <'#.ciIwous S(?lut'#i ns.. and a;?~}l1# i`? the :s:fll-
#t#.#:?rz to a sa`. t
. ; :a1.e.
62
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
~11 other imi?ix?inxI1.s, fillli:i cirn ttl1:]iI1<F a #3ol1m1ez of a oIm.3lz,
XX {.'X15XVIII
are fii:i:iii<'.'fl by.mc1fing ti:?epiS];o:-nZ:i. ThC.:.ii.?`.`lt5:d
pd_3ly~.iiwi can be i.~'~}pz.es to, a~^.53l.iÃa
su? f i e 4itt.xl. i'* g.a4: iother L'`=iriboc:zinr#..'`#ia.~'i, t}li:
pi#l'y'nner 3 s i::i7pl1L'`~l tt? a soa:i ssl`azi:#?.C.{.>
and is then ;n;.lti=:1 tc, ioIi`'3 a polynnwIic f:11l7.
13: ct;"ia?n ::~ibodin.i:nis, slibiltt<layered fihn5 are prepzs_.iti:i;; 1.
or exanr le, a
i".`o#ya.i3.tS. is d'::i`,E~~ited oI#t<? a 4i33.id suf-faGC, as described
abC?t'e tl`, pr?tt..#i:o.i fi.i#:''1. A second
ps`+3.y,m:urk ziAl.itFon Ã~ ttlLÃa ~t3e~.?f?si;'L's' o:7to tile first film.
Polymer fil`.~i.s is~ :. 2, t '), vt, 5 ct1'i.iz
6, (;.t. `?'lctn~' la'.,L,`s b:: A;31`odÃ..L:l:.d by this l`.ietb13i3t.. hi
t3i-iiUi {.i ?bE3'tl.inmits. u.ti.h p, ~~nls:,`z
ti .i# ::~ ~3~5?~..lti::~.:~~ ~'I'~?f7i i3 i3S3~ ri;.~~=~ f3~ ~`t7~al~i.:i~
:~~. ~;i' 1r;~.,~'i,~.~~~. ~I> 4i?.+L#;~la~.F ~ifi:~~ix.~~.Flf`i:?f,- ?F-
o4..aulÃ'3Z..:f'4 i`i'weudo a cl'-f-i"'eItz?t polymer, such as pi?iy(hai:.tl
a.4id), pt3ly(i? ycoiaC
.c
~?t}z~;~,~<3i.#..~, i.s.;? ,Sut,#.~4`~.;i..z~. cii:i<~ti.
~3t)3'v;vi1~?'CCy~~~.:~.{3?lf:.
7]C?~~?~~iir.^t~.#:~#~f:~~^='v't`~L:T"~3t~~:i~} A i i~'.ls;A:r
pozyea.;boi#wi i3`- ptiF = 1#.=x1de.
: #i.'~ .~. .. . ~' t ~5r
zi'.~ . '~r~s ;C~4 4ziY~. d ~'ir.3ers :=i~.#'#. 3:?C. :vfi.'E<:=+.=a<:i
to ~ :. i l Z y? . aS~. 't3'i., {. # ) .?`i Zxi:'.= rz.~.~G z~*
~~
i 3a w,, , ~ i
#'i?tQszo t3i,.`d#:et,~. .eb7t e4 h-i w.`iii:3 i.{#fft:Ti.t`Z
a,'t~;L`ntse:3:i":= :i'#ilud4d ;F#.i layers wnd i"c
a ~ t ~ aii ~ t, =. q c. ; in i'i ~a.C#w~ta s~. ~z;.a i~if:.t ,ilt~" `i~~.
For C.?S.cil~ -;~li., a .II'~tt ~~$L I#~ ~ti . ~3~'. #.~~~:#.t~", ,Iz a .i#.4
. ~ ~t? i'
E 3v-e?" di <Ã;trwd to mZ .tiL a rapid r ~.li..aS't' t;.g., within a iew hours
or sav i.#; 3i3 s; "+:.CoI'#ia
enr can .'.3i ,i3'e~A~:Jird #.il t3:. Lcoxl~ layc >F t.lesiga-3ed to
PI'oS'#.de e.'it,.at.Fea~. IG,.s'~'?st`AT'a''C?i;
i&
`- _ õ > .I
< t>I ~3L~:.~;., -w. `. `~. 5 ~~`C;<'.~... ~. .. '' ' < tE. .~~.ltE'=~"Il~iti
i`i:=~:~, an ~ `~i.~l. . ,t? ":ci+~~:3a''{~~~ can b',
~ ~ z # l~3 .'e`. `. #'E'~ '
ÃtaL<Ignti lii?t: :v i.lÃ.'t~ses:in4' zi.-i:1.iE, bilt tC; iT?Carly
`~ia.l".ty i'elea\Ã. 7..if agG .Es Iiw sue7SC"qLiia.i:`.
~':` #F'it::i ~i= r ~ by 1#'i Y.:'a'~i.tc-,#;.3 ~'i.~..~tTd#:~#~o ~sl, s:
~~c~~.:~'.aFi~#.'~%ll '~.~l.) z#li7 c z~ is j~Js'w`t.~.<2#4f,. ',r~ Lr'
.a.:#:g i:e"?#..LIu'~`i..l.i t3~ a z11L:C`~"I"# w?~e. lC5i i:x%i 'npEe;
u.i'{..tt`( 1111ct #s's='i#.il;;0 c_.#l be E.S:,i?
~ ~ i ~ ~~ ,a = 3a F ~,~t,. f( ri M+ i
~L; ~~:+~?~.s#~ <.;:li?a..~#Si~`i ~.~?#~?.t.#:~?ie:';
i~.~~~i.~'a.~~.'rs.i ~.~,`~i 31i.'~~t a~~ii16~# XX L.r. A 's~ 4_t\.:'4.
ti+~FF. !`#. ~..~. a ..w~ia#3i.
~~.
r~ ~-= ~' f~li::' s ~..,~ ` '.+>#~'~..L:i:=f T {~ `~ ~..~=}.~. ` `+
~ ...liz such <13. =3..4..'~ r`, The ~Tl: _E:I'~D~3i"ii2~:~` ~S:I'
#.1#~..:'t~a~ #i>d]~~ ~ at .,J a .,~ '* .~.: ~L1~~i:I1i..iz
iI% a cof...s.,s.lei manner to A"Yrly.l pa:ti,'=: 33s Sl3C:h as stripes
and:`i_?.i' &?ts. 'ri:e st?lvt'#it iS
Tet27E; wd bi cxa~,wL;l't$i`.:fn: T I11'.i 3meth[?d can be per.;t?maed with
more than .`a~#e i:s( i-y.i"3.Evr
~=:7l~iiia..<. ~c ~ i#4l5l u:i ,. ~3~`i t~.?za c.F'c ~ of q.~ii '~ ^i T~1~~
or .`~.X.:S.Z' 1:~~I c
~#I3: y'. :~. ~C.~=?iF:?~ a ~.}~vZal~~::,-cZ. ~ ce ~ ~ l~Il t.]. L.. .iE.:,~~i
:;wC:TiL s13L . ;?S 3 0}-;?Z+c~i~`Y\f :~ed ~~.rtS,3'#ls.~, i?1%i~? ~.?4.
fia~`~':'~1i.o ' onto a solid .'.#t facE,~.'~b' fl:'i:i
~ ~echmiqtth to ::ftbT'd a rt3_:f omC'i: ao-i=~ i containing ~.7~:.3~i, Such
~:~t~'ttzi'iiL,t~ can ~efi:~`:Te'~:'I~
~
l~3 ~
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
#Is Ef3 apk<in>~ ~?1.~33i`4+,ai~`r.Ã3 .~~ ~:'u'`? ~Ã"IC~ ~:.ssLi~.;~s as
deiL'~n.33i= i by the pei1.,.f.: pal$Llrf? }f
at l\: ' iW\2 ~ ,~-"#, Y;t,h, a5 ~.~. a fi1i~~~i
` . .. . 5.,
Mt.Shod'\ of:~v~`~ak 'i?<fP;ra?L.;k4:"i
3fi.?f~ iC :?#.1F IC? a P;] x#3~:?~:#~ls.C~
'IYi?. ~3i3~ F?3i iLti \_L.?i=.`,rfbi..::7F'.#tiin i:'<S.iI bL'= t1SW to
t ~ . .
3,tsir.~; ?~. 2'iiz#:Ãs kÃ,sa?t=Z'n in fhQ <3rt: For t.x="s~mplG, a water 3in,
o.l, eli.Li::s3o.1 t#.:chi?Equo
s\:ribed bs `"AWnd &ad ;:o--"vorkf_.is' (see 1:d:(t:nza et al < AtIv.
Pol4ix..eà Si;15";6; -1``'
-,
A: ,=,a~ i, . s s i3a3t .> 3 ~, ~~zl`L'a'f3, a ~~li3r~>l. ~ ' 31+l. ?-'"~
,996). ~
~.~4 1 A. ,. t i:3 ~^~~C)~~'(? ~ =~`~.~x~ 3FSItt >avo. a ~t.?>.m4'r
is i, fL4iy? s i.le #3? using a \'f3TtS. .}nltiy device. 1:il
\:i'=.i't`t.l#.i. fi.ie
;i
i < ~
L:?,\~ is \si "'i in tli..' an ca r ~`r such ~1 ~ '\ 'S:=i ` ~. t~Ã
~.7 is~.t S~ ~t'-=: s~~s.. . ~~'.~ G~i i#. ~tz"iw_. ; hi'
z~oh.itr.ÃZ>;.? }'" i#.ÃC',f;=d in a 5% p(7ty-k'inyl #3lc(~hcil sE1:Ifi'al:#,a-
#`it and YC37'ttx.}.(, (C3r 5t`r+ycaAi.la ~i3.FÃg <
}:iÃi bfv tÃp sonicator) m3d 5$Ii'iLd ffzÃ' 16 li~.?im to ;~rc#%lu::4: F:-
r#t;aZ?p:ÃrE]clu1. Iffxc
~.t y ~Ã}1~~=:~..
mi4=Ã'o,"4?arf.C.C_t 3Ã'4 collected ;.i:"is`i'''...s}.1ed wTt:e3
d#T~ilAeia`d:kion>.:;Gt water and
T+. PÃ`#"3ducL: :3aa.3'Ã'.?sll`tÃ\.:t:.S, fsT:te oan if_?I exai31pl4_ me a
m:Ilit'=dE'si11uit>3i
pt?xy-,t-#.i:A.ir..<.#b':?Iz ÃT?iths3C?' (st`o, 4 g . Landfc-st[=r::'f GI/.,
N':<"1Cr<3i?';t?lmuies. 32:5222 ^, 19fr+k+ ).
Bi4flyn a :.32TEa~#?it;}i C~ I as C..f. 1,\'Til? ,f.Y{l 5=`; ~i~~'i>Ã~:#.il
initiator +'~ tls C> ~ t, 1 l
... -
^:7;#wt il~. t:#:7't~ #~ ~x.. :~`: x.~~
~mp1onÃti-ilt..) or fflbs;..`ed#t::iz:3d1lZ=e:2v
such :1:Z< i7ir.Xi:Ã7?w i3ei7:?'C.#:o' t3li.#t.=:3e, diethyl f.ho$ $
C;hlot;i..f?i`Ã:3., dhr.c'l :Li,C.~~:tÃ:t+::='
3..~~~^i e1#.f3:C:ii1.:, `tlÃ1 ~~~IF) bicLtot .<., ~(MCCN).
(DW), or fa3ld't:t:hyl SIlIl-C3?::iCz=e, f:i: C.S..itZf;a.l an nt,
`'suf..,.# as I.e,.(:fi:.:x4l >l õsl4Ãj d:Essol:'4d:d #.i-} th`\'.
S[3lvf;:$?r. Thf. ;,olvi'.iat is t`u.#.C?\ 4%La 4 i:i ao , ry
U~;?~?f~ r ~i~.;<3t' ?;a:%1tc ~`#S~~1L?s ~#.#.T?~:tÃ:l.ei:.~ Ã"i:=dllx~?Ã1s.
~~'~Z,~ 4'`sJi~.?i.,~ Ã;~,Ix.EÃ~':, .~ :?l$~:s..a with a
~Et1Ã?a 1.f.ÃF..~ ; Fi~.{ i t~:iTtEv 4t~t }k e#~ c~ C3~ ;~i[?1i +?~
i~?l~Etitfll ~~}f}~t C~`3 Ã~ ~cls ', 3IA `sà ~?ÃE#.~.~.:à zs; l..#df3n.
L,nSÃ~" ~:.a~~L,-flt.,= is ii'~?~~i'?.<i~.~:i~ Etii } .~'~. i. ' i ~ i a 2 ~
~" ~t ~ ~ W t L Sic3315:~ pulses ;~'#ti aL<i:Ã L, E3t,n}' snV2 Zvi.l} 30 ;~Z
of
power, w-hicb a+~)##.,~s ffiw.' mÃni\'.~~zÃ..~e`~iark <3sid allows the solvent
to ei'..#poic1.te. Tl1,,.`=
mimim'W`3:f,?n is .'siÃI1S':t=Ã"Ã"e~.~ iÃ.1.a? a iÃ.Ãdstu';:;''s: at 65
'Cft}Ã'
21 .?oi?vi:-e .i firce--ri3d1Ls:3 pC?lymer`z,..~.Ãti<J23. Optionally, the
:I:s...lfifà . Ã+t: d?; tI3:;#.'#.'~:
.z, ~~i Ãl~ ~. ~t~y~~.Kst 5 ~~~^~:; ` ;s~?~v~:~cts buffer, .v : _~.: .
i~~lfr~.i:. :~ rx ~ . <?~ .~ ~a~I 8 ~ ~~1~~:<,::F Zuiffer>
Nct1rb<?.aw iyL:.,4.I", sC?La:ÃEi.,v.l i,:ltri#..e :7L#r`atL e.i' fZ'.'c#
ti~=i,J d"svwJ, riW.rnf,3v= #%ce:i430 `<Ã% fc3'l:iaia and salts.
64
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Aft..e :1:Ft vi:a y #3aÃ>%3puft,dL~ ail, e?~=' produced by phi?W .,:i#i_F...
.Fi?:'#, For m<funpk~, a
nwTi~?i1E .? as O,,s.:3'=Ã.beCa li%F'e..: ci;f, be dAssol,. =::( .k"1 a
st)lvt.3t, st c?.# .:is ~ ~a c3 3t ~ be'{Ã zcF?.t;.
diethyl abE:>F Why[ e3#:=otatf:, C.'s.fchlf?foI?tctbief`s.L=$ ~~;3iz S4Fz#i',
(THF ~ :oi_t ~s Ã.i, ;#:L=i~-fg?1Ã~3~~~'y~s'~~ l.`~3, ~Ã:I?C7~ F~ ~~C's,
2Ii3f3'l#e~~ (DM2 i or
d#;i?C',thy: 4Fi.['i?.YC'.Fl3i:. II?. CfeÃ'tiI#.n embodiments, an agent,
5Faf4:i3 as px3:'t;=litiF:Cf'.~ is ..lso d.bSi::dJi;d
in dhe 4i;ai ef.e.: `F A3L:= <,ohr'ent is .ie-mC?-vC~d VÃfi ,"+`E?ei.s?. y
L'i'apCi<$iÃ(:>n t1.E1tÃi a i'Fsco.ati #?:l#lt?.il'c
>t.1.3:Ã:f81t:. ri':`a.': vIs.:=~.?us mixture is Ist.fxL'd vr#th a
S~l})#.?fl?F#.~ ~1'aF?~<# f'<fl#~ solw1 . ., scxLh :is
sF3d?F::mn doZ..';w'`. ; .#..Ãn a 63#.I. ~,:w ~.4oit.16CZJ?, The mÃ\.tllf L'
:`s' thC'.s1 sESÃt>ci'eic(> tor ?0
F'f:.t#Ã[Fli.'s 1s4:'=oon<? w1t,`F s2 sLZ'.i.FltlF d4 lclv) I4'#tb.?0 W
.`'b;'#tt#F 5.~.:~=
kF#id {3l1t>Zi'13'lg the solvent to pf.d;~i:F;.Fl v evapeSrel.:.E-. :..i34F,?
Y
pr'#`olÃtrtsEi.. .z3`e i,dd+.'.:ta to the 5.:3'?uEas.ÃiZl:. T-1hL'.'
nn.F3t#t!`e :4 thÃ::.n o;Ypi.?s!w=d icj H#,rM ftC?Ã?; FF.
soFf.i`Ge such as a fneÃ'c:.#.F' j t3rC l?1Ãi`:c while the solution is svi~mxi
vÃgof oF.:si.~ Ti?:` Fcmudtz?Fw;
pxfl"d.Fdws ~i~~ s:ÃaaLi.i wvemÃg"In ok3eFl to tho <k':I` to xFfli3w aY i'
:"eF-F3: sFI3:I';....'ro3s``i?i:a?: to
4vsfpoÃ'iiu.. Optionally, F_iIe ?t?~~Ã3i~F`iG i~3i3<?~~<3:.fS ~Ã'S are
tl'fc>i. dialyzed against a ~~".~u,,ft'i'.+?.
~ }~ . x .., a ~...i excess i y
: r~+ ''~~,..i14 ..~~ t;? iS .C:?F.f3 u a= .'~'S..L`t~#ii t3I3d salts.
~ e ~cs be a y "5 =lt~
~fi?=r:w3~.`>~; ~~1Ã't.C,.,.w: can also 3~.?`t. ~?f~ ~~?aev~S..d~ by a
~.?ft.C:=.~F~:Ei2tiC?Ia Ã^tl~.t.~7t~~a, For 4fimmp+e,
a potv#^iFa,F of Fi?F`113fahl XXXVaIa is t.~s.i`'s4i3l'L''cCs in a solvent,
sE3cF :4 ..l .: .: ... 1.h.~.: ...,~. .3..C`#.e~s
w a.h afl w gÃ,:13::; such as pe.lti,l1t&N.t:L I l?'''~.' '.^'.i]l`aFiF[3f7
#:1iidC>i:i~ to an aqfa.L;FÃo.e, `. Fà ~~Is I.fà f
,L d:.#t:C?7l. 33.1da e.Fs si?dluÃ?l l'.~.ittdC.l 4ri ;tf.Flfate in
s=S=';f~f.'.r, JIC `.'C:=.1'.[1 -Fn~,. mÃxtF:.3t-0 is ..uÃfs+..a~C'd :o,
p.{.xd?F%.. an The .1n.,:i,ttZ3`C: f~ sfir.i'i:.d while C?po: to the
at2't?oaps.::S. .ÃP c:=v:1p+,?rai`=
:~i.~. i ea.c>. . . ~ :a < 'F? .. ! r -~\~:=i., <f.>Ã~ x
s4 ~i.3F..k3 as ~,~Ã~:~~1lrri~#`~etx'#`ck`t~#V> ~~:f~= I"iHlt..~Z.ig ~
t~FÃ~F+~`~>.5::s are = z~~.a~.~.=d
t 'v ? ~`=
s:,3px.E-mii lyZa:aF=S z:,=dusl#'.w:i3:YF..C.F?i'<3I..F#Fe w3t1?
tf:tz't.%..i5vC.vx.i::S
4i#1'fat?t:;:i at,
x.. _ :s~ià t ~ 4Ã:~:~} ~~n't, the diameter ` ~ i.~i` the ~.fi x~.'~~.
af~F'Ã'f?~:: i.."J`" ~ ,: .g ~~.`~x~~:,~? a I f~ t, t..?:, iz: cÃ'ft:
c"1~+~ ~ C ~Ã:.. ~ *~ .Fi~~,
iO fn.Fcrf3 I5q e.g.a :?etweeÃf 1.0 l2t.f:i~ and I a1'Ficrfl:Ã1. ~evtvmI]
5~.~. .fm Yind I bt.t1iz:cefi
:eL`':.i'#: I and 50 F'n.lc?`oIF.`s.
100 ..1'i"f'f mltl 5(10 mm., or bC'l~:'
~ F~;;~tF#E FI t'Ff of i117 ~;fF .lf ~~ 1~?11I~ N":2?.~#"I4 Pt#Ft1s`.'.k-S
A`#S= faeffi(?F kÃÃov Ã1 in th iÃEt for o"3t:iFA}itflatif?g aF# ~ge:'3t
wFEilfÃ~ a P+? yf'f?oFf?:
pc3.~..=.elL L<i33 be used tfS folal a poa4":11S,:r:`agC:,13t vs)mpleA. For
C.a-,,,a:i31pl4, iF3l C,.l : nyFfF..sim;
Wi;bf?lqt..? :F4 usod, tt: fz?f'fT: pachum> containing pt1:t'~ici: s of
F?..7Ftiaa XX. A P;31y'Ã ^?et' i?f
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Fot't-nuia XXC".FÃ-. b~= di:~sowed ir, .. solvent, ;;u~ch as
di;e:hlort?mu?haneY in the pze~sefll;:e ofa:l
:a<' e.Ã-., s...C~l.s :9ii.~,~:it~.F,1~:?; ~~l-F.~
~?C1lX"aL~!'=`~3vFe:i'Iti~.i(r~. `~s`ti#?i-~it;.~.331 Fs +. ~?a:E k~.:~. A
sF~:F'~.t3.~:~F:kÃ~.Ã~
~. :. ,.
SZ#lEi.Toia, s:ach as 51,Ns p{3ly\tn3'` EcC3hnL is added to the and
the rLslÃlfi.li: ?t?lFÃt>E`Ã,, iti Y<Jr`~ex#~d fi3a a-b(?u: 15 ,3'1)FAi:Ãun;
followed by sÃ:n:tFk.: fE>F' FNnF? 16
bi.ZF.F,r:i. The rtisuifi:~g pi$r6c:C's ii:E'Zi colli_'.(`eÃir.'it w`sFSi-iod
witli. w<ilC,r, and 1}`i.3;3hi.FzeC:. Ii3.
E..LF-t<'diii r.=i3':kbod .'¾'3;x7ts, the m)GapJV101lat.Fi?n efficiency of
PaZ:litFxeE lbt #1h4 pwrt;#.:C:s t.SFi_,~ th'Fs
ti:i;l-lizÃL]aFE,.' is betwE'.=c'1=a 30-99%, hi another etlibC3dÃf?1s.'.F"i~
tbL' ~.~n4,<i3sL..,:itFo# efficiency o,"
Pn..cli ,aw'! by fihc Pi#ifia,los t3s;?,ii; this tecbn't;11iÃi: is
~.)i:tw+.;`m. 60-751.';i.
~llt .~e FFaF~.i'~~k`lc3 ~'=d .i#3It3PE3l''~eIfc IF ~ c1F3\a ?~cF TL~~1
Any 'CGA7mt can bV 2~5~'\y~S.~'V~Aii~~=W ~i,,ril~~~,i~. the polymer flSnn1?
and \J4l.F"L.n4.4~ d\.sZ.'5.i[iS.v'd
.i3ert'ii'#.. ., a>;' e,.&ixF'i3fq4, r: ;?i]ly'#nkF' fillF;"# or PartÃ.ciC:
LlL`sct"Fbed bebG#.s; :z,rF .Fs`iis?:`;3Z?s:_Fte a
pl.`ÃF3.ns.cU:iL.Fcaz a;;o?i: s..~,.ei~.tf#. f;ao.m a;:Iit?i.2tw (I)
F1m??zsteFi3id:?.: anEi 3.F3M3tiaai3 a.i=y i.E`"u::~
f NSAUDN,i i:i?zFlgsõ~,11'C, sud1 as t`Fic$Z3fcfEiie. 'rbi~3'I'ofGIln
~"~.Ct,apaof:,n~ :i13d n<l:pF:>xeI~_ ' # opiate
ii.?Ft;Fk3ha ..F1Fg-t`sFcs, such exs, L,otlE iT1e, fGk7lauy`l, h4'dF'on-
wrphoL)tn.,.i:=1d I;?t)i:ph-in = 81i
~ci~ÃE ~`~i~iL"= zÃ1~~3~~~ ~~~~, "'.,tz:Cr3 ..s a~~~ir11a (ASA) (L=nte33i:_
coated {'iSA)?. 2~~ l+ :}.ocker
antihi4lGF.~~~inW~s, such as c:vmas:h2o tÃ~~~~ terfen:~~ine, (5).a2 '
blt?Q:kcr k:ntÃh.s4amtnÃ.rs, .'iicl.
x.i ?:'.'i i7F1.:Fd3I1c and 1'iliilÃ3dFx3C' (6) SFla:l^.Tl 'cÃ:_3b\' Fgsuch
as
InliPAe`x3* 3, (Md ) iFnFi;i:Elcir:?`f3hii:: ?liiti-i`e3f~.'i::ikYS,`s,.,
s"e8t_h as and Ni:nC{ myc:Tl:,
20 (8) cFl'i~l~lÃFi :i~: i3nt,ibÃ(kt1ti. .:FÃ.`:+,Ã :m'oo.lv4ti. 4LFa'i: as
n1.F"1photC:#i.E tF^, sb> ciotr.i'n<i,z_'+,3..~.,
llF.Fct?i3:i..}lc, itett?Ls,i#.F;;Fziz.L.; (9) 12k<3c[:?lfdc a1ziFbF4?t"a. <-
i.Flfi f::fi~~:'SvC::i, ti.at,, as
azah,"wmyc_Fn ,.lF.:i bet;Ã-li3clti:FT? <xFsÃ;fbioL.c i3.$,3:i-FF,fev6i i;s,-
,
.
SF.FC13 as F3a?d (11) pse..,,iUM :Fi0bFotic 1uL:x3 as
n:..ciffir F3xai kfl.`i`.. p..=ii;.el.il7.i3 G. and penicillin V; (12)
quinolone ,.in`.ÃbiC3t.... ;~:Ãit:".
25 im\:ctivus. :Y7:FJh s?SL.'=iprofloxt'.2eiii <t-F.nd norfil)x[il-iA1, (13)
tvtriac\cliFio aunc.F.b>. fil-= anti"
3.i>rSõZ.ti.t ,}, .>.F+...., as do.~ycS`C.Fi`,4,, Ã'Ã.in'i;cy4linw, aIId teF:
<E'E yr:.v.iFfC : (14) t;nfit.#'.Y:.,=.~f'c#.fl{3tixS
's3mi -it:ÃfE'ct.i4'G~ such as isoniazid (INH). and d'zax'F`iipÃ,,r; (15)
aFnt3pF'C;tozoz3l wsFxi_='Z .., ti.,CFv`t.FCi,idille and C aps3:Fi`FC:,
L;6,Zr&ntFiFm.anei.l
antip?'Eit\?.Ii?3l z3Fi1i-.i#.1f\.i.tkv4s, such as u,:=hloJL?quÃI'k`v' a.#.id
s~3~5'11A3+ t~Lw:F27Ffii=.. (17)...k}Ã f=?`sõ3} Iti>;
Ft^t > [~5~ty..Ãi Te Y i?~.!=LÃ~~;s4= ts7 ~]tS =}L:;.-~s as , t* (~,e~s ';
sM~T't,~} Ã.V.\.}
[ttLtA ~,+j~! )}/t}iti~kLrn }-s(?y~ antiviral ~nti*.3y=i.i ~ {=A C;21SY .iy~
2.'=v \`~ s ~s 'Y t>
Fr C`~ &C?S~Cd\~. L~ LFLSY`:sF t~ \Ci C].igk,t'2t~~ ..1.F~An
~iCi
3 1J
c3`'s rFcyE,.lov_ii, waTzi.'.Fc:.ae7L'=#.r, i.Fz:Ãt'.rfi'Frf7:'.F alpha, and
huÃi:c3:Iit,.Ãdi.l.kG (19) <$lkZ`lx-3.t?i g wat n4t}")iwstFc
6 ;1
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159 a1gC1~~.~. siÃt"3~ t)S ~.~ laT~~se~~~l(.t~Ã~
and ~:is~~. :;tÃ~~, (20) -nÃErcÃsouÃesà t~lk4l(xiis~g '111,611..v;_Ãi<asAic
aAy\-nYi'!Y SLYc#.]4#s cii1.!mF.vCiZl:~ (BCMj) (2 1) aÃJ.timehCibo Lo
CL.SS:i?i eZfp:.4vLicL2gVtF..~. .TuT.^ha+4.}.e
(22) p`orÃnnldine analog r.l:niii;l{:'=ti1blS.Siti' (?fl"sInL=op,_Es ts`s uaga
l-l`'s, 3.7t,i: as
fllxr3l{1u,uou,l (<.' FU-) and g4Ãiwii:1b i1LQ (2') h,`?ri:37101`1c`2] ;:51
..SY3t'Op..>`.s6..s, Ll.;~a s
1`,,.p".i?hLic. (Ã:Tt3 (24) viat:Ei':1l 43T1fink.oplx1stÃ.t;",s, StIc}. as
itSS..t..~~~x:YS..z, d.t3p.3sSdc (VIA46.), lI3'.eFf63.i'o1R>.'s~lpha
p.aGfitc:{ol, and tÃ'aInt;)iÃ: (,.Sa.+Rs:'s); 125}t
anLabamtc ..'.i>i.in4opi.a,4CmSJticik as 6Jl1:f.s.k~yciny d..{cF.imm>yZ:in,
dauno. L:Lrif.eiL:,
do.='~C\~rubit+;ny:JAia miifrml='1.~in (26) vi~ilLsac}ikalolid nG~~il.ur.;w
any~mmiA'a(stwc:`, such as
i iFÃblc.#:st3:#e .:3.iad vi72G.I "st1>io: (27) :luto.r,l:onnIF: agents,
tiS:ich as Ã#ÃE",:3t:3`.i+. =(2` `(3.i,Ã.dc1'Ã3J..x-It'.=x'_;:~
<'r.utt3.~',1t3t1i a i:lgio1tE. ~.. ~i3Z.h as ti?e#:lil'i.+p17...' iÃ.l3d
ti"Iht:'iy'pht n.idy~.; (291) >?Ã? _Ãm':asimriÃ'?ic
' C w _, . ~i?~.cÃl`
~~:%Ã
. :.zt~ I i5; ~.31 ~ ~ r~ . ~~.. t3~i`I'~?~,.,.J1 as c ?C and ~.~:3i +. ~ p 1
`r ~+~ #tj'~~:iÃi, (~ ~1' ~_l
:~3 ~1~..` ..1~=Ã'<~. :C= ~ y L.~i~..\, wi.wt:xl a E.
;v
il~,k <Yc ..ts, si4h <38 : ... ~~,c?E}i.: Ci t?,:rx">S t*eirytFli: <3~t, Y~
~iz7G. [: .: ~# ~:~?tJ~,.c~nl~s,i-
paà (,."~~~Ã;:-~~~i~?.?a~t#Ã:i~~=d~:~;, such as ,~Ã1c?~,w'~~irÃ~.; (;~' )
.- .
\'i;iG hi.[S pyi7iaSi>tigm.3Ã1LY (33) alpha'bt4iC=ki.Z tiESch
.a..4Ã::t.~~a. ~. 3y,i i~.f~iG= "Y- ,~y~.~.~~.~. ~ ~w.~v ~.~ U ~ a 4~.Y o-
as pn;im^=Ãn, (34) :fri'tr.i baf.Jf:ker s~~~V.~{ipafh~;F3~e~L,~vs. `s~~A.~1
~~~` ~,
=uxYCla)C>-~~~Z,.`a}~>.::i5.i.=~5~:?1.sWV..'S, as aSR7oter`}2 waia
dob(atLi1,i>t?L (36) GS..nhkJtas4uSCLr L(`r-..c_in.v, ssuch a^..
i;4pSi'1#.i t W:l}. p..wvi-N (ClC3~..~I6i?g.i'C.l. bisl:E.f{i3tt:') ett (37)
bÃ:ti';#-:Flockos `.~uoh iv4
i:l';LS`aiS;.%S. SFio,p op-anESloSe ('8) ca:5ci:Ãm tll:armel bli?ti;kt'#'
ca.E7t:c.Eiw f>nc',.zs ; o:o;. (~..`s n.itC.'d]::33:nC.`,
L~.i4.t V~iiklt~~3wi.~i>.2l; *3.J ~ 5?S.'Li~.~.i~l-' (~i1t1(Y.il~fi.fiiil,]q
.:M~~iy.:i>. as ix2~;sZ~xi.~Ã L'4' .S!\}.t~?^4t~b ~a~\ "1'4t }. 4~ }`? r
G~CtJ:~A23.it=
glycoside an>ia.rrh3~tbinik,sy sus.,la. rj\-, d,gc?xÃn, (41) class I . uch as
:;i.ocaz;:.,, ÃnuxSleta?.7i., pheI11 t<3i.1-I, ?Ã t3c-a3~:na13`iÃG.~e, and
pAn1dSne, (42) f.l4tss 1:1
such .,s :i.4i'<?loi, m;::opF'E?lS.Sl, p7~5.>-fyra:nol;13. tÃ1I7fSlol; (43.)
L:,S.i3sy III
:>tSl'.h as ai:i;.i<?daAf?ni:=; (44) ..-S-aws IV ;:Lke': as dalÃÃ 3zcm >t;
i'~.' ?..i
vC,l ;~.>t~ S2 # \' "~rtC. '~~si~`~.'i" .! .~<`4IÃ"a; (46) iiiÃ~?
"~ii.~I3 (451 i~~t ~;iS^~L>:f3~.:f`s&t.~ ,'y~iix Ã~~a k~i:~ ~i li:."~~ as i"fr
*'.~ ~. v'. . ti n-
4L9ii .`t:ftiSg unf y.me' imilib;:ti3" t'ACE is3h1bitt5; 1,lntSby~.^u.
ioÃ1Jti, us, such as i.x.zrtt;>pi .i and
immia-p:iA, (4-') betablt}ckcA antih.iporW.Ã1sive,i, Such, .:s amno4ol. and
p>opw.i+3lo;; (48) a._:lcSi#iS?-%h.Z.7n+.:l Mixt;:ksa.i' it,ntihypoXu,1;five
EMoat8, such t.Es firRxlÃE3t..`..'.q (49 central-acting ad:'e-nLk"gc
,,tÃitihypc3'te.ISiv;~~-S, Sucl1 ,.s c,lo?3Ãu. >m,' all >
mothyldopa: (50) dÃuuoc~io ~.~~6l~~y1wÃionwitre agents, suL}~ as 8rnÃ;<>ri&5 .-
:wr.~ fata:i.ie,
i.HC'I'ZI aÃ:t~ spironolactone; ~~~~~ pe-6p~i.o.,al v,;so.>flatoÃ>
i ~ pti.``tE."ii.srtvE..4, S:10h, as hZdIe1EAid:1#.3o w>Li minoxadl:t (52)
aTAiF."`pi'-rn:cs, sooh as
67
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
;.~Ei71~z~3FC3r.3i e117i-~ ~}fi~~~ #e.:,~i`~: (53) b7`L, wl'#i; it,iZvSt;.EIIt
antilipemics, ; LEvEt'3 ;Es cl.:s~
(54) ~ ~~"IG- Z oA n%h.Q.asU Enhib:iLi.'sl` stti:"h as I~.~vc?.`.tt?~in aÃxs.a
p1.;vt3aiclt`;Ei; (55)
F:1L#tE'opL ., such t]s, zEmE`in n, dt;bEtWu11Ã3?1`r EzEd dc$p::Ee3]iF?C; 56i
i~,zixd.ac ~fycio`1;,::C:.
#.nolE"f;pt. r, 5::i<h, as fiiy+.~x:ns (51?) fliE`{3mb'i3rylacags.,nt:9 or
.~.'n':! ET3E'.5. :axF+. Ei?s ` JtC'.;,?la.s`5. ~ T}~~ ~.r,
'amme.`cEikiso, StF..r7wk zi:`s4t:a :1Fid i:lrt}zh#.xi'1 e: (58)
d.;r.eT?cj>o.z?gEu faw .3ts, stFoh n` co1L;:.31QR'>i:1
Inil:i.?x'1dil, tw:nt3111 Wi"R-Ai (',T)`~) dormatÃ?;s;i..v._,.#?;;ii<
%o.;b:cC;,.i.zw.,t`>id, <#.Eiti iE.f.ti;.:17.::#att?Av aoGni.t, sClcht tiS
bm=cfhi;<<'Srw and ; .. tioxbE:rwf#:stsor ~~_'. J ~t:t
~.~, 2
i1.i,.~fii iHS;v t;3p%Q~{13 :? zd1n.3`'L'`i;tvi.~s;, sLEch as amphotericin B,
f:;lo`zelmc^Z>.''f 3li;', m.ci?twt~lo, and
'61 ,2t,t;v:.,.k top:iml <`a:F7ta-iE7~ectZves. such i$4 ai:'trUl;34 ir'~Ã %)
tc.;#iu=.i.
': 0 czal E,,7eC`pzii_;,,.:t ;, Auo~' 35 x~.8::+)","f)'~i'wti.El (:?--FU).
(63) L'~ki'.'i.#EI`C. ~1~`a `EL; d T
z c c~:ta CEiili i;1 `s. EV a.`s
h3i.,ElÃ##.),sf..; (t.`'-xi-) loop d,uroi1cs, such as filrCr`sei7;idE, (65)
pfftas`3'`mn' sptzizir3gg d#.xli"x=fiLs. svia:i>
f`~~ Irian1tei'i I;f; ( i`3~f ~`~~ 3~:idf, a.~#:.~~',1s~:S, ttii;'? as
Z~.~.~~~ {' ;R~ .~ ,
EaiEE:i?4E:E,E C a~ L F E~~ E.i .~ as p= f3*:3f,',.E-at;e1dY. (68)
t:.E'1_ly.T`tE:,s such as RNil;ic 1nd.DNa_k't (69)
a.~e:1ts, SFa`'on isFi L'yI;lE:z`3ptT*a:int..,
5- rc`it.. ~<'i.rtn, (.70) c1nt1o n1t.i1 ;s. :eLEdI Fl4 ~~l:i?L=ilE2i
F~f~'.'<?L:(70 :i~AEq.,`Ii3.tt'.
c w tA ~ w `= ~ ;c~7 Z ' . #2 ~ 2~-
>14?+..Ã1~ti, r ~.~ r~4 `a~Ez#~":i:4~`.~'...c:~Ãi~t.. ~ t~.~~?j#."1+:
:::;E~p:amp
i:?.lIb`tt)r, iElti-okeI' `i,lge.n:'R, such ~$s t3mepxt'E;.~:ole> (73) Hj
`+,`_tloctiC`, ~2I~~E Ãc:iLr c gent4, 3u%i1
<~s LI :E:3~ ~'{\~E~.i::~, fE.EIa~~'Et.;.71;f, :iTf;:~.~.3d.E#3~:~, and
.x.':~.~'Z,'~Et~.E#.i:.'; (d 4) +~#<jt.s'~za33 5. such as
~) .li t ~ ~#~3 t=t ,
("5~, # TrZtr`s.iniAj ..>ti viit\T `.3.:`1.:f2 as ;:~~ItbdikmVi,=in. (76)
t.FpiLEti. a~,~,~,o#a:.sft a.n,.#avcv,+Fus :ns.7fhefi~.:?
20 ~~ such i~~ ;~ i,' :~) hi;f]Fi.ItC;poi%fiL <33v_ f:C I<iFc~ ilk.1 such i3s,
C,'# >'thl`+!pt`a~..;EIa, i` t i:st:An.E
(f_# CSI`) wnC S zÃt;nuI3.i?si#.lal (G \.I.-CSF)? ~~7~~ t(#i1f~ES~='t
'zf?il <F?fe.S7E , as Et`.'zia3#z..e3o Ph~I
fa{;tE?rS r H; (AHF 1 -10,,~; (79) f:ilt{coa,~~;`i3lwats, such aa -wnfarlE3,,
13C.Ps;t:"Ã.`.+, and i.EÃ`gatI'obal1;.
t801 growth F'f cLpii3:" 1I1hi'3hE}i>,~ such as LI'li.AIllxb :2:E1d,
M,0fetl8`zEbq (rt'.~~21'r ,E,??,3r.if~wÃi`IlÃs, s;ii=h
w" Fl`E ~.i3 w{ p(~'s: ~z;~) 1n..i t;z4~:Ela_`~, such cn ({i t"~) ~.,
`~~.'lt.:i ~;.~c.# 3~E<' 'E:,. >. '~"`v'lE
t"~E E:3s`.'.~1~ i3. I#.i._E~~IS: ,.~1r~~.Y~ E:`~, ~::
25 :#.S L.`strot":'fz ;E's.wt =3'R3gL'sC'1.1z; (S3) p"zJz ~ 1x17 ~~1..~', as
~.v v'()IE:a?"s,z;;:~t~'~:I `E:1~
~.t`rgi:<sf7=el (t46) s~A,^'ogeI]s s E..h. as i,:f?I3^jt`+y EEtti;d
::.SLmgC'.E J, d.i.'Ih`r l.11bC sta"e3l (DES)a v,W<3` .~.:i;;
(LstIad:ol, o4luof'o. i.:"1d i:.`stI'opÃpaiic); (87) fertility <$,,;<>F'EE"sr
such as i lorlt,A".+hs w hEl:`nf73i,
chorionic k;:?.'`.?..:+.FZa3.Fi}p..n (11W), and 1'S.3t;:=F:oET'f3piE:s; (8i))
r'zE3ra,hyE't#xid cz4-#=.'C'.E'ars .aLich~ i3~'s
t hEz3i EiifiEFE , (89; pizu' 3aE'y hormones, such as dk snFd1pr4 ss:EI1.
;~(?St =L=.dÃ, >3:{vz 1~~.iAA c3-Ild,
30 vi.#:i<)pr4s;sil:. (A~...~i.); {90} pi:?t.:.'C;st1F:s, such as
113edz[?xyliF"+Fk t:s:* on and
p`' )gC.Ste.o31i3; th t ['i?Ed hi?1iF'li3Ãte>; 4E.lL 3 as lC't' (9,2) 68
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
z ge11t.'>?,. suoh as f.3tez'fefon e3ctc3-~l 17 and ia"ltt.'fert7: ga1;:uml
I ii (93.) ;Ã#.iL~"::
as rtmalon,. I<?btrhÃ: iM, ÃWG, IGIM ai?<i xm~~~umo globuhn]V, 1VIC. ~~IV;
(94) waizdL.
local an~ ~thode4, such as ~i(iÃ3caine; (95) ost:or Ão:;zd t::?esthefics, s-
,Uch as bonzoua#ts.; anal,
.z>
~~I~SC.t?#.?~1S ~A ~~,i~t ?m:#sc3.#.lZ?"I&Oi:Qi.al +i."i:?,.tlcotite.'(?Id
ilt3ti^1.nfli?F3?'#?ia{toiy e:.g``_i3ts, sf,cih i3s',
'3t;tafa?{:tbaN+.?Ã?e, a.ixr:I.`ti.'i?nU. d.v.4.cll :C;~a?a;iC3'nU
hS'drt?(..oS'fi:iC3#?v, and
pri dy1l.::o#iv; (97) :-?3.[1.: m..1o4;k+'.>.l''~'.it:fl 'i#.nfi-i:1lhE-
n'4:I?i#.tt?f'L': l~b?I71E::3[3hai~~3Ã ~ } ~~, iF .'? 's:S
3Ãs'?Ão?pr3.11e, v.`dophi?spb:?#1:Ãa.ii;} alta ?n3eÃhot#"ta,xa.:C'.; (98)
m?.t,.ct?:.E,;,k~.'letG:. ,?=f?stt'Ã"of#;z?l
v
:?n`L? '~~~. ~li?.~:'tt~.~, drugs # .`4Spy i~ t ~+} >s~.2~.~5?5i~..~. t~ ~d v
2: a{~~ >~,?~ '.ai.~1. S~ !
,i~. L}?. ~~. a~A~:3~~ v'112~.'~=2 t C?:3 ~~t~~\.~;.~,i#.v~~E'.~i:a
~cE..~~l~?2~, ! ,f i~8C.=;
=t?~`~) .~}~+..i~,ti3: :ill.:at'<l.r E#'n~i:i:.i.i4, such <$.~
~?6,;~?'~L.~:i+~.lt3rtsie.?.. .#~ i;
dl 3 .e;?al .:< Z'= 00) Ti.Z'e.':s..'. ?Em7'omu1cula3' blocker skeletal
f`a]Lascl[', x'L'~3i3,.:3#3t... such as
pyYri (10 :'rri g;.rd~~.?e. t10 ~ ) iic `'..#.oEo=.,;ci~~ ~gentS, such [?S
'mMG di~~~~.~P,0, #~I lvo1x awLtii I-?~5,. r_.n3_[
t14lE:p?dÃ.i?e; 02) r#?"f~.:c}?ÃES':73y:; n ts, such as, c'41Ibatn<l1::.p1ne:
ga :?Sipi;tifin, i;?n-lo'f:i'?glÃ?e,
:?#:d vraep:i'"t)lL:= aL'.=idr (103) b1:i'bi'ti'lir#?ii s3;.#...2.3 as
I>:ia5.;..#.ieb.3..xb?tc.'tl ::.#.l-id
phtniLaf>m. 104) benzodii:nZopil?e :IÃ~~l oL}s:vu1sanRmfi ask.,fC?ns;zepamry
d3uiFfvpan-?, ;a2?L:15 lt~~rat.cp..`,`?, (10:9) a:#.E>:.1 pa?"k>oZ?i31#.in
awt.3`1t.: e, S#}.cl? <#k `i:i'c?r:?i?E:>ipi3i3c;.+ :t3dopxt, cw.7ddl?~`;:3.
~.ert ?..:do.. (306) ank`!"vt.'#'tiglZ t?k~iwn~~`.h~, such as mtiJS: ~iAnc,
oplt.c g.:Ãa:islt `s..ich ~as
md 7
r^C`,,a hyi: ;r ~ ~~.Z>lTI'~:Ã.l>=3~1~,>aÃ:, ~S?>~..~a 't>ciC?``v'I'ii~v
atl;~?S'?i?oT'j?cl~rtÃi?o, (108) op,ma..t~ ,av `~
va.=:,>..s: ?~'~. -. .. ~;,~;c.~;~?>?i.;`t.;.
ko.aÃ:1.Ã;:3,.
StÃE h, as a:tialE?:SoÃÃ.., 0 091} el+.'.ta b;.oLkCI' anti-giaÃ:#co:Ilt:l
i?ge#?ES,, 4ud;. as 111,-w1f)l; ~s 10) t:?;3.lot;.:%
aliii^g#:r:;EucE?3-na ?.g-OnLS; s3: c??. as p4lZ?t:tl.l'vt<iic; (I 11)
ophthalm.IL c3il:?'1.Ã?or',ly i:.os3&
tilÃrf?Iz?fCs ...ves, s,:.1~.~ii as Ã7e-aszÃ:?lf>iÃ:, neomycin, and
%t?'bFamyitl?, (112) E.3pl1E.iõ#. :].a;.c
such as ciprofloxacin, F:3o7"floxaiJhi, anduflt?a:al i.; (113)
3)
01,11di?:3:l.?3?i= '.:">or'E?ct?;?wI'i?ld ant? t1;flammt1tt?rr' ag!wea, s-uL:7
as C?L;k::.`:':1L:h.st`ne.: and
pliA>.3isC lo-z3e:, (114) opl7ffi#3lm#; nC}a1.`it%?i'o1d.i3S ia3"`zigS
(N;:.MDs) 4uch's:ti
d#e koff'7?a0.:: f I I 15# w,`6Tmi<L:=h+?t7c4, :~lit:h as d1[?z#.?p#.Ã?t:,
hi:Ilt>por#dt)>. and ni\pu.d<?IlG', (116.)
2 115 bo`,..nd.z,.`.s.,pint.. ,a ax:Ão yl#E:.':;:., sC?'.di:Iti4=4, aIiCa
hypnotics, sb.cIi w> d...k:'`epy3Y?'b,
p;'aL.C'pas3'1; (117) p#sy:h<t;A1.8t.F lan$ .; such as and a3e?il<?la?:c-, "
118) a..#fii:l:s5avE:=s; ::lu4h as et>deiI3't+: (119) ba?I1ohC?d#.a.awas
ar?ci~" t?:.'s,
tht:=C;phZ 5li3~~, 0 (-'} t?dI't;#?eÃ'#?'ÃÃ`, aLw.114t NZ?n~.~hod1la.'f[?''S,
such as x.lb?.et::rt?z, E12;i ~
3a ~~?s#'iI(C? i i:.[j."t.iC.oStt?'Ã3id tmb ??fl.. .yniT?alf9Ã'y :lhvll:i,,
yt.#t:.h ei:? ;(1,~~,'..2)
.a,3tiLaf?:es; ;I3d,., t.E'.1 fl#iTlazt.',ml c1.I:ld i?i.#l(??:(4 nc;: t 123)
hi::v.'y
:r?~ 3~~ . S~1t 3i ii, a à ~?~ ?~~. ;k?3à 4; f `~.^~) z~r.',ieÃ"T'[ .3'Ã~.
st~.~lSte .i1t:G'= ~3.:?1.[s~:.. ~i~::t t . ,~i:#t,;a as :~.1s.F3~F~s.?Ã1~#.,
69
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
f7.FltI'exmnt., z.nd nF~~C3fi }c; (;,2'') withdrawal sE.1bsl 3.#..+..w
clii3.IsL=. <?gi;m*x N?.Icl, as
(1 21Es) minerals, F;,ucl"i as #.3't1:`l, c<?lL:3uF-.i3, and i 3s ?eS;E.#.i3,
(1.27) v.itwi?z#.l B
i"~~rn:?;?F:#za~~3' , sL#ch as C 4'aTIC?Lobc$I m`.1ia (`t'3ti.#iT`xi? B 12)
w?lf niacin (3'X ,.i,7?;#: B3 i y ( i ) 8)
1'itt???F;.11 C cEfmpoi.F;':tdSY slid, as ascorbic t36d; (129) vitamin D
cÃ?r:"sp.m#wis, such as
<'...~le-#:`'#'id (13,01) vitc?miF. A, '4']taillii7..`.., <Ltid vitamin E
t.,iS.F'aip;ut#.ds; ~13 : i ;?C`.FSont^, stwh t4.'<''.
:'~ .k3.; ~ ? -. ?} <?F.?~#--~3~~(:~.~#F~~? i3r `4~"1~~< :~F.#t;.~5 eE:~
~?t`i3~~#11#1;:; ~ `? 3 '.~,.#?~#f#:~:=~f?z3F#~3,:.F..>F x#::~,t.~:~'~~~.
3` c1dd:t`.t}.:F to the fiE1rew;il~ the f:i#ilob3`F#.?g less t,oI'I..:3't`~
i.. dmub s can .k34i} be ...sF.'.~Fi:
S.`zrF'a[aliA i>yp,s,'3dlaif'. F .7 S3iI: estr .~a#.t)l vaatv.Ia:l% in t`;::
fimbffÃ;>i:
flui'bip.i't ..a.z3 tit??iiÃrn: i1..eÃm.,eCti3:#: Icvt)df.+pa; nafari,lin,
&ndGo1:3;fz?p#.i. F,?n.tzet', th:`
ft3il.s;i ;fFF dtw''.. :aFs i3lso be i.#.:;`~.'d: i'eco#:21biF';.:3:i3t
bet#.3 SrlF.:cc3#.?, bc.Z'a.i;c ?~` ~its#it~ ~(?~).# !1r
cmFtxIIt.F 3lc; bi3 v#ne Su;3E;'.xY??;.idL= d15:1'?'i1tF4C; the fm'itSh-MoII
c3c`F1p'n"'iikg
c~~"+#nephF i3c, and bovine collagen; recombinant b1mdI#' I3,IZ= , I
3:~T,:AaFEF:#.?;Yb',f:;
h,u,I??I? ,~F?fi ]FA.~: `-` :~#5~e1~`~t?~:~~~; FLirtt#?a~5~#Ft~#_i'#t
~:t1.1iF~.~~3 g~'?'s'i'tx? ~1~?~'fF'lt1~Fe .~.i:`:'?fiFi`1~?c;F~~t
=
155 'hi.ii2?;<3I1 hu.E t3:3:;;ol?i#:F (a f I.e ct?i?_ib #fic3.nà hLF3'm332
IF:eirei?imil F E#;-=1 GJ F - i.r?; i"ez?mb .2?.?Ã;;:
ii"#.t C!'?''.r l3ri ~c ii ? a, ;w'j'.i}z;.::l~s à i i? (G- -~~S F); <lhi :Iz
{ip ii3z'.; Ã:C'c o Fi?b Fh?wn i. ''1zyk- z?id JÃ#lr3'.#la `.:3??
hormone (r-T:"+H); and tt>po~r,4.,an. F%Frthwr still, E}FefE3alf3w1#iM'
..3:'3'a! v,xoa1.s i.`+Iol%:o;.,~ e,'=an be
uw3: :?.~g~ii? ='.,# ~?+~: #1??'; a.Fed4siiI3.~.C#i, t:teda61fi?l:; bleciÃztw
,i ;iulAawr human t,alS.:io#.,.v.i;
i'i#~3ili?'J3 3wi?~+ I~C3~2#~; ci.l$rbop3z<i.th`#; eiuF..~#a4lF?`;; di3Ã:
sF#3i?i3::win. dc#I..FI3e Fb#.c.iF.`e L:It{z,E,.i1xc:::
da?wsf3i7#s.l~j 1-i3:1; ~:,F?()L:1.n alpl1i1: d :C?p(?side (VP-16)
flu;3#"o^.#=rs;t.I,(.~ FU); F3?~:~:.5'rb'Ãe
Sc?dFEFr?'t = L.?'?trJ.i7F,4:i? si.#ff3>3., ÃntL;rfiI`ir#1 alpha;
hci.#p'r(:}iFt:t.
tnCi.hadCyi?w i'IL`i. . ,?1eflxw4:fi:s.itt'.= ;i:?diFta:s pacht~.#.,~e ;;
#"s:3n#ti: ll1e HCI; r 1z,.b.iz?wt...: : :1..~tlt.iu,`: iFI?i3
:r;d mal;h'}s = Z ZTS
= ., y: . ~ a .
.~x,~?~a, b~~~3,w, Aa#~: ~::SS.i~Ã`#3;?l;ti of ~.~ ~~ ,.=xa.E~i ,~h
Fl'#~l:i:C~LFfi:.al fFoF;~3 the abf3vi:
t,`'ate~f~x.F`L'..'a il'ly?3.#C~'=. {,t~) o`:ti #.i~#~.z~F:~f~`itr u such as
2#.IIch'~f:};y`4vi#iF'l~~#.~3itt?i~:+, ~;.'i#?.,~,'.$~~'`l?#.ItL`,`'s:
cytotoxic aF~~'rfi.as receptor F..~ 3.#b'.tis.'S. and F~I1J~ 3"~C2I~#~}+
i~~u4:C?F ;b) eint.F-tiUSs?Z t;',,,i such zis
dV:}.?i,ome~hoipiEan ~~`.v 4,t#5,7b#t?i?Flde,
FifJscaAf.a?~~vqca.bY'tap4'n\4}.iit,. c2C3G'W.
and .`=hloi`,:}llck:.,.#.F#Ãsl hvi.aC?c}?,t33fS:xi (c)
.@ii#:Fi?i:it$#?},vi?.e?r such as iFa<3leai:e.
pbwa3.il?i;t3y~~.sfl'~o-~ w.#:riFt4, pyt?hlm.lnC. maleate, G.3x5haFI:h1e
succinate, 3?'td p} C.FAyew.1i xt3i~`?1#:.#fi:"
i:..iÃ#`cite.y (d) dlicoF..g:;'A<3nts Si.'.'~.:.~~.? .%#q r~icd7ylE:ph'lyie
h.'tI~~aos"h:K?i' &
hydrt3<:h.s61d'1, a;:eeIktriS`~.."Phti>d.i'FnC,ah,rI.F"oddE7r1d. and
ep.ht1d'I'FIxC; (e) Z'i7t'F\3:3s ,.F..is.F;:lz?idS S:.#c;.i
Y`' Ã~
r
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
as codeine ph{~sph'i'StE. ~:=3:3#?#:ini. s13lfatL= and `1~a1t~5~zli1~; (`)
afit1Q.,aal s.3pplLmLiY`ts :4E$d as
pt`io3asnt1ml dlt3ni.,c, t.M4 L"'3101-Ide, {.c,aS.gE7a1l 4=a# b'#JTa.itcs
3na:t:i#bti..m.? {3x'#.{r~ amz3 i3t.aci a? r.: Af.
I?,;ac3l and ca,k;:iz?.i3L earth metal siilÃ5, i{?;:i fi.'x:Ã,A"#.;FigL:
I"SE.`F.3;ii such UJ
, . ,
~) i:Ei~.t7.~}i'#~~"{ w.
:?YiE~ i3FA:.3 ~3 ::~?#b a :i3:.:f..'.~I z~s N
~C~.~.~'a~3T'oC~i:ÃÃ{~si#1'lidi'> 1
~.L^=S anii: m's:l'c?c:*.Cit:~ss svich<
~ as ~~~1eaT~,'l-
at=4tci73-I`.i1o~~'{e .#, aS~~ ilfa i#.ili~ F 3E7 `rL~fi=al., # c~ ? ~
~~Gtit~: :i.~.~~)IE.`s>iiaFlws s31ti'
~ ~ ~~.
prop,a.Flolclmi,int u#" iycll-Mi~~ (k) as ggi.Ec?:,a`.'.1.,ch#.i';.~ (1),:ai,
~tai:ads ;msy'h l6 `r#.:EIma`~.~'flm tl j'i3t:'i;xid{y 2#33d 8?1ag11e4ruÃ`t,.
hyd'#'L ::idt'.$ (m) b;Io t`,t..l.c:a .s J,:ich a:i
p;`ptÃdL~s~ pt?lypLp{idy.s, paAclns and ili3:iilta acids, hormones,
.31lenfi.ic3t:.IJ or cL';okanesi #.ia~i
f ~ 'T `i'i.l .i4.:i:1.:., ~ 'c ~ i ~ ~ ~.=;?.#i~ac. ca~ ~ t23, ~ i-e
t3,t:EEi;da; such 4.<i t 1ilEei`lwla~,t t.#7S 1-18 3.31~:.1#~ ~ ~ r3 inU~.
a~'S aaii{
r, -i3~].s :,: #ii
i?,.:i.
: #lcalf3r;Li4s: ,.~<Nawi.'., DNi'i.`'sE'r~"; iE]tett`,=;Ii,14, I]`<)rIIl<?214
I{fle I:sIn`.j ='a`~.{1 "t731?n'`.`~ (LHRz l) `i.ia'IE'.i
F(;lcc1:Tt{;an hL7nnoIZC+ tS,,;fIiRl-Io-.timGfo3"#'?E..i#., y,.o15='u'#
=,3{,to B3.
fibrt3:?It3sà ,gowth a<tc:or 0't;iI-0ii turno: :ii..oto`i~ I'ac;;ot'- a1;)ha &
beta f Y NIT
4.~'~,
ialp.ha e~ bZtiz# iic'I'i`i', ts~.`aLtt:a (N~3F,~, growth hi?~~?i~~~>e
releasing factor ~_B1'f
growth `
<-3r ~'rT 5 fti.Lr . ~~:i,..~.~~, ~ '~3.:t~~=)> ~~ ~~wff.~lE~silgr'L~i=t`3
growth c: ~x`~.LE'i_.t~'E i'}7`~#.~ S r c <3T.~i ias i 2c.:: r*:~~ E{3,~
;r.\aEi~.~~=~~
~~E~t,:::71t.. t ~jF3 ..
5 hL p4tt{?wZ'tC`> groYvfl`E f+1d(.7i' (1'KF), 1i1s3_il`i2] growth factor
(IGF)~, Ii'1Z?ia4.E#n Mh#.,.'#tlng >;.~icAo;t ''
~;Ill. -2)0 bom.;. i3#oqphii gC,'I:C>1`.>i:: proteins 1 ~7 (...`.+mp 1-7)-.
sft.yli:E4_3st..atFl` flhL.3:1o1F::3-alA)lleE-;,
iE ~1~~xiE rõatt 3Olii"#., ~~Ã'r'~?C.To.S3ds. {a3s.inaEc1:je (SOD), ioi 5 fOac
..: A
Lc;.ll.# ai1i `., ANF, E.110 and ,inadin (I3) afFfi"iÃ:itt..+.t13'`t'
.lN;t'3'.IL' :wL.h """? AiTtt.fim`?;.3.~4. .`a16-
=i3~C i1ii~~ :wiE' ~~Ef:\ antisl~?ti~v4 imd t?n.ib#C+ticuv and kni oxyuv{.'to
l`C'#.i:x.'ag3z3bEl~.t..~ nitn'v' 01,
s,.ivc~-' wd&,.
a tlr$t fii:aItim; t:i;inpde4 l3fi3-anid c:.iti:.RoIivJ i}a L#S.C.a~.:;~
phi$nna..r'..'s:#cc'l agents
#i7ivAllde lw f(`la.3wxi.1=,~,..? th~;:+{'apC:#_3i1L~ s..atk.<,?'{.~ilLti;
's3F^t_lbolIc.ag ;) s. .a:.3L'.4ta3G3?i: c#tf...;3;s clnixis::i{as.
e'i1t. zasffi.1#a#.d1. agents, Lt#1~:i ~~C?~s3~.C ii;:{<~I :~= and aeltlvlf
.3#d i3gC.iFts,
:
S.~^'d`i.3a~i', Ya1Lc#E:a. ai1tiC:a~#: c-fii'. ~ c` ailtirti"a:11~+'..s,=stiSi
. s i`g~>cflt''`z a.i` n:;:i.~'.'t~. ai:ts F 3` =~ '~a
.`i~iif~ { t.;;L`i~~.:
ts.3##S~,3, a S~Ca#~~E:).. ~:.~~i }
.~~/.".~. :i#.#.$ ?,`:lE`~~, ~:~~,''il~.~, cl:Ã1~. t~s:`.". L:.rt:; 7
atFl~rtt7.i,C?.~~i~~~f{, c>~;L31~~S, ca:~~d 2'~.:5#af ci`,.~,:,rt ~~. t$~i}I
~~~~L:~:~+=:
and i ~c S i ~ ; r r= t ~ ' ~ r ~ r ttF = j } ~t~ ~ ~~ t =~. 4
ia{A~~. x .~i;a ~~4 c .l~}we~i`~i s..si# .i. .cÃ.# 1# ; c#;~i.{l....
ailt.i a'rlr?#.nail ~,Igs.,.E,Z.s iiT#t1 t'u`_i'Li$ves' kA7p!`.'fite
53..#.pp.re4sani:)., b olo3õ>i:a2s.
ce,.obE4~l d,iLao# 3.:o}!?nar~=' dilators, dei.-o #gusi-a'#'its, diurL6L-=`i i-
1`agpoisdv ag
ayffi3'+'_+pj,e:.iw a`:z'ri? 4x,3ctvtc~I'anl . I:Z'p4I'wt y+.:.iT.-.r.: w>s,
hypizoai#.ti, l>L'i*i3iz L''ci:m:c #ti,'ciats~, '#i;ta exchange t 5..::dF;.:i
.c..?i'c3txvos, t:;'~E1ae.';ii A,ar pz.cilia{'ilts,
i 7i.lcoly #`L.. agoE`#.ti, E>ouromtl.Eai;l.da{' d# uggs, pC'nphf:1i:El
vils~.)dil:e#.oi.:s; pychL3tr`.3ti:;r, Eod ?fives,,
71
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
s4itnulCbS?ts, tJi}rof.{'-an'1'. Li2ttY`fiYy-rt~id
ti~t~'.~..VntJaÃ.lt~.ltin+v relaxants, 41taS2 12i`.aL2d pi3').iLugs.
EmiFt3pl.` of spt.a.afic dS'ilg.i ffi;it. can be ti:ie'UIyiL'.li#de:
.i5pslra`?.nasf;, bE.:s-..~i~ixi-a,
E::i 3C:4;:.itci=Yi.3e., i:2.1.i'b(5pl3Ãii"i. S:'i?..f'in114fi"IC,'., 5::h-
l?':?71abui'::Fl, .Ispli3fin.
dilLiFrortPbii,'it7.:. dE.Yi'z32omar1, iif#co ,..:~el.
`s.lo.:Z?n#."32:i?:, <,w$?t?4edG:,, I-xoxÃ`s".idfi=.i6,', fl:ldaI'ibi1"ff.
., fl:iÃ?F..#i.i..:ii ihyi:i'3xy:,#.'::a_,
i0.54>.idb!`-Adi iJt..saS3L.ia2dZ.. AYSE.AoL'i=4'a3t,
5.~.~2F~iR~L3FDV,..12~4+r~~1.1t.=~Sl.'t,.iAf31S.1(! ~=',.mV.[pÃ?,-2At1a?.)
n?<?f:'i?.~,"it{?p.3a`i` ,~.? inetho.`re:5..%lt'., mitZ).iT?y:llf.
:Fl.itotan::, #:11t<":wntri?i?L, ps.fjhftca?:w~As
pL:mt?`t:it a?, pzi+.:t#n?ytii=i, pi-5.'.ili:xÃy-ed ?i'C?cui`ba:1i7?::,
rir.h?;`.a.:.bi.., Mo~f;.pt?i,+?L)a;.. te;? 'r,'`'43`i.1d.
$hi`Mm3i13ni, th:CZtq:a., v.it?plsistine, vi:?`.~hrfSfinL., ?:ild-
vf.Ili:81'cibFn<:, ..I'h4 E:=7::Eai?:..y pi,#e1`#"eC-j
drugs fos li)`.=.?.g ~'. ~I-zt;:'.',.a trccdtme1'?: is pi.EdIl.'ia?i'':ly
p`t.'l.i?'.ÃT='.:5.ed,
i Ãi?~te%un. (3:'deI'iva{ti5 iF{~th~,:4e.:i1e;,C'.=:?1xts,
; 1.ili'.::33os of <1.iIfii;wnc(~-? ; a,xtl#.?Eti3p~a!~wle agents are
Cw'?ptoffice:tns. ~ These dm,igS t?:I':;
,:i:'#ti;.lcqp..c.i k ~z5r vzrawof >lie3-r ability tL., ?li1.iib1t t(yp(ilso`l
#s`'.'.Fc1sG 1. is :i
p.aflt zilkslEo_.a isolated ffi).n t.ILL':4 7.,ldigent?ws to Chfiai3 a,iid
Pmdo`;s ;h.reof such z~s 9-
3l::1}~~:~?~?I~3~~A~GaF~, .`.~ ~?>~~ai ~1a?~~+?~a1~i i11. ~~~ ~~~'~E'7 4'
i?F:i~?~t?F~~t #~i= ::z#, ~ 1-
mei.i1yl#.>}eci::.i3iY.,~i3=l1,;3tÃ.;th<`%I"i, 9-i?.tP.'C?-IO..11
#l~~~d#~'.~:?C~?~'`t~~<~` 9-ckK.ii.`SC?..
~ ~~~ a f -~~`1.~.~ ? A t'~,`.~:.~ ?~~a ~ Y~ t::7131~?sL~3~i.~ t.G=a.~'1, ~~
$Ã'$.7.1i'~? ~ tt~, ~ ~ ~.?w~.~1~,`~~I?L~~i `~ti~? ` 4w $3~~?~3';~,Ã;~~y:a,
(C31.1.? 4722; C), and. other analogs (collectively 1'#,`.forred t"L? ht`
.1`4,',l3 tEs, G:Impt.5ffit:`dn dI Lg s:3
2 C. am. p,'.'yeiffly under study worldwide inrf;~oarC:h laboratories fell"
In4,x';2?'14i1t c3; k:cdoÃ?:,
by5 aai:, and t:;tiai..r {`.is:3cY<i`f.
Adi.aFi.:z' na;3y Ãile pilt3.i'm8:ccLttk4lal i, a:.t?t can bc a -
riid1c)st,".3s?fi1.C . -,'aic:'`; as
sbwnsw:S?i\:e or ~ ^i.Y'\r%~C~ ~ (l1a nul. (3ciure4< by ~.~ S ~ ~, ~'N}~=~Cy)
`?~~i
i5[ Et~.:a~)~~'S.S. = . ?~'4 .VD. }l x
(made b; :'ion), RSR1r (mado hy Alfos) THYN41TAQ1:, kftmi,Ic 11by AgoÃkron).
olai7.1dcilt?>e oT iirb lgÃ#-as:t:(m;?Ã?ufiac:'urcd by NyGt-n7.Ã.=d):
gadm>Ili>la?, tC:;mKph:"1:7. (I?.i:d~': by
1"a.amni:3c4clec:S): B*~~,.1DR/Br.t?xE7('. q:mado by NwPhurm)3 iFIdR
(1?:Eii::sc by Spa"'"-ia): CR24 12
~elke:l.~w= by ;.,..w=la Thi?3'isteÃ.`aiI?..)) JLIX (made by Te_iiap.il),,
c;gent'.~~. that im:n#.a~n:ix \ hypo:~;`aci-, and
`._;: Hkc.
The il.'`a.=.a.m ca#? ~.'?c selected fr`si:tl a :?PÃ?if7:,Ãs .illy ~.we:5'e
h,.i:3Jt.nC;c. 11..c biologically
uwÃix; :SÃ.#.bõiaunL, can be s.'=lef.ted from tli~` g1 ov-p Ce.1i;i1tiElng
t3f pi.'peit{i'.y, pE {y..; i.:p.xf..S,.`,*'.:
pa+.?ti3?.`>s, c.#.ii.?:T?Z xit`..idi'? polZ'h`,k':L'i`'.`xiiTif.Ãe~'`_''z,
growth fc1.S.;:i?'s. ht)rmnt5nwsw ll:~l i~ 2M s3~~~~~=:i2
....
r...
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
.fLtclZ?as, or M!ir#i34::[iZs, and pao-dS1.4{w+f.I#I weLL2F
t.~ÃSaboR.Si:.~iioi^ ss fl.W
b,,O1Ogia.a?:`Y Fa. t~r~ SU~~~~aDCU is a t.ic..FapeuF#e dni:; or T,Ãr, t
,?xef..mb}y a i>.rug,
.f:'f3i13 t~1C: 2~i:3[3~? ~:~fz141 ~F31`Ã~ l? f :IGI~#J~~~li'=~"~.3:tF.~,
zi`'+..ts and (?:.l?::a i'~Iat#t:;4'x.t+.i?.::Et;~
Ã,t..fz as p<.#S.aÃ:ta:tiel., iÃ:FÃtib#()ttiLS, .F3'.1t#i3.t.F74F3Iti
3#?L.Stht"t+'L:4, .3,.?fi~nchnn..~Fflas. ,.t.it;,.
.:l.F?d c,ntFf:i?i .qF..fl:mrs. 111 cC:~A2:1.Fi1 useful L#F3~3~)C~#F37F 3',`,
ffit= ~kk?t,# :3C'3_t~F~= i$?t#+ {
or pF'ÃS-E : ~,.tg t< <õaG.,L:cA Fro1''F tho gmntp consisting of
LlheF'?1ot~~.wi<.peÃ'Ã1:= -i.goiFts and, other
:3I.i`'iÃ;L'.E3patÃst#C.a :ti:3't;ii as pa+;=_jitc:mi:i, +:Itt'boph;tIrs and
c1:#plitu=?r 1,..tF"o4o:.#.zE.,a cilkj=3i:# :lF:1g
#xFi`.F#.t's.~~~4..e~.Fl: w,C,.~'i?".. staf.:.3i as a;EFl3.~F.F<~:~.1~3:
i~B~ya~;~J; ~~OS3aE):#i.Fc#. fw``'"~' U F ~1?# `'t:.'F#IL#...`.S_?.lF+.',
hi)#`mC3'#'i". .3Ã:tMoopli:`.iLsi s3.s, gi,31a#`oaFa. l(:.i:prmfit,3e, and
~.F~'.'?4Zx.#f:%n, -rC>.=q p~t,i>
?#`.>.:h#tt;::^ ;;LlC;,, e:Fs tii'lo:#..F:.``,, fs#.,fd,`=#]I Fb, s1:FtS:;3?t
S:SF' aFJFta-=-kz# :I1hib#t[3m 5.-#ch ia.,
na-uF-~sz's af~..~Ãr-coph?tÃc1, such asaldesit>13k1F1, InwrMAÃd1 .=~w,
doÃ..e`zi:lxcl...i7px??id:-, fVP 1~-~;,
in¾Lr'fZ::4EFiF alpha, pawlir.FxC+{, i.nFairefinoxi.i (ATK.=f'~.).
hi caFit'sk.?eI' iz?e b:t?lt?~4;.c<3llv acttvc iÃ.1b4tancL F?liviw=.c 's.34Ãd,
~.;::.`. YFIF~~laFu acid sequence cm b`' selected frti31'na s.lz oÃkg) any
DNA or RNA
. .
5~.'~~~:ei~IC;= I?~ i,~'#~Ã:<~11: ~.F#.:?E1i~FtTluÃx'Fs, ~.iz~, '~#olfif~,
.1ca~ly L~,clvve s. SsE,FnL.L. is a D~aA se;ixI?i:e
thLa wF4,.odesi-i o4nVfi4' w}1i2?ke2 ~,?t.,.(e4.LVd from
ti2.iifFt3(.:.=%uCaE?ase ge[[1. g4#:4'.i
z+'.f...#'i?i# L'Qin It.S11."'IjiILF#Ic6:., iaaa[i L:haoF`i3#':'1phorkol
zali..,~tt`. 's.:'a.E3a4`feF,v`if.'. Im, cert.%lm
c.~'iibo1%ija"3`w.st.s, iho biologically i1:d]v suti?4t~an<'e is a DNA
S'L':.quE.`~#lt wÃ.:i:ft f.`z:.z:=odes a a ;
a33
~o r > 'c c}t In a.~ckl:iF:t3;~`~..z ~'1:~.p~<):", a Jzu:l?:'L=s3#.. or a
t'~.di`i~^"t%1F':3.z tIaI~`'sc`I.i:f,F:= ~ <~.tsi1w factor. .3a c':`twFt
i;F.i:?oi3Ã azoi~t,~s thw b'1,t3lo"~~,:ic's3ll"', iFf;f F6 ~:
tii.IbSt,.3$lcl.. Iti a DNA ;s`a'.qF..5;.F7:ce flh:il G#.4oda::s a RNA
`'sE.,.ea..teil f#;(t:n tile gYO..p w:la.siÃ.Flg of a SG'R]4c RNA, ~il. :FEFb-
~n&~'~ ~~ N`,l, siRNA and a
r.! bi?i?-y-rn's::,
B#. 'C`:gFi.iElly c3ctF vk: tlgt..i'.:`i cE1:fm#3.i?l5.: for i.:so wat~''i the
aIWw zdL..sxeF'Fb<:.d
hQ.v1.n z31o3mk, w~thoi.'~': aii?'>itc1t:to1-F, #Fiedli.tdm=.::I:ts,
viIF:?mÃ:i3i+'; Tn7i#ex::?.l. s::pi?le..`f:.:.'.`1ts:.
=c a ; c
s~1.~?ti~<:a1L,e:s .,~.F.. fi>`i' E3~1~,. t.~::'i~~i#la~~ ,i'Ã:-.
p.Fiti?t.n'##CF3I, diagnosis, cure Ã#'~:IF~~~~\~.
. v ~~~``~... ~.,~ ~~t~..~~,t<~o3~<F.'' e S 1 i the ~structure ;F' i
f.,#:~~:#i(Ã'> i e of the ~3~Dcfkt2 #'!' Z.. ¾;3.: .
#a~7 ea.L.`i.~< {.~I ~'; ~ FÃ ~~F~ i.
4I'lFÃÃ;b ?;fi,t.o.;?':Ã' bFt?lo;? ci3lh a..t:iv'o ;2.F`>.1'3{??'C aG$.1vr.
after thf,'.-v.~t3C-C: been p%:t.ud in a
pfi:..L>i:t4;F.#`.F,..:=s'~``. phy; # "zf=#.i E;1`3vitiFÃ1ÃileI;.Ã',
t.T4svf3tt', i#cti'E6õ .c,gf'F,.ts. ,F?:F,C,.i?..3b?Q ff:t:F' EIse#.y1 the
i'ta iv c<?2].p<?s:{t.oTFti include 4Fd,Z~ ~':=t f;3.cmoI'a, sui:i3 as
tf'anSi[:f.F~"tI71.#i a growth fLFa.ois (TGFS),
~i .. , t platelet x ; e1'S ..~~_3~:: ' -~
a:.~} h3t~3:'Ã3~'SFi'il4. t~ ~7~. ~!'4t~.1 L~'ilti:tir#'s (F~l~'~i),
~3le1t~=+.~>~`F~'v~~ . .I:(_~ itFi: fiI:L#~. ~.. ~:~1a~~3C.F .?:F3
~~?Z+y~'t~~ a.a.F~.:Liirs (A CÃFS), (.t3#1IiLct:vi t1s-F1e 34=tIviiwd peptides
(CTAPs), ost<ot?en#S
Y.~
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
wid ti`oloq z<..~~ llx' i.l's:ti:Q : ~f1~~1( 'z; ~ i1` 3.? @ ~ f
a,~.t".i~'i`1Ia~`~' ~: ;s f. \~Z, a ~Ã:~? `,a~.~ tt~ ;r3;. ;`L . lsl~~~'a) -
. ;!..
= r ; ~'fa~t, i~F1t~. z.E.
y( s\)}{- ~ f ~j? i~~~)C)v.t~~:}.:.t]~ ~ {~\1!C af5`)=~ \}t~) i tl j {}~`\~[!
{F ,) ~~)Y` <r~ j~a> L~.r J.:A~S. ~e S?.~lyS 4 C)4.1 t~~ti4~: C~.~w w=
_~~i~i S~R)_T\.~ R}~~~i.4 ~~]:bi1:[i~ 4t` '~`\{ .t1A.~t}:' ;,~[ ~^. M?f4,.4:t.
fi;#d~il~ax?t ~?LF.iI;IY} di:`:Fll~a.~t~E=Z% 4~i:E ?31'c+s are ~YIv~.
.~:I'~.:t~.. ~'rRa;:mb`r .=`,,,,, of 0::E TGF Si.ipo7",`-~.',5:;'le
famOv <~ndl.idG . te- ~`L.ti1-~~a"?.zs$C,1~~~.3I3..;. ~?rt?:Z .~'~ ~ } '.
;i'S.?tr example, k(.3.~i- b a t~.SS{
~ ~ta a~~~~~~s b,?,i'~ind..
'~i~fvF-~?Y,. bone morphogenetic pi.,t<:ims ffc~a-i~xamp`vz BN-I1-1-I, 8MPI .
BN3:.3" :i. BIMP-4.
BMP-S, ETNVIP-6, B'~.-`E'- BM;'-8. z~~~d.BMI'-9), s~epzr.Ij:-b.}T:Iiding
growth f..ctons-, fib;
ex,3mple librobltlst t?.lu~N.Ih ..#L'=~w31` t FGF;?. '.p1dL`m1al ~.~Ã'owt}]
f.aC'Ãox ~ EGI'; p.awltt dk:Iii`ed
yC ~ (1h ~ `~i..+..~ ~~ tj 'k . ~ ~s dXl~ ". t 'C4
~ihÃ.:Ã~..~ , Ã .. F~" and . t ,~J~v ~~i..~ It;~:4~ ,,I-:}~i~~.~t.1f~3:t~~:-
#~I~;iI"4) F~.?.~~3 E,~D> ~.x.:a tpae,
~,..C.~<
hi.>.i~~in A, anhibin 13), growth dlf.f:reiifiating.1actors (for example,
C=DFr :, andaLtivin,::
(io, example, AUtFvi.ii A.A+`..~~vi~.:i B. &i?i3. Activin AB),
K, ApplÃss3t.i~~~s for Polymer r Agent Compositions
a Elc t?[}l472-:t:.i' provided 1-:;3::1'c-.iii ciiil lic Litili.zt:d >z
,p:rYmf}:C; healing or tr:`aE or
i?7`it - ~ ~ ts~Ãc...~. ,`:#:. ~ ? } ~~i-3.1,~ Y i~.as,vl,o'f'i_ ~< ~x, to ;
C?L,.~3 and t.s~. `` Yi ~ c c~ *.,r~#lv..t>,~
~11t? .~1`s~:c:~;~ y~ i }~.... . . f:'i.~,. ~ 'ct,;vx;4
.
i
~B:"~ provided i?v`=.`e3.. ci1n, ...lso bS.: EaS:a fi37" i3'(='cli'l't:=ty
f~~ ;)i3>1 tt.l33~ ..~I~3%[t~ 7 S :ft,;f >14?t hs;,~i:4~i.:s
to, pa'?iu8...iOi: Ã}fr31ic-ri1- aund n<3`s11ps?rsTC:lt.S, filI31R, cf1ati>
,L;.`..; :tiE tur:ss.
cLiY.~ #`. E}l~~~?., ,i. `t3t:; 3al,. Ib4 pohT1ae:i's à <:r a;So e'3 used
ll. various tz;tlrt~i?i:
p8.ÃL?at..C?3is, iuC.:~~: as tissue FLug~nC,Itti:f-.lf?m Sl]Oh I:.citk t'Fbi~s
can be .ti5..=d h:. #.qp%.:3r anz
ap
i ~YCllp~ ~h: fi<>7 '~ I ~..:ti..=õ ~., õ ~:,, .,~3IlLq or ¾,~,:i4.,1ta
:t`a~ct, Other ta~;~';~ of the t?{tl4E7.'.~:~ ~:?.<2vIdtd he:r6?i ~:-
i42uta~..+
`irsilww.~, of <:l'ly.; late, Ei? pI'o;.1otasl1' xl"-i..al;d
#:ikalia;n'sin:ÃC=s or to 3.tzfii"1; 1'f .lkr:F'onG.: i3f
.~~.::t_ have bQS.'.1-i ;ur~ I`f)1'F'#(3`v'i'd or locally treated,
a?'C}?d.1s3:e of aoc:`rcgiZ?r`:fl
i?'ar3ph node '3i>t=tatit::sis, <11qi?'Zt;nEiltfr)n of local vr'43u?i$
hi'<3.lI3i.; :if2i3t <{em05 in ;.1.,f6::1.on,
?;ii3nliz3latia?n 3f sziI'if:;`:uI`' i11.d tIbt7.i,1mail scar
fi3."71stIt3on, and .bI= l:il trvc#t'..ieÃ.i ?fp<3`s':-
{ 1 p' i a:ive p#.ik.
i..a sL:??'.I]L eI.~"iii7t>dda3"1'nt:, ttze polyrr>Cr:i provided herein
t.,,,E s:sf.f..: to bwclt .riÃ:ct ,E'. For
emimF:3le hw pt7ly'a2C.1s pÃ`ov1kd herein b<.'.' tis:[1 to ari'i:d$. h2i1F;,,
i,s3lf}?<2, pr..zswt:,
pafw>va:zt?.rb14.ckst Z:,At.E:er., IthC`,'d i.:i'SLLil(~ also t~='~'~'
13sE'.~C~ z~ #t~'1~`Z:#3t'= .~T3i~rI~7.~r" z:> n:.t~>iil1. ..1`t,i?Ã;t:<?
r
tc?:gvtiretiiC.u.ii. thegraft, i"+uch:,:s lZ%mp(fhC~n-ia`i and
lLuSC.:l:.i'{.'.:.. The
po..4'?riG.?c ''a;.'t#clos c.z'r. be ,.7~e~tt.'.C. or indILI:iC:~ ~.'23t?
iS;` ari?l`aF.?t3 Iizt3AZcra3:?lÃ:= tfa>2C?r4 ~;) lL3Z:cttl.v
dL>iZ'er 3~Ã' 3;s. such <`zs, .hi>m:btA3<:Tti p-.,' or sensitizers, ("}:' i#
ie~w.Lf.t. or 11,.3a..sod a>.a.:1r the s..i:' of
tllo. (7pu.A#i]n 1F?a1tiToI4 to d{;.l#4ei' agS3r1.ts, St,l:h as
i.^ri`ft:Er~`'3iotiCs, -mlSti]vfiL=ti, o gi'wE i or
7 4
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
E:t. .t?lnlg i.he.ebZ r1L'o3d3Ila s,dC: (:Mf,>t#S 'i$4Sod.:z`a.zted with
sy<st{.'.:II`.ac Ciel>`c ai` Thi`,
P+'t.~y-Mi`;1'Ãc PtÃnIcks Pa E,sY'l:aed herch. ..'c?Y2 be adtt?inIstt?ed :l[ a
s1..C: of N,,wL.i'=Er' w?d; the
intent of ~,he paTl.cAe4 beiiig camed by the 1yFx?p.? fluid to lc?coregional
iaf3d..S, T~le
particles 4s:33Ã b&:."L'o?1ic tÃappiAi at i1hi; lymph Ãiodt'`i, a.~lobZ`f.i'sg
de,.#.v~,'ry of i#f.x,cats to tumor
5C'.C.fE+,~'i thL+, r,'~ .+ w's`~~,.dt$ 4+r z ~Ã;~Ã~~~ ~s3I Z' i?#1g~.~' ~iet
:tl l}'I3-lp\~ti;'l.tS that T~'lSr "`?rT i#' #~. .:.~` t {~' .N~:~ ~ a
~1 t1{-. 3~ ~C'3 . { ~~ E:C t??~?1`w :3 ' I?~, +3e:
Yltr&~ :i,LlI1dS;: tt.B.E:3.or cells and ?7:Ã~.t<'cl-#Y<E.I~.~'.c cells such
as or d-e?'#d??Ã:x<::cf,. IS. :3.:1d iha3s
dired. o3 un3i:en byi3ei'. v:Ã.rti4'..ies 5.aÃt: b{:: utilized to enhance the
i>iatr3~tiiiÃ.'
4wt `;C {~2 > < ~ ~'t -Z.q,r+<x 1 } )` <+r~ J! fy~ .yP } py-)5`.{ { . }~ ` }
:: ,c lt. ~ ~- {t ;S~~{ Y) T
..~'SiX.. a?il:c~$, L>i.._Ã,tA...S't.Ft.=~<Z.1b.t.~.. ~t+ C!~''+.C.f Y1~ lS
V`L5" Lt-S211.Vi ~ E!4 t.L~Z..(. v2-t.-~~ Y.~'i.~\. ~~[2-{ G+7i]..t.~~,
the Z,ell5 directly t?: b4` Ã.IpÃ'+;tfi.#..l3ti:3?tf ftw #.e.#.Ã''z:ui'#.c
Sy4ti',m iC:`'figi7.t ti>i Z.EF'l?:Ã1?`,
,?>>wy~;?Ã'>#tw p%;Ã'tÃi:.ii',s and fili?~~:s p;t.3v#ded herein can also i;le
<td12z.I:Eti`.uÃ'wi Ã'o
sÃ.ws Ly'h.."C. .E..W"?l?y :C=git;wi:1h is l:#i~-oly to occur. pi; ;Ecl[:'s
and -filmS .::..i3.i? ht'
i7dÃ?i::?'lls-t.i'><.d w; i:. c<3s whae, as a L.f3nsE;=qEl(''T7'+,:e x3f
qii&lh as CO.PD or Wfit,.,l??Ini1t33`"y
bor3., di4+ 3>i"..`. or sy>'``sw#?zii` ebw;"#li):i?.C,Ã'i#.py> poor #ilec?lÃ:
;1 lT'1ll result -i:l rni3ji3Ã'" i,;:rEi3pliccl:t#E:s"lti.
In, aditttt3n, i1h#- } ..+i't:#clo5 and fil#'i:t3 c<ti:i bc adl.i?.."rk? ~L'
ist[:3`f'S ~ :s. 3 r~.. m.3I .TFs (ià .. a 15 or or tt) s.tesff>llowÃ#.sg
local ablative ÃheÃa pY:`. F<?Ã. 'sÃpplÃcs:tÃo:tis.,
~
~ :iÃ. margin ?.a4
tÃ~.' P(?:y#..ei":e ;3,aõ ;i,clÃ' al'e prepared to sidniea"`~..'~ tf.? the
S..b gi~.: i or c' ~ LC. .~.:~L~,`'~~~.t..~~t:i within
the L't?na#.?.,e:+ .a#`d 33oÃimL`'''+e: of t.~'tie r?.<1sJ, In other
cmbZ?t,?'ÃI?'. ':?ts, the part..Ã~.;t3e ;i Or 11:171s,.
adhere to ¾he pe:.t_a:f:"d#E :ai, i:::.?n?li3gi'.; or cC?llagi=?l f3l":..hc
L.i'A>wry of ailt:-.c+,t..+.:Ã:r or
F7i?tx7ik:Snl<;4tiQ .w-e :l:i. i3-i oi.h4? aJl.".b;Jdinae1`ts, th.^ iiEI-r.;s
Cc`?:tl bz ,`.'..:43lw:d, 5:3 f.redv +.3'ld,'t::s"
24 .::aLwCOLii place Ltt
In t?.3:i'. the f1kC:3;i and pitft.C.fe hl;;.,lrA.Ã can b:`, used :.:-i
w== ttL ppht.;ti#?F:ls. hn such 'rl:i3. application, :}ic swofl.iTig
%+4`Ã}L#ct :.t?d with pH changes
c.Ãa be ::4d-v:>:Ai.i <L,t.`4.,#.11lf' i.iffl#:zt_ta. For 47a:'c'-:#.171~.~lv.
1 iili?y of the ::iC'.S yle:#tc poly-m.esR d.i;`ScribL'E?
~ - ^+-Z't
3t~*Y Y ti~~"~ =a3~ ~' +...~<~.r size
5 i ~,:.i#; a't>.? :~=~. i>Z ~.:~y~ to a ~1.``s;ail~. ~Ã.`v ~~,?r Ls~ i:~~~~
la.<.Ã'#:<!.'_ `~ 1,3 ~T~ :3E 3E.. e s ;~ :# ~ ,.~~? ,}ad .
25 ~ ~t~;~? ~X`{1'Si t~~..#~:~ < +.3 fill Lt'tÃ".~~t,~ ehi: saxe of
~~ i i'?C3 ' ?`N b:. = a~ ?.l;~t,t~ Z~.'Ãt~lZt;la,Ã t~:il;: > '~it~~:l,.s or
to ~, ,??ti o
iÃ4suc, if g., .Ã:~liAZ lips or dceks. Op7taE3.+`it#.ll4'`., the
pol'S'#'?,1el`` i.'(s:.ÃlLa deliver #> ,#;b*::{tic ct,,g+~:.'ÃA :s
s`31.,.odhÃti; oi iwciid t1`<`,":3L.a. In, st}4.3k et3'4bt?Z'f7TIeI1tSz fl-w
p:.`lyx3w.:y edsC.ad for ti..#c-li an
appliL;=afi13#Ã Y3A<:c ?..F . .."r`t~-E3i~ and 9i~ and 111`i~.
30 Any method Ã.sf iÃC?he1iikg particles to b1.ologÃu3n fis-S::ie can be used
`tt?,: t;t:S
4:tapl#Ã;.tsÃ#. Few np le; the pt?lst~ wric ~ ~~'~~~lU~ ~~~~~uct herein can be
...E3~.1:~:~.l ~r~~~#~.i~A
~~'
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Plu:'oiiic 1 :.w.7. .3: <3;:3otht''r Ã.`.TibÃ?i#in'.t;'.n i, the particles
a,".'c entIc.>3"a?`' ~4:~t;.]_i#l a ~t,.~.
h4dÃ`;3+~,7~,Ca, :WhEr43Yi.:õ \4..s.aii,E>e or :+llrw;#ci?l
I:Aal~S3#~:l.E7"?ZT?L strip ?-nc3d4= fi's.D pt'T`#ciFF'E.3_iÃ:FF:,
rE I k,.~~~'s vq iih."4k$ or o4tiC,'.r #i-latf'.='{'ii#lS t)I'pi1.rtfclf.s
3.izuFi C,i?v~ utilize a spL. ,E:'irFE :#C:h
}J .3Ti:fi#1 . ; ac3i n, to h14} S.:'a4e the:Ã'e.} t.hiÃdw=Ji t time at the
s:t-..
benefit ~'#'<"?I~:1 ~~.3E. Li`~, of the ~~.`,<rl;"~}1e?'3:;
en tidid#ÃiC?n. z>thL7 i:y~~L.J s3:.~'',i#~`MUÃ`~% can
pwrtÃcIe: wid f.~,ii.n'itidt.sliaÃb#;'.d l2vre#I.i. I'~oF ex-'iirnp3C%,
flinn_: and pa3't~iiõos i;_iia: f,,.t,iit:}Y,.?'1
`i iY tltiÃ.\icrie\> _E L ) i}jL ~~! ~(+ c> \ 3tSt;raty k ~{L.,.' Ft<at `~
ay+e <~ ~~ a Cl r. ~ J4}{r~~ t},f.. 2 wc)> )\.5~~w.) YsZ+ T i4.?i\:~ca of
iia~yty . a
vniÃ~ be L(:~..L~~~ L4kL ~yZ,4 ~ \ Tn4f~t{ i 3i1.x~- i ! 4.. The
CFS~
wn.&o; anz .=t.;Ls..nc;~ can i:?C'. :rT'oli,)ngto Ã"tid?#t.C the r#.s~. of
p<3st-n q,`i::'ili
'.:n..ed#Ã? .> b.#t.:. as ~: z???~tT.~.;'cs+s. 0~ficc'k InlL'.ct3+?Tl. Th};=s
f.31efl-l:.ir p .'ov}ies :.l}a alti.'.##..wi vw; tf?
ffis, use and risk of s4s:4~mn8i: .at7'i'fblo'Ã.ics. I'l1t films and
p.}:f'ÃI..le-s- can cmilc}i}? G}nwstl?Ctic=`,
43a.#,.l) a: local 'z.'>} 3}\:o :3a`aC.s:hLtÃcs, 5~'i'~ wu'E'..C?fif s, or
[}I2~a Tt~~~ }F:1}~ 7niJ"~ t!ag~= ilÃ\. ::Ã,;i:hk ::4
az,efZit. ~ iIs_ ~`..'~, ti? rC`~ ~c C~,1..~ t.l~i. }i1sE:i,. t1}3~.5. E]`~.
E. 1f ~?extlE.:i'~ `:, .~ 'a+ a:: i.is.. c. of such .~.Vx l ~~.~.:' ivZ\ z aY.
i`~~`s ~.a'=_~
titt:
f`.utor.i%ia:+ va:l `.Qdus`.:E. 3i:?.33)dlty stF S,i,.dili=y to
dt.4Ã}'F::#Ã#.i i#.i1d E:t3T1St;pa$ÃC;I`> E.,,..f:`"C.::i:;e th<'.
length E`,$ h:?`;'?.tal Si='s:iSs f<3'I pa..1e.23t5, ~md it.i.F¾iC:'}:.
C3vC;r`ct~l hei}ll.117..zi"e \f?5t'S>
151 Ia~ ceila}:.[1 t:n1:i{#d1~."'+eIlts> E~`a7o p[3lym4"I1c -fIlIIi4 :ii?s:i
p2#,i'taU.C.s a}t. in E:=w-~..i#.'Ovii:1a
i:Iqt[ef};us C}:" organic io.}#~~on5, or cS37nbii.Yul}loÃ"\ thereof }a ~~4}
aqt1C'=E?.,is }+)lut.i.l1s can be
sE,leCt..',d ki"t,m, .amL3.I1gl w::tiC::=1", bi.}..Fo ."ed sC3 ~x).:ti
ili.'ix''i},. 4<'dlFne. b2J'A~Itd `iaa`.#t.., s{3Ii.it}on.N of
a>$li.i acids, +~~~!iug:5y'.', si51i.ftAol}s t:.:.~`~o=itc} zl.1`f;>,
solutions is I
ci)I`z'i:1iÃ3z.'Ãit>i?:`t E;}' aixy ti'vE,' or more flwi'oE`.+f rri7i.'.
oI'gaTias. S:7?aty+}S"tw cc#n, h:'.<'wli:CÃ:E:=d f:`i37al
i':f.nn[3:i7.~-f DMSO. S..tr`a~~mZrlT. nwth<3j3C;~, T.Hi',
dIchlo#Y?37.FE?rh2.i3i`. DIVIkt`, 113=3diL: or l<?lE C:T}s.: or
cira7bÃfac irttfn'? t f3a;Jt"S'i? i:>, ayi;JrE' thf:#"L'o-f:
~ i3'= ps.'33Z i'%3C`'kc particles : a1U films a%iin E,a)ni::in w+. i~
:I4.'fic n-I6A w'f :`.s, `s. ,h,, ;`u}ciS::C: acid
. Y , = " ; . , .
ed'.., i l. E i?'ii,, \3 e#3 : ,'t , ~~';i:
4S.`.c:o~3E.i:',~, Such ?I`e<3~.t.:.1'.}~?lC can ~?;.'. ~lsf Ã~ to
~.IiÃ~Sfi.`+,'.:.:~.l..s <.3'F 3 ?>
polymerie part~~les, :.nd films can ctwit<1irt i} recepko-r :t..c;>:;t:i.z.ng
~; tai r>t't;.~ig tnzfÃ~.~Ãy,
~ y.. _ Y.~;
i.>A~ of .~ ~.'~,, iFceptf:r or
~.~ :~~ltf~~F~Ã.7 ~~)~,:. A~~. z r~t.t.~=~.=t; .iit;~ a ~.~.(i. or
:~~.t><<ratic~~~ or }~~ ,ibi!
s.1vBs'qExa3, antF"s.iGelli<.3l ar s::~.?l?%}iÃngF or apopototic $,?aEh`:3.}v.
-affiÃ.;,, dhe po: 5ii,4,.;c maÃt:Ã:'#.<l`
Cie;:E:.`,'.E' hkd .. c:a1-.', be i.#3+,.'C: to :+,,.livor nui l;.'=Ã:
:IL'ldhq%i4 ,iY..t:'.i tf_s :i E,z'.ll, or to EiE',.3it., .T
:2t L}'}i be t;'~#.I~.::~3+?t.+.'C~ }i? the i~a~BS;;lEii\ of a C,~::.al or
r..f3~.f.t iI'E}s;.`a('.~I~i~3:iC'i1 or E., c. ii.i'.x~?Ti
i'. it?Firk a such as ~~~I:?3E> a or specii.#c transcription factors.
The al:t ffi.3.3dJ of using ti?E> pE1lynn<:T'3.C: pi:"tlcic4 .}Iad fi`:Tl`i
dt.''sL'#"fbed ht:>e3:1 Ciin btf
~.4~~. , Y
t 4Cs \ SÃ'~az..}ta~~. A< ` S 2.~l4' or =F~~ti::li~ bu E:C?:i~'i~: i E?'~:'.
't'fi~i31"~; ~. X~ to ` Y '
.= ~~~~, v ~?~Il`~;L~ l'l~~l t,'3L?l. .,Sii.s~'~i\.ti 3E: ~:se.e . ..i
s~3#~~Ee
76
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
p<7:t.fn.1, 1."or exilmp3iy, +3ii:i'~tic,es c(3fi'?aa.11.lf3g; one Fypo of
ti:f.`.:Ã'z3peut.}c z1gcA:i be de sg11ed
.L3f~ results Ã;Ã' ffi3 p~iltf:le~s b's ir127Ãf`g fi'2~Ãa:~~?~?G{Ã at
:yx31pl:
nodes, ~=.hi::~f'w.. t}thE.~ pt:#itfcÃtes or fili-T#:~ that contain eishe:
the. or a dff-TeI`cz7f:
rhcÃ:3puÃfic, agent can be a:ppried to ,~t?~rgj4,:=3l #:t'1aTg:.Ãi.` or
:41.#.tuxc. s1::::5. It :`iÃ??~Ã~.(r `Fllh~.? t.3.i`=
TLcE??.T.Ã~.Ãt.C.~+.h. that ~~[~'.it à r.;~?aFi besides
c~aE~=f313st~1~.i'i~~si~`~lf ut F'J1E1 t'. g, cy3:f:ikrÃf i: 3'r=+1wth
~ 3 ~2~.~1 .f3 ~w.2': x~ itxffÃ',: 't~3 +'~Ã~.t:~, .;~c3.d'~ EF.4~`=Ei 7Ãf
a~`lt...~_~ .~.~.~`:r[zh ti?~:~ 4.tfi'l :~lf?<~s1~:li of
, p of ~)~f~ q
~~:~~i~.~.~`.1J:'. L:Z~%itf~.ÃfÃ:i~} a )`;~1r.~fd=t'
T'4I~Z:~~~Ã:(~~.3~\:=sC~~~i`'d,~~.2:~,~.'. or other i ~a i~.ex5tt! U<'fn. be
e.n~.a`'io'yC(j.
b3}t-lik} i ihi)d a.{Z.L'.ÃNl[.>o Ll<~il~we
~zk: ~?~3.y+`Ã:.r.<. ~Y:Ãic c}~;~f=ii,.1,..~, z~t~il..~~>sAAA..3TIFL
)-rov-1f.`..t3 can bS- used ..br:n viLrls :$n1~ ~~ ~~Z vivo ~` ~'.
a,.~.a,a"lw } ~ , ~< ~ ~tÃC;. faÃ.f Za:~i.~if a ~.le::~..tiC 4,s ki~i~,tlf;~_
Dpt'nkh#L` E?pf?:3 ti-fC, po1.ymos S6xff::d, ti1C`> rt1tF.. C3:`drtFc.,
,^:el.;-.s4.= can be Lai'.Ãi<.f?<,:'La or
<= .
Ã'fi1F~~i:.`=~::1<Ã.~'C'. II t?iC. ~~C?l~=~'t##~~"ti provided :3~:I~uiÃ`Ã
uCÃÃ?. b` Llso; ~.E:}?'
af~ii~i.ewj~''. C~Ã~LatiF '~ji:f.:LCry` after an if~..
F~ tia3 porff.)C.'1 of qu.:'v:lt.firo`..Ãf'a<e to peÃÃsift s:.Ã git~.a~..
b\.al:ng to
of.tJi.:i", I3a fl-wS... ~=Ã~]t }~7tt?~~5 dhe po.``ayme:ÃÃl: pc3f si{;lfi'.s,
p3'oa'':C.i(.d 1:etÃeM p.ias r:d'Gi %E dual
.i3e+.hanfs;Ã~i of dt'=lÃ'v'L.r,' ~-~'J.`sE:a`1:a dr..F1.:, is Ti,:=lL.=ased
ftol'':r the p+.:Ã`:,Ã+.:1.,x and :}'aC ;,arti=lvs. swell
to dSika.Pbfiif~;:= or destroy t_tl.: Coal or ci.llÃafsÃr c}mpartnir=rA
('g.. C'.nf...osom~.'). Aitean:afi?i `it''a
. a
~. ~ ;,.~ kcz~'~ 5~~~. :~~3C~ : - t)'~d, S. 1 ~, ~~~~ t ~
~~~.~ ~?;F~F a. r.~~ ~7Ã..~.`l~.= ,Ã}G:~~,+~ '' :l~le}~:=~~i:i~, or t3,~~
_~...~5<~. a f1f.,:TÃ~?~.;. s.r>L+,: at a
,:;.~ ~.<.~i.Ã z: ~ the :
c.a location . i? Ã3i_3 ~ t.xi'Ã.+,'. .f. t0~"1~c:+~.,?LC~x size ~ ~ ,i
i) ~. :ili:~ a~.klt#:=le, .w .3#.;3 ~3i~,
:., ~~=iz',lt?i ~
i3aÃticles can bL'ciAÃTi7t.= lodged {33. 3:`.anb'[.Ã.d`'i :a':th$;1 a L~
Ãvitj=', node, :`LÃ.b..Ã.,5^.5,:, be`3Tlch`sÃs,, or
....ap"llaxy and can be Lt:ed Ão cwclude blood tpow a4 :::.x.
C.rr'bs}li.~~It:oa~ .,gÃ_nà for ~~~ecding;
:Ãt4e =i'lw?v::1Ã:'_?fFS l`Ã..cl:foi~rii.1t"r'l?ns, or wJ-n;7'r,"
E.~'iE:vi.s=L3le33Ã:i`.2:.t3C?fà E3T 4kÃÃ:3 :?l, used to a3r.'.veIit
.ÃfÃ"flm% to a specific portÃ?,.'. {)f the It33.3g w* for tndos:Z3p1S; lLÃI
g..'Ztlam`', .k,'t.dtxf.`.=~Ãiz}Ã"f sÃ.lrf. zx :'`+l,
to a'.3Ã=e only twcs 4=xaÃa'pl(;> of potential e13e;i of Ii7f;a prtbpi`.rty- :
cÃ?1 b'L`
GÃ1mgred by pai L:.i1.Ã age firi?m an Czx,t~ont]u::i agent added to the
pixlyrnC'.Ã=1 a c.taÃi S S.E71~'ix i:1
z ors fty :n vesse,'l as :iul iyC:sLtt' iI? 3 .s+JheI72#c or :f'?f;:"ted
t:YsE3e or C:tv..4 t>z ~ `~fPl an
. ;...
.
olÃ1Ã3<fi1..3E.::3~: si.Ã0h ws an endC?sk?:mG=. ;??.3ch particles can
.....Sl b1:.
,
#:1cfÃa :~3:i#a=~ 1~~.~ to ?'k;li.il:eS3 agents thatH nI[3i1Ãpi7lÃ:ltL`
hc<lll.l~..g or fibrosis to faa: lstc;tc. pLÃ`Ã:3w13i=lA
or teInpoic.i''y clt3s;.::xÃ. ai,~~the oCciÃ:filt',d lÃ:3.ÃI3m;'.=fZ or
e,.`.Ãvlty,
G~.....i,Ã en,:t'hS.di:nUntts r3>?lht invention are directed t?3waÃ:tias
pt?lvEaS:Ã'li films thi-l.:
aa;, &~iLnw:d tCr deliver c1he-fnc~therapCutic agoiits locally at surgical
sites, ÃÃ7w,?Ã'~.~,:.`fs .iC'?n into the loxeC:t$oll mwuA".Jl. Thi:.'si:=
films c.ai~~c used, in Ã"-hc) Ã;'c.:Ã :ÃneIft E?l-,
77
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
cilili.;e7' pa':f.S:?3.ti, wl?eri . Laf:.llv3..x3#sg dtugs lt?c>3l`'s'y l~~~
t11L c,1dv:3.i3ti.lgC=. of >k~t3;aat>?u$ side t.`.={l-(C;ty
;: i. }.?i ~~.=`:'t\ at >i.aic~.
s.3 0, Z s #a.
~L.=tY .~ ~S Eõ t 2~ drug l.~ "7~ ~'e~'~', & F .iL~,=' ;\ 1 1n lf?~'1=' ho
ta~ 13~
~
~,i.S.=~Ã:~>C'~a.. ,~i: :.~.#y CF.ai~ ~.~L#.F.S~W i . ..
00,11Li:i1tAa'taf?:`#ti :hat ilou3d not othe vvi:iZ'. bo ub$e\ c.d- o-.Sue to
d.r`i.ig tox1c#t'y::=:, a ...c Riia3s,, can
i'et .<:Ese,as;eni:4a at .he site of S.:#.lga:ll-;v' and il~=C:
~'~i`:~Pl~'..~a4'~.l~S v:af:}.
St.r.'~ Lc.#_ii. i~. .~~ c~~''E.'i.lti~ of vl(#:i~~
prc2:C#.:clitZ ..<? t!#c `:np,,. Ã.ta-1ioia site and to :h ;, site of Ã.t]etaS
,,tt#= tumor g:'&swth. 'll3.c
:TI 3hun >.d : i?`14n.nui'ii: films f.,. : deliver one or ia14?t'i' :at'at#
iM:liet.ei a-gt:ils'K c.&, '..:ti d:st:.i.i:?ed
ht`.ra':-n, i.3at wai. a4. L3PO#.3 cci:`k:ui or 31ati-astC:tlc (:+.'.3Fs i.'-
ma1#l::ilg .3t the ,u#&.3 Ã 3: iIMLi14
aftf... 3.:.f.-mL:r oxi..;sio.i-#. is pS.rr3SJ."'imied, Thus i.?iC; fifltns
Can .eduE.i: the .'inv#L.ie;:>{-o of tumor
rS,c;.il"remaw at :v rC.a4=c:'i?3:a3 n?<3.i'~li% after removel of
cs7k'tZ.+,Ffsiis iS:iLFe.
~ ~ c ~ rli~,a ~h p.rr<? ' i~tÃa `4'~~ herein i.. ~ i.E..t. ability ~~ E~?
f..t. :..`;'; 3.c`s ;fG~' ~1..iW.? '`s
~ t ~ ?.;` ~~1{.'= . .~.
.~i3:.ii_:~ ~.~~
i'e filmS o.sil c-ov:? " tl3o choSi. W,:ll to :"t., ; dl1ot..isc~*
3i.;#;i';?`nn(t For C'xm.ipxe, t1w, pol;ri..3iri
such as InC.gi3thC.l ;.on3;%i or in C}th4'=l.' body +~::v+.vlt.ies fo-r
Zi:iti.LisGS such as :'t k'S,:Z?x3m4. In
add#;im; .1.~'. ?`<~~iT3I~'.1'3L f3I~37s ~:ilx'. #',x~s'l?:i'pi.ii3.'(:~ local
i#:ia...`:+~.~#L:~~-r or IV ~~:::`s:;t. t3~.\ and be
<Ssi~ ... Av '< a,A r113tv . ~'!-iE:;ll < a.i~a:=.st~)~1 for ;:~~~## lY ~'~
~i.'~i" cE. or i#?
ce.k: .t #' i~.&:
i ~ `w;:'`,_\.~.=ati:~~` ~i~. t~4 i~:i3c.i~,
~ Z
s. ~ ~ >. _ , . ~.
4 t~ = v~ + ' ' \ a ~~7 =: ~
~.~`õEt`.~'~iA ,.?tat`,.:ir agents in iP#'~~a~.r t:~? Fi3<?l~3{?:i3~t~,
>
a~#"`L:3~C+I?t iti A3a'.~''.i\33Y~iti.= ~.?# 9t,"'i~.3.Y15y.r~+/ 4
f\.(~~i71f3t1f?n.
Px ~i.~#' ~~~~~.#ir' r c :.i3:1t;.~r=i~i#a3 T}] a . ~# ai`,t1l~3 or
~`~`a~il#3f,: ~'" `{a, agents ~:t1ia Y be c.'3 - ~ ~~ ;.~ <. .,~x~ ~ `
. != _il#a, k ~#, s =~y. #YY tx solid
S:#'tf3L'=<. in a Q(_ri1.Eo<lC.'d 23:aTIF.ei' to ft5rr-i3 p#.3er.tt:,mS
51.1Evl7 as stripes z'kF-ld dof,,~: SailL`., or
multiple ig~m~m* ...".=.iii b3.. Ii>:f;:i?.-p4bi3:~-i.r Ifi mlyp'si4a.t#:m
tC) cia..l'#.3vve pze~.s54 tF.~"3.C.'Ã .peu:~~:#< d.>3#'i<L::.3r
of #undt.iple z ~,G3#ts siI7'1tIhmLC}l#sd"'. N'tt.xl#~ than one t)'`;)i> of
p\?lJ _3ii.:#' fit.,3i7. (.t.Ei., be u..4f., to
C \ >!z .Y v~ t' \i ~+; r .?~` t ~ t",rc. \
tune or t~=i;~`Y?"e)~ ~~3L ~z.~~~' of the Li1'E.i>~,. A ~ u3"~~'k~,:
4i',.3~3iY.f1?.3iE-.~~ the :ilE:~,#: :;3
,~~,is:.= t ;3ii:#.i~ i t \r ca t;i ;,#3I~:.. : a,:_ ~ `~3 ;~~~~=.i' a s
rel~:~~lso of the ".~?c~#~Ã(s).
the . r(~c:~
~a ~r,..k : t
E s..# e:?;ami s~r. a 'F1l`.~11 ~:~t}~11~3JSoC~ +~f a 'r `~ t. ti,i}~:t. iE`s
acid
Z qt ( Y+ r> .r~-.;tY ) t }t> e5>,~,r y2=Jt,)p <}~ry i~,je sr such \~ ( f}}{
?r''9 `Lq ft's t~` "`~T~
i:I{h t `.-,=~t=rtt.)!_.5"stl.L:ti.,sy-.`.]i3. i..ti.i% ~ \..=t~..t2S.2j~..~Cw
with GS''uit~? .. ~Fl~'~u'ta. i~<J b.,.^T.421 ~S 2:.F~.~F-f. ~aL~.S...., ..i,.
i3.nn.1e, .t::i:.dL The fil#..i can t>3ei1'iie cdRittt:c' W7th another
h3oltr'f1ler of ths<. Ss;ic.,e or i?1fft,,::'.:#?t
coz`.txpLrsifi>>'n 4hu.;`, does '^o`, contain J1`s: e:`3.3+,~,
fi3.i'i'f3i23.w`~_', <7.71:iilt3^le-# fi,.`:'Ld 3':lfn, tE?p
M i'i',# , Ahach Sxf3L.a .iiESt h%:vc t!'ke dI ~t`g, aLt as il
s.:i(:raa3i'.liil ~r`.tye E th~. . 1?.i, E 333tb~~~
fhc reli=aJL. ,e~~ ~hf C'a.+f'::t;f '.#'onn tl}o Li3ideri'r'tYtR #lf1.:,
bt7.t <3ti the 'iom .a!'er .#a`.g'i' .f?.eS, the ht;s`ioa7.i
lii:a. sisi1`t5 io `'Q.L,_ist:= fb3L= i.9::'3.z`? hn f.h7s, fashii3.i"#.,
delayed m3d controlled ro$eci~.~,e e,Dn =3cct;.te.
:30 i3.3d a.<i::3 bx to in1:Iitl w<3[u3.d hL':1<%1#'fk; li'. occur bt...b3.'z'
d...aJ.v5:r4' of
>#L=~`=~~3thaa:'J ~~.~.zv~`? can Ã~~~Y3.`.t 24'c3~1TI~3 a.~ i'sli:i~lv <3;i
f~z#.~.. 5:..`~'.+zf';. ,.SY..ioel.tt.v:=l~r' ~ x~:ak'[~~Iii
,. :
r; ~
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
drugs "L'._.n be if,.ii,'t1~ed ti{;:q1#{:3-LiMly and i i~~lf?i ~'.I~i.iF:TÃ
~= E sr P:r=i?lC3;ilg ~l-iG` ef-f`+Yo. i?~ Ihi: other
drug or 2f`xott;~'~`vs "normal" C.i:=3~s from t"^,ie. to;$+..Io eff`v'ct u' of
tt1c second i~3iuf.: t?.. W `:'L`:sc-:i:e i'.f?llti
frtSnn the effea,"4 oL a Se{.>oI`Sd aÃ; :nt, for t'.xi:#;rnpz4 pI::-
tli'atmi*.34 widi tC?õc..tw c:i#.l 1i1Jl#.`
tt? :ii;=]t~ {#3Y3?o:til.u.il t:ells to aTitiwfi?liEe
+`;.lu."I7io1huc2p:i<`>.s iilEzi t`vt Wii:1iZ`a LC<:i;s xert?1::#;#.~
sust.::~}1
iC
Prov1do-d hi,.cl.';, can be LiSe-d tC? wor a#.tv G#.gi`=;?t. t~~~ aC,.3, ca#?
be
i.i any p.i.<rm?:icci&Qafl'uJ'a=::{..4`i.)t:.#i?f4 ff?~'"Su',;
inc3'i.#di'l~.;,.; ~i~~'t:a~l~::if-~u..~i.t4~~si ~~' ci`..'=#.C.~:~.::~~?,.C
,r^.a:t`; A
l#i i L nwm.i S a of ~3:Zt1ii#`. :li,t.4A4 i.#.i'7u k?1oI'i'.e]. #.n the #.irt
and 'i3,io z]..#;f'".i.. ,3lf; fÃ3:" t#.;ii.:: i#:`1
the ph<3 i]{i.i{ vJi3i#.#:l. l sz#'.1p{"'Si##o;K>h of i!ic ~.3<)lymt"lii:=
Mcitert`aik d:ser.ibc:d I'{eas..,.:n.
Ai,t:qAe#lfl#.. a.:,e-n~s are i.>.i:'aC:rtbzad i~ ~5:.x{I iflie$"W..`.13'1.
#indiscludi.. l.'t.t a.c T':ot bial'aFtCC, to.
i:=hLmÃJ}hi..:tgnu.Ãt== agC #?1s,. uiÃ;h as i"~E~iC?~~~1``:;i~ i=F , receptor
kfflh:butoi.S wii($ Ã3;..i#~~'s Oa"
ot.,e# ea:..#t# Ã?eitpic?.` v:t: {3.t=,.~,e
à L, rm`a nl7.tii modulators aiii: i?3oiaIvt igi'#3¾ .s:iC.i as ~ytok 3?tis,
gy,AWth factors or ,AÃ:rolds 4; .th (}z With13:3: tal4' or P<r"ihow;z'3'i
antit e%'3s et, ..:'15.,,;ti4e `.l?.e c.i7.ti ne{3i3li3''a~ri-it:= 3eSptF.ll-
sd'c3s a mf:illf:;i a?e v's,3.i.{.:1#.1:'.= & s`el{s3q37?T{, :-ft;
I ~ lo+Na;.a~.3.L>Ehot}c ah?t:nt5: anffl?i(>t:ii;s,r or nL3clo?c acids as a
m+::W~ of local Ãrcp-~t;= tY.E?i.r-ipy,
TI-10 b1i5li3gicall i .ii=t.;~ substances and agents are ti~ed trz amt3un1:
F.,.at a#.'o
,
. of ` .
:~.L."'~f~`#~:.#..#{õc_i~:`r t a~t=~~A~"i .~~ '~.?~ii: C'..1.vi~~tl~'iw
~~.Tx#.I`3#.2~'~t ~7~' a ~.3-~:i3 f a:SZ;afl `v active ,w.> .a.ince
will dqv;i`i.d: +`>#'~ thL `~,~,~.t1I'tIi:::ular ri3i3:eii.ib being i:EBk:d,
f#.1'a3C?i.E.i'#:t~? (?f ths' b#F3aot..:.it.zt>; t' active
S t')F~i-#f I Ft fife' tf? about {.,~e ~vk,. S;]i:a ~, ~ ~~ `{ u.#,}~ZF~$a.\
can 43G .a'~~"C.L, ~ ~ a`C C.#~3RS.:rI~C.a. .~a~?:~l e1~ 65% i# Ã.::~T.~ E1
desirable. ~E7 to
aio-~. `:~ . .<. =: .=~:
_ tcl:=;:i.~ ~ " c#:..+`~: s s
. ! ,{3s
~ ~.. ~ 4{ ia `i..i.<#..i..=eJ:
~~~ {,~>3=,,:i3c..si.is L'~'`OlJ 3t{. ~i~~t:iit~;at.`~:. I#?r' 4:i:~' : 3
c:~...E3
I'hw amount of druYd::~~ve#=::d per mea o ~ filwi iu~ per p_u-:icIc ;;.a; .i:
,}ezud z?x; t[:.c:
t}.C.:<lpt:.I.fc r>i t1.;e of tt#.c drug, r:, toxicity when dct#.vC.iC.d lo+:
`ffly, and the olin1oiil
i the patient E}f:if.~i?e i.i't.'.~'t~:~.S":3. ~..s~i~.= number E~a
G~i`ticSC.s or :'_?4~3"3.f of ~3'3t
.} m
1 ? =. a a ~ = ~t \ ~ .. . amount . q ..~~ fi
<~c~~i, _.....~ ti? a ait.4 is SL=l~~.ti:li taL,~t.#~ite:tllg on Ek~i:tC?~";i
~i~-F~.~s as i .) t A?c`. iiF71+:?tua~; of .~~+.'i:.
.{ rZ>r y~r f ~ ~ 7, '~:. 7 ~{] ~ f3 ~> .~.f. ? . t~~" ~. Zr :-#l t(f~.5{.=~~
~r S`~. t~~.~`w~
k3`~.Ã.i~ ~'Y~~ ~ i_.~.1~.~}c.iy~i{d~iC, "_.~ ~,~C.. ~.i~"#~~ ~~~A~~u x~i#
w'~= f. t:~C; t~,+4'=~~ the t ~: . . '
t b;''.ir~,i, ti'i':.ii3:.`.d. Tliu L`aevelz5pax#:ca`t i5.?~
f{tsQ and 4) tht . t:=h:13~.`,;,i3. C;l1.xra.i;E6:'iisz1e5 of the ~''i<i+.
,.'3
di;sa4 i::s ?.itie4.3 Ã5ii ;h t.4t'= p a? ain, t3tel,ti i s i"o1.EÃin:? l?r
pi`rit?I.rn4d by th~,?ti. 4k tEl L~.. li'~rl'i~ . ~iT"t. ~?;.
< <a
~~#,~i.e.~3:'i.t~lZ><F` v and L~J;~3C~t;. i?`i~',t~Tcl#`i~:. For ux~;iÃTi.~~i
l-'~, :?~.tZiG~~;~:? I. iiJ' and .% i C.
.. ,~:.,
pczrft:;'l':L l:m L'. i.il be iidr3 :"~i"=~t`.'1''c.'~~ to a ~~+:1{.~lf~::-#.Ã
i~. :3:I'~:~..
Tlhe rt'.lo:ise kl.nt .i5;:s of a ~;.i$'Ã:?z i`.FZf(';'i7ti:r fia'21 or
h?itrtÃo].Q i:an be fi.i:C. ~=,.d iiS:lÃ.3
atzk, #:+:G:`.' b-y".=,<3aL'lnrT; tl15:= i'L#txC? ~~'f l21t3nC,`m<'"1` units
i :iEb~bi by ::IiCS( ifv.nXY the side s;,;3.1#.s Ã1f
79
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
given 4?ti o.y:IIE:>. &Ã:, this ~..3<7.#'4.ns;<Y'r a fi3#37il'r, t3f
G(:pt'>ls''#7,.i.r." with #'.''lc.z;e kincfic;;
i'iiii_ bC' t!^2S.d ;.Ã} .i t S :?lA3m [>iiaic the d t'.l 1ves4' drf
tiC:veY'iil #eAffi.'.1'ei-`at dm g\ ?i i d: diS.' d ^t'4FrC7d
#'C,lÃ.=usr`~ k?no&:s. Ftr:' c:`i:iniplt:j 1,17.1:LiS.?23g 311f3?"e Si1C`
chains along ttxc "Foayi::i.cr ttic1,t uti
hy d'E>phÃl#c .T'.,d] eriÃ.nl<` ~~ . ht t;li" p~zy731~':Ã" I1:+3rS~`sZ tF` ~r
`.`:~.~~.'..#c m,`cF G:.: ca !d b''Ã"l. also
gone1%#lli Ã#`w-t.i..:ie the .t:,h'.asc à LiW~= of an agent ;'.E'C?[i3 thlG
p?Zl'c'3?i(:it
m S:E~#~`3.F.#.Ã#3 ~:::i~I3~?t?d~2~3:1C xtwi, i.ia&;= ~)+.3~.~'';x1~wa'2C:~
pt$rt3'w~'Aes or fiI1.;.3. Cir;.`xe:?{` rC:lc: s`i.: of
a,,gea`ts. The dL=s~.yUd Ã'Ã.'iei:lsi' can :;o1Ã"i.Ã.'IClL= wf-Ih~ i~'~
#,.#ni In
i'3..i1ai:`Ã Z'?'i1bt1d:1 7e7:is. drug kic]iv$ary is dl tl <.l' 33r a period
of ilpp.i'i3miT3aIi..Ãy 0-6 In other eii?:?E?ialt"1cutM, the drl3g ?s released
over a pG:riC?d of a. 6 wi~:ek4. hz aÃ#:i,Ã.i~er
i."11bod?.I1eL''"#1~< th .: drug is released weeks. over a ~?~'IiC3C~. of 2
(:ek5; Irl other c`1Zy.e1#,neÃ.tsy
m<, pa :1du's .~ by iFi:3?"S'iÃ4g the T:A3o of t;2iff#M#"e3?t.,m(?.3<?."Flf:.r
units dE':r.a?+
;"s)# a .c3t;,E3ttf .M0:80 of glycerol aÃ1:d caproic a.#h:id pt>lymo:"s and
Ã"C. *t3lt#$3g 1`:i3c"#`?.?ps31z3i;=le5 dh<3t :'4"ae<i`: dr1.3got'cr five
days.
Provided }1Ã'I'47,.# are p..:Ã'tÃde:i, i.Ãil;lUd1Ãig mu"C;rf..~pi.ÃÃ~icles and
In
i: a =~I,,.~3C2i~.l.c .l<zt~_S~C õl_ ~G size of t~Ii, a ~3i3l~'I7..f.f' ~ ~
particles ~.~.~=, ~`~ ~`~~ $" ~i..;iu..~i"~i.i~ `~?S..f? ;aÃ~.. 1~~~. i,,.%
C.3::;1.~? f>
...
- ~ ~
~.1~FÃls"'; #.~~
100 I]Ji; in dbwY`ÃZlea. III o#;l1C.r 4:1T bod1.~".`."3s:zaõi, 3,hÃ,. >ir':e,
of the pt3h{llatt#' pilit3+..c's t `S; bc-tv,;C:=i:':Ã1
0.02 . 0 iF., i ?a#.lc e'{'. In o:e}loÃ" i.,mbC)d1:n1:i."nts, flu ,-du of
tl`.::= pol'4, ;'DS;r
~3 #1i1C ~~= ~aF`c bl'-.i~ctnn 1-50 ?"?11L'=Ti3ilaG~~~ in d3ii3;.icCC'1".
Oflaer poi4`Ã'ias`,t.<z p>'l:.rcl<:S i,,. <3 larger
N i8 4~, 3'i.it uÃ'.;.pei.Ffi._ 'oIi`~..`=s, iEIch as where tw;^.T:of
r'egr:S`+4 th 1s pr4='viEir;,`:~. For
>.._`
{
p+. +~L trxZ titi.~ ~~c y ~a~r,r.~v'#~ C7~: size r ~,~~.. ' c ~:~~t~-=ti~ul
~g 4..i ~; :.. i<f,li ~.> ~~~~ii.3~
C~,\t=:~~~':E~. . . a~:}a.>t.~{~~#.i+.i`L:) ~f~,t. # ~.:~~a~ i.. at t~.
,~x`~i3:~kr . +~Yt~Ãa~,
~quau.ÃÃ#Wg or stapling has Q)C;C"LiÃ"#'~.'=id, f?Ã` within a Izi.iTVe or
treated i:i-. .ioi' Si#C;3 as .a;i. i.RbaeÃ:Wd
trs=vit't'Si;t.Ut#:da?"S` to md.ofr':,quenc5 ablation t}". other th<.#':ipy
.+,?I l=Vh`õ1 .:: a.Ã3t7a1`i:inci1u'S
c21';.t'r such a:~ occurs in :iq[1a#.m"u5 Ci,'ll t. a..io.i#1oI21`ci. P?<3c-
si`i7.i;?3:' of r`,olyuieFi.`.. p'i-1:Ã'fiC:"}G`.S
2 5 within oflhe?~ ~pont.-me~.?.~s ca,iÃ~~~s could be utilized to xcsii1. M
aclc.<r:~#s i.:a :it:: ca~ity;
C:=#d3ei wath i=L';~lGase of spcw'.ifi"S.. ;selcios#.'iig agents : #.Ãoh ws
m.#L 3i+-tido#"`, :Ior
do-x:rc'=yca..i# as cx: a`;ip>j~.5 or other 111?ti approach d?eTl .m .iit.fin-
:s
in ._`Es. , tie<3mntui'#1 E3f bu:.ut?=s d4`..'age :31 emphysema o.i'
1...fea,"fit3u, dIsG..lss;..s *u4h as
L yS:4. toi' :'-":{amplL'..
'I }iL new i?"?t;3"<3I3..i'2's :#i:d polymers can i3l5t2 be used to p,-
c~;':3ie bÃtrzl gF'c$dable
tr~TL~+?:i.S 3<5 ~~?.'?~ T7.~~~, f3i3~#i~#?1ti3~[C,13.~~ r z xd copt?ll'mi>Ã,
using s'"c~E~',is,iid ri :[ ;]I3Fqt1e4. ~?`.ic
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
olI.s ;?`11`~...'t . `34:3lymeI's> ll:c3t +a3~lks3~E ( 13~i i and
i.:i:rpf}l`Ji71ers c:an cont.3; n ..k~'3. .`-.t3& chains
~.tr,,:3Gis between i i) a .33t.'?n{.Ame.' f3: :3-?kcl'i`5u7f?lt'cid;.3;'
i,in`#t i.:ok'I ck.i?k#ng at 1s,-z7s,. one functional
~ide H #i ta r 12_ <3lky3 dma?A s ConIal .u ; 1-5 0 carbon tk?"?tS; w1 d,
?:#. :.wktskit >
[' 3 a sÃr:3uteiaa: 4' dkftZ.li.l':: 1':1 om"M4.I or :'k]acioft"kG>lC,i:lk3ttt
L.Ãiat. 132 's:=o>tain e.nbEfdid>1o? :; ti:tie
ca:k be clLk3tÃ.c solids Cxr t itÃ>oe:[2s'?.:< ~)3l;V~i. ir, v,.kl'o114
4mboan:>k1.?4'ilts,. the k2;atckkal;s j9ris,f;dcd he.e.k,` are ..?ydr4?pa?obkG
tF.k'
hyLE,'3phlli+;.. ~~:I3 ~?[hcl' ~.;Il:~t's(~11 ~~=I::tS a provided .1#',t`1n
u?k{xuigoÃ-.`_+ a :,l? ?ngt'. fr':bnn 43ch4J;:)hobiQ to tiyfb?"oph.`allc t?'`
:"k:.;+pon4o to a lrhang ?I:?pi'1. i':i
i ~t~r~ka? S,iI?b(`dzx71Ã:uis, :.Ix 7n clE,".f'C?mole`,::E"r:.7iG:k`
f.71e.',tk:.`.F1cl.3s Pxo.`{t3E:=`.d hf-.i=:'.n ..wG#s ~s} a :,#.n flxat
i.i4:+ .ab...l`.I::ti i?a, tlsõ`?fft:iy8 a a:'.LÃl oI' cÃ:llLllaT
i:r?mpt?nmeI`a:.
EXAMPLES
T,it; invention is further {lt`4crib`:;d. in 1.l1c ft?.lÃw:`i.kg d+_. I7.c::
~innlt ttle
C ~`e.T?k]k~,.
seopi` of t..~i:'v ?a`?Z G;T'?t:on described in the
~ f > .~iS`r~J l
6~ L~.t~it'if f3
t~{
~ a ---- `r
l
."~
~
T
t
:~ P~e.~.f:~Fi.~; ,,;. ~.~ =~~j~-~fii~"j,?~.~'~'.,?~~i.'+~5.}I`aP3i:~1~~"~~
'~.{ '3 ~-~`.~ÃfS;~.ilFa.,'~.^su'4"^{~'.~.I.f3`Ci:kikr. i'vas p.ep'~.:Feii
st ~. i'3c<3l.CCtn C ., 1~^' a p#-OvlÃff.kslr =' (`Lf ~El. ~1'a h . { 3 .~,~:
Z. ~; rY ~~ka,.k.. ,S: U
y=-
~` k`f~~7.7k,'`~ :~:=.i~a.~~ t ..<.. vC~
k1Q3:i7k'dFiv~g, a xs~~.3~~i:
1.`011~.~ .f 01t '?004), First = 1,1y :,-{=kS(hyriro:x~.'incÃi~z'1
)eÃ.~iaziG=a.ld'~? 4.t?..
wQrG dissolved in tcÃ:`ahydroiuk`ain, and 5 A rzic5loG.t<lar sieves
wL C 's3~i1~4~ i3~ a t~. 1 ~.:~Ihõ A c <1~r:k~~'~k~ :k3t'~.f)`a.k:`:kt
k.?f~i^tt33k.Ee~~i'G'`Sz.l~~i?x3.li. :L#i3 ::.~,~L>z :~.i3=Lat.':C~:
to tiie miilurc, and tizc rLii:c:ii3nw13:, allowed to pIs,3C:ci:=dut I"?:?,3nn
iempeI'fkltkle. Whc.i?~ Cie
m.tY~t?a3 .~,. ~?:~ ?.:f~flr-:<a-x;.f~kf%lxk~~13i]~= \=4 ~ '.<5 added ~ ti"I
~~eSGI.t:.s~ ., i the . L':i'~=:~ ~, t~iL~;.(;~+C.~vt?: 'cta
_..?~7.1:~#~..~ ~a.f;:, ~~ ~:st_; r
2 .; xi<. = ; i~cxe: ?omt?3'k; e us:Tlg IfiliÃ'11tio71. The solvent was
I'omc?vt'd- .'?_k r:>ia%'y
e+;kPo:iaÃli#fl u:i,dG>` "edw;:~d pÃCsst.,,c, i3:.ld fl:c residue taa
S4i3lvt,.d in i'r3is
~-..:~~G}E
` `x. at~~`~a L '`Z < .~` 1Ã. 1 :i~~s, <.~ .,k_.1w:~ , ~~'#. tl7 100 t~w3
i"v~i ~;`.*I s'?.~~ )F?t3), '~,..~t4 ~?`:~rf,.k .:i~:1i.# ` .
1k;~ .:z ~~~t~ ~s,~.~.
81
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over :uia3vdf"i5tt;, ; 43dla3Tn sc.aii:lEc?. The solvent wclssi153sequm"~k.,-
my3t.t'Cta usla3~ ~'s ~~.<I.ti'
ii apoi`atAi,?n L#Ã-W+u? reduced prL'1s#.Ile, and the residue L, 3s pu;.,.&d
using f:=hro I2'latoi(~ ap;-ti=.
~ ~Tcffi vl '4 14,6-:r~i-neffiox}`l?l3~n yl) `.,3 ;-5-di5x-miy1meflim<~l and
Ã~ ~~thylamun<::.~ wu.: dissolved in diehls.romGthuic and chilled to 0 'Ã_ :
chlf?'1dL was then added drop wi s% to 'rbL:= Blt1lixl-L3ri.. After m:x'Eng
Ã31 16 h., , ii. n'%.txfiiF'e lxas
then s;`asscd UaTf:e times with 100 in.'Vl pi'l 8.0 phosphate b'L'#ffi`.r
a."`1d f.....,ed oi`C:;x itnh,ct`::+13us
<
s. r r ` L~. f..~~. ~A.)~~ ~.~a~" a~
~iSi~il#.~~: J, W - ` # e1"8L ~~'i2 s `~l:#*t'q~.L i~tI~'.Ã'f tllf`''t t~
using E~~t. ~t pt> ar:_ w'.
rod~Ã;:~~:d ;',ris;5t re; m>d tffic residue, a: xI tbi: title ci3t~~ipt?und
was isolated ~is.,atg <~ihoa goi
} \t tIy~~(
~ 4Sta'ih.t`at.~'i F}~~i ` hv~ ob_.~~Z~..~~.~Y"~f3:~
-- --- S
r r ~ ~
,~ r \
(?i) 3~C:~:[: dissolved in i?~43. ^zz~f\\\ .t ~ i.1~I 2,9 .i e >:~. ; ~ ~,
.. C3i.~.~'C~<: ~~.. ~ ~ . ) aniLa
(03319 ,`~,., 1 t~? i.F i~~
sz1rrG.'.d afi 45 'C} foi I i. A#-th:ti EI:i-ne, toli.teE7.1,`. ( 1.0 i1:l.)
was 's.tld.v;` to the solution, ,ld
t3?hE#,'.,1G4me.` s r!-N distilled Ã.va of dae mixture at ~+~, C. :`I'f::Sh
ti?.iui.ili' was aiia(3.ed, and
d.dstltli4lY:<!h L..a.~ i.Ea e==` ~} t. ~.l`f ~~,~.et';'.:i. I i~is process
was repeated Fez3:~.~ :~s~,., was 't,~~õ+;':`Z'S; .:i#.
~Ãi1t.; ~~
in fii'F:ti: di :A.1;.%#te. SJd313m bii,iX,bfn1ate was added to yamwh flao
acid, t211iz fi..?:z..5~; 4fJdh: x?.
bFE.s:I`bt3nc.fto Te3T15:+ve% E;ivl..?g fils.-rai1L?n. T~~':ia l'om::i.llll?3g
to.i#..m<.`=mas 1::.mov~:~d: ~0.a ;"(?i: a'oi
;:V2p<;rafiitn, Ic: v>.nÃ; a sl#glztly yellow oil. 'T'his mixtuiri.= was Ãhm.
sopstrated tts:ng ~a~~:;=~:
g*.I t?'iF"f) Tn cbtY?g r t3p h S''; T b ?:, j?.f'C?du c : "+-v.:4 (Yb t a i~i
e d :f.`s a ~~L, 3t o s 33I ifs t 4 1.~ s'. ;'.o,.~4~.
3 a 3F~1~`~~ ' \ f' ho`, < ;3 7 Me~ > ...~f ` J l~q
-.,~ ......fi
(0.504 g, .2.42 :mn:?l) <.nd,
in`Lts3yl i:,.3?`lc (0,68 il,.l, 0.49 4.8 2T?1ilol) wci'i+ l.A.l,~sol)i`d à ?
and ch-d3::~:
92
CA 02653811 2008-11-27
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$.5, 0 :'`..~`: .{~ `t';i~,~.L~?'~'l.~t %`~'r~it'ii~'t-.`~ (~).r~s? ~'~~-r
0.:~7 :'~. 3.tr} ~Ti71Z ~.~' 3~'<7~ `t~~.`?C:Ãi ?t~tl.:~~".~~. drop
~Z ~~S to
fh.~`, niW#..aY=. Aft.t<:' 1I? xsng0b.r 16 hi3i.ii,"i, then3.;4.tuwo ~4as
then washed 100 .?..NI pH R;,?
p 1C?s~o;:e~~ ~'a.~f',~ ~~~Fa~.{iZ.~' (5~} xll::; X 3) wllt~'s dried over . j
r ~ ?~e~t'~:.LtZ~`a8 ' ` 3~c
~. v[~t3~1::..71 :~xat<f~.G, ..,7es?.,< a'ikt ii`as
4{.E?4eÃ,ue :dY^ .L'mtJ-v{'d using 3"S_3~ilii t c?zlptm3lbE,Fn uIidk-
r.rs::duced pF'i...~a,_.c, and the r?rt?t>txf
wa's isolated ki ?1~t SlIci3 gel at 83.9{' C;'1fi; la,
~ Sylthcsjs of ~ i b]4bc-,zvIOc2_..y....m+.:`,b t.`y'late
~ 1\ ta
0
fi.
. ;~
t
t,3......r---^''
`tt ~~~=
\tw.... .....+~:'
(OA5,mi.F.. 0,50 g, 3.8.nini?l) and ui1'+aF;.: .;ivJ._:e
K511,2 m ,. 0.371 .._
f, 3.73:I7:FY]i,~~ \i`C'3:"a dissolved 1#1 di.<b:o#'w,'riS3:banL', and cH_
4z~; to 0
~ ~~
.'~Ei~x: .:~a ~i'3~~~'~i ~F.~~i~_~.'i(f. 3 tm a 2 'r~a~3.:, `!F .. t was ;i
t1i{~ (~? cF.~a~3 3.i ft` to Y
. .. ~ ~. f ~ pi_r......+ ,`~ +. 9 . ~.C~.~~.~~~~.?f}'. L:~:3g.3 ~ C.~~Z:
~_(?cini.Siturt.. A> 3.urmix1?c7 for n. } 1 s#~~.`a..'= ~~~.ixo-t~.niC.' Z~~
i .+ t~7C~~ ~iL'el~. > .E~ EL ~ `40.;~ q~' ` r # t~>. St ~~ `>
~ z~ . .~?t?~.~.:~~~~?<3~~.
btJff\!2 = J;t~ ?~%>, X .i)Whit} dried ~l~~~~~`.r ~~2~~ ~ 1,. t~l'C)[~4' sE.i
~ SÃ~ ~i11 .~ 1i,.iC~L<:. s,1 ~ ~','i.> ~t was
;, ... . ~7~. ~ <3s
st-b:ii'q(1a,;fly removed u6`:.1#,F;ri?till,P evaporation t.Fndei'1ed`zced
pz`t.ss..#.c. and the p;'C}dLiC:t
Ww.`.a :3si?l...o-ed" using "I ?a, 2. gel 3tiztF3:t?aliAgwcphy at 8 > leld.
~{YciF~~~i ~ ~~Y3 ~#~5$'[??1~~?{i ~'~y'~~f~s {eti~iDllelZw i < a 3#iFic?if
~
yF!''~"ti,~.:f` `.~..f''..~ `~"~-Mr`f ~ f'=~{~ + v~` ```- ~' `?`{..
Ã624 .T?.<F, 3 Ia 11a1:~ ,.3~ ;i^L<~Y~?i3 <.4$t:s.ix '
24.~ .~; k.5: s`_'.~,y. . . .
'~``= ~i1~.x3 S$4 ~ t,i?:.F ~ :~:.it?~ # ~; ) a af;>. ~:::~i~ . ~ .f ..;.
: r ~>~' i 31 i?r Ã` 10,0 ~ ~~.~?~-~l~ in a 10 ,? ~. s~~t~;7 ..~. and
.-= .
~;^
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
:~~?bs~:q~,r ni~~~ ~,y~~~~u~~Ã~~:~i .;~,~. l~~.:a~~L d with ;~;~ three
trti?z:s. ~:~,:x~~~c?;~~i.~:~, t~~.e c t ::~~st
f=5 L. 0.02 ?l.:?:71ol) tt?L?slff 3ati:.+#113~_t%S~l?I ratto::z 50LS) Z'cEs in
a si.l.;..l
fl41i3C 3I. ..aUs. Tht? SC',bj4??k flask Ft`:bti PaTlÃally 511bma.rtsf=d. in
a th'wA?i{?5t.3t1ed oF.i
ba.Ã~~, preheated to 140 Toluene (400 x.FL) was added to the ~:.alai., st aiid
.ho. mixture
i=4}1s ?.1eC.t{:d v"I'a s4'i31g+`. :t? V>C mt>11E.1'2ic;[.sz. The
I'k.;.3C<tioE, was S.fl`red tt?{ 48 hours,
a'L.iT?E?t'{:d a'::om bt.cli, and. to .'f7i:+II`} te&71poaatUAC. The polymer :
<2:s, i?I4solvt,:d in
d~chloromethmo 0 s> m[..) and precipitated in. cold med=an~.~I. `Flie
sz~lveiit was {iecant,: .I
a31E .'',.lbst.ruendy dI..4.d by i.b`ip{.{Ã`atlt?;'?> ~11c
r%='iuffinr._~, polyin-c.I' foInitia L"=3.ffi`+.>.F a t .'`'sco{.E: `'~'1i
or wb_Ãtesd1d precipitate depending on the ci11`bt)$`iaw a(?,la-va .o?` f1s.
Ui?po 4net'..
'~t.lli~~ p'*;c 4, t;~'~: ~:[3r"3~#{;i) C') ittE'~ t~`o following ~:} 1{iil~i'
~4z'^. :, ~. ~~ ~.4, t' ~}. 1f)k;:.,~..~r?
~ ~ ~, e~~~a?a y~kc:= _i~3i?~t. .~ t~.Z:i~+t lx... ~.',
; ?i; iJ. `rk i;.501..00.
x;F.~.`k3I ` rLbIV ~>Vd1 Fx~
__ --___.__.~
~=~t.~ ~~,.~=r~,~,~,~.,,.~~~., ~ . ~ ~ ,..~,~~~~, ,tih~.,,..3 k~.
~ r
Pi3ly(~, .~~ r ~õ 2,022 ::?t#a:t4.3~.) was
~~.=E?:t,\~~C3~.t' glycerol 3
~: :~,~tl~.= a ~-~ i-~~i ,,~ ta~
~ia~~cik :=~~~.~`tl t .k- ~ ...L ~`#k Ã:'~,:_ ~ ci_r, c.:~ iis~:~?lt..<~r"~x~
taxi 1~.~3.a~t,~. 's Ãzis P~'t' t3i ~ . 10% ~,.' `]{ . ..~;`~~ (50 t CYZ and
20% p{:(0H (. (R) ?l.f,) were tliCn i}.f,d41d to the d.e3lsii:ioi7. The
rka.`:..ae
cv ac?tawd <;nd, puTt,ed wi-a., hydrogen thre-c tÃmm The fl,xsk was tfcr,
pwsw ~ .~ <:cd to ~> :3.~
psi 3<:th md sha-ki'>? f}?"' 24 3rit?is,?'S. T}?tL #"mi;tio?". n:E?xtF:E.1'c
.) c3ti a;..ri.. 4.i..t: ti1.`v'{.iLt3
Ceh#c: aiW the t.lter cakc v,:;~shcd ~=~:t~~ 50 nzL The st?I-vc:rit;~ wt.m
then
evaporated 'm S'Yidtl thw. 3.:'i-1al ~..~ol-~;n?ib:r.`, J1.E~. 1"('s:iid13.g
~..`oe;~11"41" fo;I?..r.} cF':~1e} a 'v`.st,..tu"~ ~s$l
or vv.hiÃe so:zti pÃ' .i:f-pau}it: depending :3'n t61c L,al"~.'?f?"iaf:t:`
s..i).: {: A`.t i. f the cC?pi? ? a?"Ye`:~'.
C a;poE-vmcs six ui'c -f3nnei~3 WYF'2 th~.' ~i.`.'HC?wÃn".,; cit'b(3llaie
il]i;ÃC. , ,r,:ci`,.ons. 0 f,5, 0. 10, `.~,220,
ii'k t; `{+., 0.50, 1.00.
Table I }.'t('3oi! 1i:CIiLatLY: 5hc C;;.?n-14"3osifi{1n, i-n('let.u.:.I w.i
?2:t, und thermal data of
~ ., t>.~ `L L= ~i ct.?po"1f'nmcisy whià n. [1.1$: 1.11 ll:itri.$tba=fi by
stritltuFt~E f(}}""`+.'3~4:>... ~s, bok:~`~' dw. _,.sWc. hy_:
Table 1, ( :i._= : ct7:prola.-t:)nt, CGI {,:abt>z7ate o'c`g,.yct:`,I'Z3~ ~ :~ -
_= f-mole p:.'~icent. +,:ub{r.Iu:t:'
84
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'n7=jt.:oF"n.cF' Tn po'cTnt i'11at1o11 to.C:i! F~~.~ :::1'f7Ã3lG por'.%flt
ci;abc3#ta`,.. 1>3:st,:?F:3.;r in i:op a`pt:'T:
s,:a;:_ ~i~~ :.ii"1~':Lxl~St.=.3 ~i~ ~~, ';Es.:Ct~
TABLE I
. ......... ---------------- - . ....... . ............... ------------------
. .................
molelulA ;:~r WeÃ~ ~~ ~en Aal Pavcà G=~~
--
"~I, ~~
~ =~.
c
s k=c ~~fl
~.~ ........... ..==........ -----_.._ ~.,.,,...~. ._.=___.... __ .. . _.
~___. ,_,_ w...~.,.f.~.,,........_............ -. .- .,- .. ,...<.:....:.
0 +~~ , ,;;.3~~E :..~J..2 ~r) ~ ,~~ `l. t j~^x Yi .~
J-. . . \ ~ ..' 6 Z -
c ,.. l.<..3 9(r-i,.t.Bn :0 11 61,700 13,300 1 .~~.M -54 ` ,t`~i .. 8 t. 1 10
11 5 7 ~0 0 1 2., . '0 ;: 1.t.`}~` -59 -11 ,r i':
~
Ciw '0 ;~Fa .:..jtF ~~ 6~7, 400 1~.},2~~ r 3. {~6 49 4 3 2 1, t
~ ~ t.'i r f... .;f=~_?~: 2 2;3 57,400 8.60#~i 1.96 : ~~'> 0 :I .' ` `
: ,,.
(:.'<i 10's~~ 110,100 ..;91 -47 .. 45
2.0 '010i4001 .9 6 -46 '5 :~~. .~.,.~
t. i:O t, 20 t ,¾3 NT; 20 68,700 101, ::) C.) 1,94 ~~~? `:s S
44
3 i.! 7 1 .E0ix 9~300 1.718 ,.43 3 Y 14
f. a. ..~~:b ~~~3`~Ei= ;~g~ 40 4.y e "' \e'?fi0 ?,9V0 1.94
~~, i-~i ~~ ? f=>"a~:a 100 1.00 104,000 _t,6t+t~.~ .~ 1. ~~ N i i?
-
s_.: t
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
:.
. t{ fr \
~1- r. \ ;:`~.~ =\, ! `\r t ~` .
lr \.`' \ ~` ^ \ _ __~ ~=~:
ff"-`. _>'==~~: r'~ . r \.. . \ ~.~ ~.
~_- r rY1 r;.;, .:f:~+ ...' =2 . =v ~,~.r ~... ! ''~-y~ ~:. \. t .
's. ~... ~ , `` =. ~~ .
,l \
.
(
111 ;>41!
~*.
86
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
------w -------- ----=-~-- - ------------- - - ----
=t
ti
1k........~ :~
i r ~ ,.= ; ~,
:.~'`~ 1~4~.:. ~_~~,.-.''r'~~.~ !.' õ~'~i~ r`~.w.~" u '~.~i'`/ ,,.~`
(1.0 _ 2:02 #t~:t~.<<~~>
nivf i:i{ts6v .....W (16{e+0 g, 3 13 nlmi.?o '<3A't<i (DMA,P) ((. i.f . 3
1,01
tn,mol) wei=o dissolved in IÃ~~ trrs'dichic:rÃsÃn.thani..
(DCVC.'.Z~ (UM) & 2.42 Ã#,z-n4.~~) was added to the reaction a`.{1#.:;5:'#uic
ciÃ: a `,4l# r 3ri:cÃpita:t'
- .. r i ,~ ; ~'b i q y, , r ~' ~y
aij Ãa~:.~;Ã:~Gi.~~': ~'~:{ti ;,~ t~i. rv ~._ ..:"~~P h~.>LÃ1;> cil
IÃ~t_'s3~t3 r.a~~.Y.~p4=~"i.it~.;;'c Ã..Ã~a:ia ~ Ã.~~3 t.? . : Ã
p) mtp.<iwm wt<.) ).oaC#.t.cd by fifltiCttiuii uY.Ãdi.he filCrList`.
'c..o.#i:4)2[LfCit\.=fi.i. 1,:#1.;
ionc::m,T<.S Z:d fiftt'aEe dissolved i,k diil--dot'onno.h.an-,c and ptr
cip:t>.~tcd in .:old n.<.caan;;l
(25 nIal t.~ .~:f' v33v:..~t was L:4,.Lamcd and sLÃi)Jequal$ s' {fi.-iC:i~
by evup(tlu.t2>m. ~'h;=
r"~=y~i~~.>l` pa?i ymer was a white solid pI'e.=1p1ts2tc.
imli_ 3b3lz ,S ~~ ~~~SSEc#ÃI~ ~L~t~ G<lÃ~~~Flx~4 +t3 c ~~r~L~ sti~C~a~f i
11{Ay(j)G"nGy1ox " glyLt,..fC.< . Ãia3 3ll~i~t tC1H# S :$~F]i't~.~itti~f?:i7 ~
(1.0 g. 2.02 ni.:no ) ,`i:oaÃ`.Ãc
.
acid :1>.~
;Ã+;`S` . 3,5.> ~m.31o';) .$F3ta DMt'3~ (0 123 g, 1:01. i7?-nol) t~i`re ..
54:3I.1..d Snz #.a~iL
ti;:
dry f~iunl;Z#.i.`#?':s't-lba#:.Z:. :.}~.~~C (UOO g, 2.:42 mYT2ol) was added
:.o the: roFli.'. :#.a}." :ET:id
a j>?'1it4 , Ãt~~ipitat.', f0mred: 'l]v ii21x`iLite was stirred fC`~i 24
13at#.?"4 at rowTÃ
à ntxer nafÃe ;:en, Vllac prz:::;ip.tatw, cox#tpc~wid was ist?iated_ by
filtÃa:i+.3n and S ,.;: ffiltiate ; as,
i f 1<~.Ã'23Ã t~ i;. #:4at cL>F1ct,'`nt1"a=:i+.i fitÃ#'e"li:o \`b+i.i:i
d1t5Ul'v~.'tid ii iÃ.tl.='tT.Ãro.i3tF.'.fi+,h'<`'s31i,. 'i1nd
prej :pft<3.'tt'.3i .ÃF; ...tyli3 n`_t..tii7143t (.c'.5 mL), H~IC:
4olvf;`..I.3t was dd;;=[.c..Ã'~tcd and Aiub:yequi'.>idy '=s~>.`#.t:=L3
by mapZ?,..?I;itia. T,I: "esi:tffiig was a w llie solid p;L.iiZic.t:f,e;
,~
`~s..,
~.
,~~'`%
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
=-~- ....... ..........~ _ ...õ-----.----.~,.,...,,,,,,~ .,............~.._
F`o 4,''(?lwt.?:t%IO3 yi,' glycerol i:1Ã~?i?i" i1~L u.t? i
i.i2:~3~17~%1?C3#?L} (250 0.43 Ilu?'li3lr w<3:.~,-,
d?ssi}IvL.d Ãn 25 m, L c+f py.Ã::di?:te and cooled to (} '(:.
3ra8 :?ddz_d t3:top by dTop< The ?,31x.#21'f: ~=~i casti::lÃ'I`i?d ff3> 24
ha.~?.Ers, c#i tx?Ã3i-?"#. :t~.a}Pe;'"At:eE'e tIF?f?er
?lltà s3gt:1#.. a ::.3v pva'.3d,T3t was removed t?#:1t3eT` vi3ct,.3??`[, i-
f1i.' i:3'Ã.tah~ p=E3df;GÃ w.z. d.?s-staIvf ;xI i:.?
Iai.:=Ifl1`.3roa?.`E.'.thim%'), and. precipitated in cold ~ i ={xy} Gi'
:~.i~.>,5 yx``~5,~ f~ r~F~ x.~ s't,i ~y?'''t-'..?? } ""~?~~~ \` t4\.4'1A i-
.t.~~k'
i~C t'4t~ ~ i#D. T, :
i3.nd s.<:#i:{:+eiji.:5::nfly &aL.d by : S'ftporat.tol3. 11u, e'f'sult1#?g
_lolym.:a was a 4i'h..t sE_tltd
precipitate.
E.Si.i3.17;i`5~lOA]T? T v F x_ ?) t el~ pol 4 ("'<?bl?7Fa?t< Of # 3al t Cia:
co L apfo t4t1?3ke
...... ......... ..........
- - -- -- -
f;
.
{
?~~ ~ ~f ~ `~~.=^ {~- -''f . ~"~.~ ~-'= +j ;,,} i ~~ ,+
~ jza
A'#? :i:?n3lts,'-C7zt,Fv1.3.:'ed c<3i.':<`lZ,mi'=:pC7ly(O ,.?'Ã1=:'#:tzai)-
hexiS,.-#-tD?z: :.C#i., 2-0ai ;. 3 dtf?x:?#t . ;_.
S=~ L4.+v',F' Li;?wf;~S i;?I'i?~i.i..Ãt?i`ia:}f ~3i?~ h3`C:~3i1I'~=E~ L~\ir?M
41~L`. ~.c33~C?:~~a-Ã1!; #?;:5.:~3t~t~';.
i;<< 171 j?~Ar r riJ ;{t<Ifs~' ~w:t.+~It itf #IF.ki'?::>:3G( .?t:':wf
~ ~ f~ rs??r'Ei/L~t +t13";t'?
i-yd,:Ãd (1277 g, 0,78 ?#?o").
(l. 5 g, 2.6 mmffl., 22 moI. % .t.)("(-' #0 129 ;;, 0,63
: :~`i~f.tl) were ~ v~ {~...t ~ : ?-,.ar, 3 4 ti 3<i
r~:,. , ut~., a. . ~ t~~5:~;.' ~ ~.i~ :~-ÃI~ t.~~=' .~. Z .:, 1'aw
m i ~ and ~x~` ~~_~'R (0,1032 rf +.2:` r~~
wi#.n wt?..zC'.`d at R 5 ,:<o#. .. s :l. The z)CU n`r1;: i.Ãh#'1-6.'.Ca and
li1G #izi.v.,.'1 t G'vil.,~ oIi=t Md, # iair
pÃodi.:c$ ws,S dli;so:ivi.6 Ã#`, f.i#.cb1oromCfau-?1t~ (10 mL) iÃx3d
prec;g31ti?.14d in c:5.i1 #:'?~'=~i3.iF.t?i.
,11s0 'a''#,?1w?-?3- ~A c3s d4'cwwZ:d and Si`~b4quf;i3F'ty fL['Yfad bn%
Lv%:pt33`a.EtÃo1: (85'!:r `tir..'td), Mh~':lÃt?:i'#
o., Phe i.An}:.f'sss<+.tL~~H=~:1Ã3Ãx w[is, deLL'.tmi):L'~by Ihe p1LsZ...~i?4~x
of :Mink, l:.2#.cCh\I.L':we group LaVares:t
#.:a;)flp as wf:=~l ws thC F'#?-iot= ~.~?'otC.i..itng Ã'1?Ãip 3`Sf,.a, .3.ih
p4;.t?ks t.n ttie
Ã'Z`2tL'Ct.Ã>?g ..
.. z NMR suC:c¾run~: [l.t 3. w%,#...I 19 (a?i 2H7 OCI--.k::)3 and 4.45 (s.
21:1. . .2'.,,#'.. r' ~8 cÃ?n:,
:t, :F?'fi ?3i~.#. ~ r=k~ f t ~3~"i ~~'.
8 IR
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
i.... i.C. C%;id ~r jL:v.3. {ft~ii-L`.t i~i ..rt i'f'=-f;L'~i~'trt~:+`..tLi~a
.: . ... ~% =. 2c t.1..~.f r~.7 i.^3.'.''.{i1r~i~?i.3.,r~F33:`.1~
11,3,: i:>qptshy3T.er (300 nig) was d'{:;~solt'ed in Ã1 -40 21 o.,pTj7w..
idi.w, `~16 mQ
and dry dj:31o;hyj sC3'~~2 Ã~`3<~v f,.24 r?1Q and the }:ci$a,3C?n vvm?'
sdmcd fC`a 90 P1.:i1. 1%
,~.+ 4L``i s t.Nswerc Z.`'<#.poi <3.led, UndL r'}'.ed1.3ced p. e3S,fSi`<
da4l-flo:Cmaothad3e ;10 IT3L# :?.d pi'ek.ip;;$at~.,dl in cold liielhG:n:3l,
Thest,.t`~~.:nE.i:.~~s dcoz33'i'#::d
and s}ibsL`i3uo`?dv' d"I`Qd by ei'apC?ziation (quaiit1tc3t11`E:~ JcW).
Complete dLp?"t>tecttm was
di,t+;F:xllnei: by à :e abs.ci:ce of the Fmoc protecting f...`=zÃ5tb' ~o-akS
ir, the El'I NINMR '`~ oe?:ruzn
a, 4. S<~
1_sc~r~ `uncrif,md:c~i N.}.V t'`aMoll te o G--- ---iTi?I-i:f~ --J
- -- -----------------------------
}+O
tr
4 7;J
r,,~`. ?c ~ `=_.
} ~. .:T f }1 f-<i,.
rr
~'4~^` .~~`4` f -..~'`'~. "f- +~~ ~''+=`,~"4.`'r ~'y.,.ir S.~-~.
t li f ~
y, t
se#f:
A -,xYa:i a'y xii.Z?hitl.^'di_#.; r'itl...ed c4:3polyia74.`.F c.c: >?-i;xÃ?
; ~r- r= ~ c l z ~ t ti~ r` `,' ~e'"
3 f~: xc~ ??yl E ti.. =T C? .--s=t?.~:i' rlt+;,<>~t~L ) i ~iS i 73t~:<'.511
.( ~ laSFt3 L.i ~s ~, ~ d ~?4.
r i ~ # ?EifS ;C>.F`L (W 0.38 -#.1'io]), bc.i7:1'yl :?:rt:+md.e ( :l'A ml
;+, a s {.>..ki), i`z-#?E$
p,otslt~tlEAm hydIo.'tkhn (113 g, M,.~:81 niC'1l) wL,r~E:, d1s:sL3Olveii:1Ft
tZ?l::C.Y+1C. #200 I xLi, Thi'.=
remior. fl::sk placed in, a 120 i,{v ImeSeded oil badiand :-s:.Duxed o4crMgxst
under
il Adug. ,n-,).t\=,.' A)rf..at.:.;v Y?412s.~~~~'~i. wj4\2i:~LF~i.FA=\S \i.~-
SiF~~. I ~M I-ICtS (300 S1F~-.~. 1.i.3e LS-}It:~cnae
20 i...traporat~.'.d f:?Dn and the pr#'.+dC1& <:o,i3.1=Wd .Ii3Ãg dichf
C3I<yTiC'th<ln:i:`= L3 -x 3f30'# "xlr) to .?ffÃ?.F'Ea a
#.:ixiia.e of nts`J.?o md d; t?!':.ltea :et` 6-i2ydlo?s`:y hLxiI-nEtILr
a(Cli`. ll?:~~ cI..It;'F~ p."t?Ci7::E wik~"'
4 apo:3.1fi4:.sted v,-i:3` I "I.N.1 sodium `~.`'t-vdro',ieds.,' (200 llAl_)
i:lEf~i :,1.?eth<knC?i (20() ext?"....t.:ted
i4Sth (HS:.I'di?:i=o.iY.4t~'':41.7c Ox 200 t11L):, and $h%si?lvt:ni was
o4ap+rtrctod l.1::de. Eod3ÃC<:d
preJsLa:f- to si~.}Zrd" kf;.;re 6"i3'vr,.zy1f,>xy f.ic.'~~.&noie ca6i,[
f72?4 vY,wEC3y qC NMR (CDCQ :38"
89
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
1.4; C ~y, 1w5 ~'~~.Ã,~ ~~:.:~~r;1_ t [I t4
11 -2 ~, 2 .rtk ' ?~ t ~:;''~~ ~`Ã I>~...~:~11}, 3,42_
-~ ~ ^~ 214, i .a y~ ~ . !r, .3 3 S
. ~, r~ (~r} 2a.q'~?`\~^ , a~7 .f4.^~t~'',
~.`37 ~.^ ~ ~~}lVK~3v~} ~. ~-'~3
..
2 ~
acid (OX' 3 g, Vr 8 ;2?nnC.~l);
23 `:iLA,`x, and. D,,kAP 0.26 Inin~.~i) were dI~solvE`:ki in .~'`~.: IN:: (20
ia'3L>, r''hL 5=3l1:t1on:
Was ;stirrxR~fs.'2 a1 2' i^E}r 18 h, TEwcD4.. E_, was i}F.tJ;:iC`ki'cll'#t}
ffic SoF1'Gl}t <. : s.}port.to>. T:,}E.'
m~so;.~vc d i;: diE.hac3rs n~:~eÃ~~at~e (10 n~Il,) and precipitated
ink :::olc=.:ineffianuÃ..
Th 0. sÃ1l va;:;;it Y='ti a4 dc5;',antcd ,.d subSErqueIAd w' d3'1#;d by t :
<`spL)-:<Ita;}n. (W:i; yiiul d'). AdEH ;EoÃ:i
~Cj oa d.Z;:ilcob:~c side i.'=hailt; was dekf,ri'#':ined by 1.1iC;
Pt`esirt`s:c of Ã1hoi;'1effi4<ieT#E t,,roLFp ..:s;ar<`..ti
-d;.i'. i' 4,t~.1` t~ +Ã` ~3iM~Lliõ~.~; g#'(r~.ly, 3s well t~ the t.,e~ 1 -
~i~,.ct`z c;';.'t, t}) ~~'~A ; il ; , ; .
3 3 ~?F ~3 ;~ tt131"l. ~~ ~?`{~ ~'r.~. ._ ~.~ ¾ .~4a>h ati
~~le Fi 'NITVIR spectsurn at ~33. l0N3.44 (m. 'H, OOH;)q ~a:}d 4.48-4,53 Ãs~
.1;
~
:~~:S~~s w:t~a.~;zv.
r
The coqx`ly1'11i., L.,?i>`'~.3 mg) wii;a dissolved in 50 n1L dxt
Ila3iÃj`+..'d:}
c~` Titl4.= '! ` .~.k 2?:T:e ~.,e ~ : $~it q i}\7i5qV ~ .f.2iiq
t~1..:1r~.}~nw+ was a/= ~t )~?t24~24~ti:=\~ ,+S 1 tS2S}-y } ~(~f._~i.~ y21 S:
2~ t ~' Z} {Z S~K y~
~... ~. .~n.i4~~ ~.~Z43.tiZ,~f~}5 l2. t VK 1l1`y~[:~a. f~ .2_Y~:~= times.
,?f~l4F
:e
: hE fla was P[ien pt ssaiz ud tE? 60 psi ~viffi hydrogen <iaid shaken for 24
hours. ~ 1
~:,'~0 icaii.lan I}:1.~'`i:tum !-v}s lKiiS:r.t> ti.:}'us.:gh C3,=. itr`:=
i:1.iit3 thS;i fi3tei Qako we:}sh~t:: ~r id v?0' i-n%.=
~t a rt~ .~~<3 ~, Q
t~3~:?~3.~L;FE~I~nv}i~~bz3L. ~~~z~s~ st;;vei:~:;i 33't~'~' t?lf:i3. i,4.~;
Egr.~tir~i ti~"4='1~:lt: ~i~'~.i~~ ~~I,l ,~3t3. ,~'.3wr
.`qac3s3EÃtt aE} v}`.'. ConiplF'.E~.'~ deprotection was d4$3rr21i1#1od by uhc
absenoo of the bcÃiI4''l
;vcac:;_Ãis y sup pcak~ in the H NMIZ. sp"Ã.rLtm at 4.~84;5s (s,
(m, 5:11
~
~=-~ ..
.:.
.~~ :~
\
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
xa.~`iY' le ~Z2 ~Y~~fbx?'S.y31c <~L3Er FLllaL=ti~~i~u1EleLa ~~"(~li 4~zt~e?1
41~~ ttf
..............~.,................~............. -------
f3ic`~..'~1'l3.-UZ? E ip;"t3li3::l}Tle
_4~
r ~
r ~}$
q + `~- !r .~4.~,= `'ti. f. ~,}
:ix Z f +~ 1}i
A C,.:A'bz#xylzc, 1Cad d#.ri]lfizoi} copolymer ?,i?lCf(.1eSSi.~11ct;iC`,ic
s:,JE #11.?Ã t? ~w C3 tf ~,~
d.t3x.i?I? z ?) f't?f3i'+'i.Vzds $iyÃ?:hi.sÃ:r=acd using th,4 fibilo:tim?js
`teÃ?s,
~ Wi':f;i ]3 s {?ir?~ ~13='>..'tiF iW x'z`lf:i 1Ã3o3tf+~s?.',t'izvdr ester
DOW,_.X} "+(+F~t~wX3 (`- henf}': ff]i.M=rl.tC'. ( 10 mL, ^31i'.~. and :ldapi c
.1c3d (2 g5
I'Ãii?1) we,C, adided W owtai3,,~ (I Oix?.E.:). f3?I-#.em.lxtuif', wai
.i~.'t.ftix4d ,t?t' 4 h<)uÃS A 3 00 iTl.,; aI':
the CaudÃ: product Wa:i pui'ifii:d, via Sific.'s: chromatE},..',iaphy to viL1d
s clear, colorless lÃf;u1d
.;
~r
CH-COGH)Y 5.~)9 N 2:1-1, :(lhC;`f+~), "..:.':ii 30 t~u. 51-1V ~~rom<-btic;.
F+)r st.z.`1.c acid f'i~s:J;Ff.+ ~ "-(+].~f-~, 5 r~If3:xL3 ^,='i3 'Sdi:? Ãx
t. : t<'';"iJd.s>t1;'e'.c'}
lle4:i;n<'.d1fJ?= acid i13t?.,?t bi 3?Ii'1 ester q0.184 & E,, 18 Ã?'mnz:}l7,
p+3]`A : :~~h.'oLY ; ,:.`-
E~,t?~.~x's ` z~.~`3w= Lt3 ?: i e~?kt7zs i i.1)z~~~ i1-5 .~`'.{? 1umoi, 22
1'?3c?l % s. i?~ i3t;~ siv :3 DZ ~~ : t3. 1_=%'3
003) 3n;Ii3C?l), and DMAI? (0.032 g, 0.216 rTlf`a'.ml} were dl ty()l'v'ed, tI`
(20
iI?L~I. ~1.?~` ;]:.;,a:ii?.i'~ 4'w ~.~ s:k'37~:i.~ at ~~ a '~i~Ã` IS h. The
~.~`l..~w! ~~.,$o>c;s~ ii:'?:`~'~~': tiirlZ'ont
,
"L.vap\?roWfa, r3 Ã~~,: prCiZfu{::ZSiI~'"+. (.ki,S.st?iv~'<dIn {dit.=i
loÃarneithai:t' (10 n:i. and cf3:d rnoÃhr.~od. T}if: -~c}li'cra was decanic;zl
and subsequently dÃ'i.tx1 by ez:vwpt+m.zon, (83`J';.,
_yie:.lki). .ldd:ti:ii of v.,~~.c carbc~xyl:,: acid side Ã:has.n ~~~as, dete-
nm.;~~d bv ÃIae -p>osuc~:~ of tli.>
;?~z?iÃ:cÃi k~,;4roupi .4A=it:~ peaks iii the 11-1 NMR; pLci.:m-n a: ÃF6 (s; x
: f1hCH:~),
7 ' s -33
riti.++~ # lg ~?4'r ! tf3J.3 h[.:~~i:iTe.fJ[.` {E[ sd 2-:?I.U- ,`, `3 F:=
f ;sk;,=t,sE~f<i3xtz';
;.1f'w.` ,,'opi. df'.7't?" (NO .T]g) was dissolved la, 50 md, ihy, aC i?
trrt"~?~?l `, lc?Ã t: Ã?~.~?z.~ a
ParÃ' bo.t ~~ , w. I p : fl~~: ~. ~ (50 Ã? g' 3~<~(~C3~~)2.'~_: f.fi(. t?3g)
were ~ s+~ ~ a
i3~3.~.;if .}.~r.. ti, t~ts>.
91
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
iC3~t:t1(?I~ T .: .~"\..z.iC~t`'~fF~,. ~.z'11IS:~#.lt"`a~'= '4~'i?4
4'v'~e::~Ã:i~Isxat`s.ta~~~. and ~~1i .'~~ v 'd : ~.xq'Ã~ (~ti ~'.i_~ .3. Ca e
[?I ~t;t,
T;?~ .: ~-k ~;EeÃi ~~~~s..~.i~.e~~ [tJ 60 psi ~.~~iY1i, ~~~yc~r~~g~:.~i <~::~.
sI~~~G:t:? f~~r ~.~ hours. I~ ~:~:~
di<]ct?Lr?'4 r.i#x ;.t::If was a7ft-Qt`ill Ã~}T<?"iti''~? Celite and i'iiC
.filteF' cake i4' thx t 51-1 ??`ti._
c?`.ii:!'1I0'E:x.t1?Lt?ai:4,,:e. The ac7:v..t?w1 were theixa c;vi$~..~F.>l:
lLd to vit;d ?`liL- atn<Ãl ::#oiy,l?;.:'
(\F~.<?~?~#. <~ ~ t'.'w rt t~~,ixslot~: di~:~~-~~t~.Ã?~tst}t~.
<.~.te:~~ti#:~z:t:~ `~ ;' ~~-~~. >~bs~:a~c~' of ~.~:s. .:}~~:x fxs`
c~s
pffrÃ~.~ctin;; group pca~,, m ft3~ 1-.1 -N.N.-I.R. ~pec:.~rum at 5.06 tw, 21H,
PhCfl-,j, '7.A# ;-7 ? 3 z#::,
t3ao>3?wt3:c,
>.
axs?n~} e L # 4'f~~L11?lc 'Sv ~ v4~ ~~ Ã~?it}~ c3i~~? t 1Ã< s f1 r L t~)T~~x
~.? '
....... --------
,..
~;.=
? G i i
- atz
i hj'`a # i ?..di.t}a3an^2';JnC' and $'__G:.<;pri3-'s'h.fC1ll:3C.t{ snC: <.;
t:=i}'mb3ileta
W1th ii_#S# ~# mfit}:?> (to a L4?~i.l.l of 10,0 1I3:`f?ol) 1I? i.~ 10 I L
soi:?lc.A. flask t?E":t .I.1tieq(?eT.Al v
5 t <3<.u,atcv <nd R1?sxxitad with N t}.1TÃ:i: fi.12?Cs. Meanwhile, E;~c
ctaÃaly:;t 6,5 Ãx a_:..
0.02 #,n-mo3y ratio .;: 500) is eve.i'4iuatut: in a :?ina31 flask foi- 1,30
mit.t-t.tr,s.
'ffie ::<ch;<,nk flask is p&rÃ.~..x:ly sub-~~iea-gcbl in a Lbr.rmostatted. oi1
~.~ath, prc:u,; ,ed to <40 C.
Ti?..Li\.a.':e (400 i:s added to the itIÃwli`i4?s+ ;;;1'3ti e.hi., TI1??2tlae
13;ti 'tcd via to thi.:
?-~.f?:1?i~? _ 1^ i < bt.lm5.~ ~Ctt' 48 l?o#.1r5, i`ciTlÃ?ve\i '~.i~'m?#
f?[:4it a?.f`.Ã> 4 =i?3i':d .}_Y ri}t``i:i
.~I4. ~~l.t. I4ii'i::~.,+
1:0111peratur . 'IY'ie pc?ly^'?-lcA is dissolved in di~~~loromcfl=tm,e (10
n:_I.) and p;,.cipiÃated ir,
wid i~54.,=ltllv\JnL is d1:Wa};1edLi}[d f~SYl.}A Vl~~ by .ti l?c
f's;suffing pt>.T:i7:t.?` :`.nF3s a v1`cC3ll", Ol.l or white sol,d
prcõ_.px$.a\c C3ii;p:."'1d3.:?e. on the
t 21'bl?:?att! ci'i.nwn: of :.1`` L= vpC?lyn?c?.
92
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
r?" \r-''f a-..r ~.r''~J i '~:/- ~~`~ ~.r ~ ~~.'~~
1.~t~
~=
l ;t
l3i r yj, Zc1P1';`:t3ti4 ,~~ i~:.Ea ~
4n.LL.L3'C; :3A~3> .:< ,t t~= ~'3 `+ c ~:.C3J2L T Ã`s ~ .f~t3~ IÃ, 50 niL
dr, a F`arr b: i;le, I t)"N, 1'&{~~' #,50 m~,~ <~.~.~~ 20% 13t1' ~.)k ~ ;# ;
k. s ~ 3
,9 nag) i?i'e ad>; ed i(`? 3_ht: SL>ludi3Ã.: ThL ..4.e.ctfon .11l:Ã?b(,Ã,t'i:
t e'` .2ciÃ,_.tt an: p;1. tged 46ta3
hydfo.;.`,~,~'.I3 dl,cE i;:311QS. The flask is pÃ"v,~;St#x12L'.d to 60 p,,,3
~oi`ltffi hyd:'L~gen. and 1hi:\c:1 fb.` ?4
f3L3um Ã'w`.ait:i3z1.3nlazE:J';.e ÃS filtGt.`L:'i.ht?'agd3 Coliwe and the
fiRf:i &Ka r:.~s-hÃ.'f,` v,.its`z 50
Tf w sc?z 4 (:Tlts are evaporated to yà 'L'yci the final polymer.
F`S.aIT3 p]:~o 15 PoNf\t4adÃf. .3L13l t}lli3n ~~a?~~~11rt à C z #. e:f3"3 c~~
à ~t3i~ #
. """'____.&__.._.. ... .- -_, .._"____=_ _________ ________-.. - ..-. . . S~
. ...___._..~
~ ~--3+ \
~.
?. y 4~ t j
S FFF ~
~ i3ii
~ lvcct (? 1.~'..3i3, ~teaF,w zsdld
D'~IA1' w-~. dÃ~,Lolv<:d in t:)Ã~ i-t3_I_.d y DCC. is added to, the
rctic;ti,>n
and i3 white prf'.i.;Ãi)1.<.EtL i.i}rms, The .II`xl.{twe>s fit1m-d wZr 24'
i3mu3`S 3'+:ZZ?r3i
1M^, t.aitperi3.tuf'~~ unda 3':ii~,;i,4?;:n. The precipitate compound is
F:st3.,..to3.a by filtration and ti-ic
fiffictt:i': a?ila.L#3t1"atod, ra,`1,c +`.'.Ã3}`Is".eI3tS;attJd j-3i3~at.; is
dIsso~~a! ed;#i a~,~ ~eA43lti`fllc'~~3.1#1 and
pat:i',1;ÃSf`cat~.'-d 33 mRfluuat3l (25) ;rli.), _11"#.aw= ;iL?lbea:t is
decanted tind . 3i34c:{ Ã ci`.tlv, dried by
a:~ Ex, c mn 1L ...t F< `31`1G 1t F`I of F';C S?t3x l Ctlnec?zllaÃ>s' 11 LJA
N`1c:"o~,O4ÃF "1d i
B.Gc:b.4.tZ..b ab 3 p Si:Z' D.L. -Ia(..,~.Id k:,-LC3g, - kiy4{..;Ãd C ( I
a~.~GA~ 3,<'E1~."+c{'tC.b..... ?
ac;= a153dwht:eIi of paLl;t:Z2d . "I'hZ fahnita,.1.oi1 ttS.;ll_E-x.qu...4
l.is~:d to create P;.X}A
9V~
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
'`_1C:=l'opii_u4.~4~~`s We2'e modified fI'o,Si Ediild3d. & ,^~lbo:i't`` 3t;
.`.3?d Wang `. :ii (1..:<3lul:ts #?i. ':~'?.,
At>v:. PC>, mw=f` Sd.. 15':6: 412?i}01Y tVai?.g s:" a.2's,, Chuo. l3hw~m BOz =
` Tok?ro,,
4. F 93:3,. ,> Ã'`}96) and ::.#.#.Uz,C'=kk a ifmaer in C3R C;12i.uf;stÃ71>
teti1ll11qi7G, First, 0.5 g Z? [ fi..~ 25 ,-11.=GA
,`~AbSi3d?..b:e Pi,E ya1'iZ',?" .:i-#ti'mao-ioi1:3l, B=#.1'I3lit:ghaTli.
Al:1bi1iI?>l) ts1blf:tE (thi: yc,'L.=...n:c~.i' i.llc vat.i4?
of l<lcfic acid to glycolic acid t1kt> S..owtaf' the i`~.'lea:*C".) were
d?gsz?lvW1>, 4..li.`i_:
<11ihlfiF"s.33.,#t :hx....t, (k?i~,~.~.,t.~ia Aldr1t:.=1). St. L'C?li-ds, MO)
i.s:ent; a vortexing dovi: L=, Afic . :t w,
<vas co:-npIote g dissolved, 50 m~~ of paclitaxel ffax( .> MP Biomec,ic:.i1
Irvine,
0011btYai ~) ;?rvt=iÃYt~~~y sol'Libi.i:.et~ in - 100 t.~i of zlinio _fiy .
s:#:lfi?a:du f DMS O. . :dac:t'
flatF i.?kizi... .Nli t. Z4 a:s e:~t~ded and fud`diei `a=3.~Ã"texod. M fl`}. =
fi1?fiI(,..tif3~n <?, x>:i?"tI.}i~~ PI,1 T.:~
beads only DMSO wa:: added. The st?lW.tm? :icis Pie;L'C.d i3't 10 ml t?f ~~>a
dly-vz:=1yl illoolol
Fai f,iL.:i...it. (Fi4i i..r) and T`:?.E'tl.:C~.`G: it}i' 15 I'i?lt?wtes (or
u`oi,icatcd using a probe fip CDn.catoq~
and Sfit`.cd ;tvL7?i# rhit, {I'he infc:E1p.Alt1cl^'.;s ws;;rti, i:=illlei,Ecx
ilnd washed Ãhmt. :.fliS.s it:. 50
nA. L.'>:td.is.#l,led:dt`,:,'i'r?niZed water. Following washing, Eilf'
IYOs~hÃ;'1.zOd
4 ftcc:?c st#:ed,; <and stored c3; 20''C ti) insure the qt~.?il1.Ãy
oflIaclit;xta. Fh4 e:,Ã::tipS..i`::{iÃ;n'.
~ 5 cffi.,ii':.i L y z.?;' ta:r?;?l by ~lie i?i#c.iY?pw.t?L;le:i was
Ã:tieterm#ncd to bÃ, 74~.5 4% by f IPLC
Niini>pF1.itis le5 Y.?V:.`#.`C3 prepared i-#s?.1?.v~ t3.I1.`aE?difiG'~,'tii}n
of a m;il_ie32`#1;l41oa
pt?ly?'.?xcicJ...:t.iot3 :i'l:i;;t}1,.\ ; :-;.'?'Ã(?u;iiy Iep<3TIi',L~.~
(L%171tilE',vi*,..i el t:it Mlzici'i;F`~..1tk4..3cu 32..5?2.y
~ 1{1'`~9)
< ..
(AIBN), a free tadiia; initiator, wenk .
Lii-s:ii,AZ'i..ta in xd.?1&C?w~~d by #"f:I~'A~#if`t'i:#l of th`~:~:ik, oo-
n¾.viil. t'owFY' cv>_iSC3nat.loa`
Ã.i?itii ii vi,.ic Ã:i:, . ?i:t#lf4 õ4~iil iÃ;~.~:=Ca,
.'~,t~'i:?.clt'~\'',3~'. ~~lb3t ~S7b'~ ~ ~. ?,i? .~#F:3iEi1Ã?~:'; ~~ ~a=I~
;,'~?r
A 3150t:ix--`ri.i]yimi:$hyl meth.ic?`y-lt!te, 0.: :? Iiig ttfpc ciit'clxe: and
22.3zo 214(2-
:3~~~~t?=<'E~ ~Z~~ :i?.?i~`.`?iL ,1 (.AIBN), a 'i'Le i"cadlv:;ll initiator,
.5.rei e
EtchC?ws:d by :"L.=Inl?vy?a of f:ie sÃ?l'S`=L'nft via `.'eoair:}' evaporation
i123c3i a Z isco i.`a,".i?i~~t Lit"C,',
rex?,.;aned. Tht.s.'IBtii,t.s i.7ixtuIc ~,viIS t11Ã;tZ FI3ixi.`d 3iii.i`#. %i
it3l{.fili?tr, of soti`>.v?:1 dodecyl
5..#ffato, a in 10 1-111M pl-I 8 13111i43sp:1ate btaMr. .. _}3Ii: miXE-ut"ie,
wati :hitõ`.,?i
sZf.tlccttÃ.d eÃ`z hour ~I si?.S.%Ã1'L.Er pulses with a 2 second x ?th 30, W
of power,
"C?#.`i`.='It.t'4w tili m a#.iein iit s:i?x?. and .i.:Elt4'4 iug T}1L~
Solve11t to uS`ipsi#";.1 ;:o:
94
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
tdaÃ..s!"s.`rreCi` oil bath and 4t1l-rE'.l at 65
'C $i#.i' 2' hi}s.ns to an#tie .te i.3e ~iGU^f~i2~#s ti~ p1?ly7:?lei?zaldt)n.
The ~<:'.~''14lt1ng
li3'#~i~ p~1T"tFt.~,S.:~ were ~~a~,:i3 i~#:il~~l.~'1~ Fgx.i?.i~ j~ 5 ~3 ~~
~~. { ~ phosphate }'bffi"r 4?4 s 1" two days tE?
it.nZ?ve L'<<3Q5s ;~t%!'fiat:tant md SÃ$~ts.
.:
1" k ml~i IL S, Syi#Ã 3. sik of Nia7lc)T} zs iit 1 , Ui#. pitmo
3p<<FÃ rÃl
1ec3.s Z>:14,.,?>lvk:d #F. by ie#?'F.ov.il +`?~~the soavea; via `.:,?tary
QvS,p<?>atx<)>:t:laÃÃ:.1. :isa.u;=t..i?tUT<.MItUAaf,od. A~terxiativelyY~~~~~;~
dioxa;~yhFsc .i'h; I Fsiei'aaf;rJ-Iate, wid ~.~. 25 tiag of pailitaxel was
dissolved {..?::hzi37"s?nif .ih?_Fnw', f.3llC3wed by ?`~.'nn<)vFti of tx:d::
Solv4=F-1t via aoial`~,` suvaFp+?`.`FIt.om until a
vISGi}L$` mI <:`i31'i, f.'::n7i1.if2Ã.=d, I i3-i:s viscous od was tiii::7.
mixed w=illh a :'s+,Axi.itFt?..7. +Fi,sod:ZurFi
dit.Jdt:cy.i -ndfiac, fl;.c s:~sa~.~fllze.ilg suÃ"iat~=~F:kAlt; z-n 20 anr4'`F
~Fy~~~1cF14 ~~# 1>i1~3 bEaffcT'. ~~.~#Fy F.'!"1#x`i:r:`.
was tih+.u. Si7n:c+..-t.;i`': foI" 3 0 31#31 Spuli:S L~iffi a 2 s i{ei+.y-;
w`_F 30 W of pw
oei f<?f'.i;si>g
I a} E.1c m1i:::8t}3.1k#t3n ;l;t. [il;:3wil.Fg t110 solvent to t.'?a#
ba;.3k .'vaA}[3.eAte. - ,?D: r14=t=1g ;,".:.3#1;...a.\#k:;n,
.'o`iiF'y and I VFny]2-pynol4dG}nc wesrc added to tiF.f: 'L:rnF:.Fi4Fo. .- g
LC.. flina3
E3? '.1'2 i.3m ..CF 2, 1#t~'~, ri:sped#.vi:l?R%; 111.i 's _F4 thi..n
eapo`iõdu;
light fi',.im "ca arc l;:iinp operating at 300 W for .~=' F::i`_lz i~~.~tÃF<
b;:tt,g yfÃi`E'od
e -LF?"~:?E `ly.r .:iiL.Sl~g pi} ;'nnel"#.{iiE~Ãi.si:. Following
~!!?i?.~3~rt?~~'?IG~Fr`cati,.+#1. .hc ;,1;#'t1;1c3 ;=:'`s.'=3`R:..'.
I.f?e
l~l~~)~ai333
~Eli~ic =<< L\~o":"f;~ t~'2f~.i', =C~:'~liv'~';L''~~ c`~fi':~st 5 f7e 4l
`r?i:~ ? i~l
b,,ffor s?5 <.i two d%iyaS to remove C;Ncoss- "-LF#fac1~Prtt aÃ;t salts.
~}>t+1pix~ ;it3si,~tC`~~ii
2~}
g, 1.2 num!3 wid bei-izoyI peroxide (21,6 m& 0,011 mr~iol.) _:vc=c dissolved
:n dry :~~lueric
(1{3 "ni...). The Ja:ik:'. as 4?t= U- l::Itl .d da`:iC. I"G'fifll"d w7.th.
n1t"f;gE:nAhii'. tha1e5 tv .: 4i23t4\e'e
o Y~p ~?6 .'#, r.^.~~li' #.?3iY turc `<1':3S t:S 17. S~ l-rS'd at 70 c'C R}?
14 .3(? r . The 4.`a r t 1'1t d w; J v,}1;S # i3
~b\e .eiZ~iG.~ v CLi.~~f.'~b !.ttF:~ :rf.f'..a~~.{~ ii~.CL~~F=~.i:~l was
'~i~1::s~~l~1~L~~F. :~1 C~~F._``l ,_ ~`5 7~ F ,):-~F~~iL.?
"'.z
. . . ; õ ..`~'"ili;F~ #\..~~
~:'+#. ~.+2 ~?i ~ l.::f., i". L:C`, ftJ i L3ltr.~ ~ ~ ` 3~ ii~.: :i'~I~, ~~'.
~'v 4~ L.i.~~. .F t a. `F.~.\. `;:..~3 `Ea ry `+'c3~:=Ea.aa..
,. .< .~i~= .v~a ~ .:i`s. solid t.,.i,
filtx.A:tt.#. T;te p.E'i?t7ui:t wa.. obÃai.3.ie,d as a whÃtf.' powder at 36-
5fF/i, yÃ6d.
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Na.:iopa.,: dF: l: s :3 G=r'.< prop ared by first d.t~sol`.'ing the pf?` i
n.,x;:, ('53.; A?-tg) :n i 1a-:C;.:
~.l .5: 3.7.{L) a1.2d dissolving sodiLary( d\1dl+c1l s(.alCaCe (50 nY,~,;,)
ii).i1lF~..~~t\.Ã.wzF~.Eid water (1() J.iÃ.~').
AltC.Ã"?`;.zit.=vZly, :~%aopi3..t..clb`:t w4ae prepared b' dIssC)a-vÃ1': j
:he pt Z''ilea (50 nng) and
pad:wxL, (0.: n-,~g) it: CYHI(.1. = ~~ .t? ~.r~_:~ ~~~ad rAissol~vii-iw;
;,,odiu:".n d;&.=S`~. sulfate (50 a.z~;:;b :a?
d6w2 .I ed water (110 I,1L.). ri'i#:: organic 4i3'~utPon was t~<,'?e#; <3ddc,
to the t2qFLo>~s 'szr,wfbcti:.Bne,
4L?l.WE1:>tl and ffi.s I":i3:iAwav 43'ta.a S'i;l:iwziied at 30 W of power
f[fi 5 Ã:llwu`?os w produce `:'l1c
+::.a~i.Ãr~'io:t5.. The Ã"3Ã.:Y~uÃ4 w-a.5 stirred wl31le opm to tt1c
ab31ouj?h'.3v overnight to eva~p{?A.3le
Hh5,,, '.:3.>;e"^'s Dialysis a il2"'-v'~Ã''iar.~ ~~' L't'~if.l i' Ji-
kS.i'1r~ ri 3.> ~lf>%:.~~i.> . t ~e r ~~i'i.: ,=,.
using ~ a ~:~ _ ~:"A~ ~.=~....i. ffw`sb>
Eaw ti? E.>3:.oi='. . Xce:?4 :Si:1.F"ffiL:Ulli:t; ''`+ian4"ip37#.acf.e.s,
dl2epaI"d Ll:i2ng t32s ` ux.o. rl\.: iat? 1t+;a~
swe 1 afi. pl, ., <
l~~ S~ ~ ~'%3~3 ! 3t5'1I ?f ~~t~SE,~~1~d'o:' x~~.t~t1~ L<~I~7 ~~c1~tZ GFs
e F 3r~~~ :~ ~~rat',s
Eacas?
aw
i]3~t lac3:t 4,y : i:i~I~~43~'i3 ;Et3T1~ }~Tlr4l': t~c3Fi~:~$ M '~w:'~'4
used for
Po t.`'(h~4Z~rZ?~.~=' ~{l}~-:b',i?? A;
:ht'' de;.ivL of p6...nitirexed. The f. bne<?iion tet;.hlliqI1o4 used to
create z.hi
i#tiJt;t:o' i? .13 {?ln. $:.. wziti;s fi:iz%ulSiC?n, *:i;4"ll'Ã1iquC'. I`Ma. U
of 20.80 j:3;: >Z { l~r`i~ ~3;~:
S ~' ~ ~.~`a~ C 4 ~~~~.+. z?: ~..<~~'~ ~::~s~3.~:~~.Ã~ ~.-
~::zt~~'~?]~~~.=~~~~~.~ c~is~c?l.`ed in -~ md_ d.cti;orÃ)meÃs;an:
Aldrzi>1"i. SÃ. LoudsY MOi using a ;v~ilextng deviac. A>.er th~po.yn::e: was
.i?mp1e"o;?y
d.Ã.s,oi :?cd" 50 :ing of pt'Ã?zctA'cxod pxs~viZ?7.~ly s7ltIbilà z':?=d ]i,
0r91% ~`~t'~'aK.. .4::;~ .aude: <1F-fd
K
.t~.llÃtVi::? I.Fi ttte f::1bi$ci3t.Ã.f332 C?foi332t2`oi' pi',?l"V~a~~~-dxoxy
glvreb,'.'>'.5F ci3.:'bi' nc.#:tecf3-<s..
C=F1pi<?iaGrY}314,'.) b,~~:.1d.' o31l'`d 0.9r'C I-N:iCI wi14 ai~dQst, Th:~
solution Was 2?l,,ic:rd ],t 1'.~ afx3 of 5%
poly`'viF:'y. alcohol :[?ÃfiaC.tua (f'i~ihea) and voaie-,F;:d 16i I
S.Fn.nl'a~~`i~'.?(ot so:;.iL=cif.C='.:.i uwl,,ga
p?F:b>vbil? 3w"Ãi:=aÃot') and sti;3ed The f:"liFw.i'opK3iicle.s v-c~t`o
ct?flQcÃid and. -w<zsE'?N`i>
Ãrll~:,:~ ~im~.s in 50 n1t ,Ã di.q:lled:`de,z?Di~ed water, Following thie
,TiiF::.zopw.Fx~.,~le5
,. . , .
L',Grt: ;.J`i3~.3~2?1~.Ã:fed ifP'4`.`.o1..+.' i>E'.1G[=! :wwStt:3iE:i~s, al -
"20` C t[.? 3Ã;.S[#:I'o whÃJ s:: bmKit'd o ;.3s;.;LZOiI`e?i.ciL
~_X,_$t~1 3:<? ~ ~ il~?I~L ~~~ Ã L3~ ~~t3~ ~~i~'t~~t3.'{~': ~,}tKt=::G`a~?~
Lr=1~~t3 ~_l~iõ L<? :a'L:cf 3n~3~c~i."~t1 i~3
_~`_______,.__. _...... -------------~ .. , __"~...._~ .- __ -_~_-__-_ _ .~
........_ --------=
~artldes 1`rth;..FI.1E3T4"4L1~'~~.._r ag
- - - ----------
;~,.~:~ 5~4:1~;~#'.=?~rL=C):Il. iF~.?~ J-~`i3i~?C??S~~:i' a~'~3d (0.005 g
19.5 Ã1#.'wl)~ p4?i
(1.5 g, -9.6 x3ltrliA., 22 .i`IFi?l % uEt~'bt3naÃÃ.;}.
}~: y~ao`i~.yli"r1t`.~,>.~ ~.~"~..) .'~=a i y ~"~ s~_f ~b~~..t;) ::~. Ã'(
:.. ~
i7 i7.6_ wu; ~~3(Ã~.4~3... ? d}, 0.26 ~~) ~.
96
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
F ), fE }' aa~sir\ ,~. a;~ C~ ~i,i fl.i k"4 . f pa =~~~.M.:~r 1l. `5
hC~ti.~~`'s. ~1yvht. a D~-`~~7 'ar'i,:~.a i.~tCt 2 i ` ; ~~ >L~~ };ii,~:S i~v
"~ .:.. -..._ s4~i ~~i i'+.,. ` ~=~ ~i:~ ~,~.:.fC.=~'i't'.
Mf.._ f
+:.1t3:pib:Ea1t:.d (q!1?nifti3ti`v`` yi;ld): The t.,`:i'3:si~ae product
'6xdc2s -;'ed,b4i;`,..:i:d 1I"# ~~~LIM, pun~~~+.C:te
E1swa, ~y~fz ~ t 1'1 ~ a"} n?d t r t3 T1 iAa~?~f'i1~7}~ ~ }: i1:3i~ f
flIE3xIf'F` :1.. =v'l~"IE~~ ~,::)f:'Ioi=, f?5E.~i ~a a~ ~:
' x v:+~~~) 1f;-
~.t:~ S~ x:
o-.o9L 48 how"; tt~? L"ns:b:o, all residual unbound Za3ro w4:s, Ã't:alos'C-d,
C.Z_:ma:i33 i?C`rllnd i:op{+SL'IrWI'.~-~w-fi9::lL"'4 wU"`T'e prLpairt'i.t by
an
:.z apoÃ.atlt?an :':ac~~aod. Br~~ fil} a l ;~~ gof copo`y>n..:waa dts..ohcd
1.1'1112,0 inl.,
The S'[Ziutxt)n Wi:s', pourC:d into amil:du':`Ciof 200-m.. deionized water
0,5;C +E>'v SDS. ``~~1~.'. unui;iiZ'/n was stirred tC?I 5 minutes bE ;oro
being
~
yL~,.lioGft~ ~~ s ~:;3> 30 ;~1#~~i:~~:C;S, vkt7.~. z~~.Pi<.~.i.~" dialyzed
a~3r 3.~?a~,.if?~.ixTi3.i=~" ~4x. , ;;~.f3Lti'Cit~~ ~.:~y ' ? ~ ~ `~ tÃ.
remove tile SDS,
111'.' :3i3.nt5pi1lfic.t?= ko:.k 4i?i.`ai7iei (5 7Ilcg+_i7? l.) was
d7laES:xa to a fini3l ..Z?.`. i'=L;'3'tt, i3.tIf.~#F l3f'
0.0 1 i'i?;y z, with :~C'=lsii7. ;31'~~= I?t<=Ci ~iYl'a (Di.llbeccta s
Modified t aa?e*v M.'d1vi?l), A549
hllman hw ng cuE,.,I.'<':'~.?~l.a cells (.,Ã"$C'i`xi? TY1..~x CultÃar
~=~Z~~i ~~.C?T~._: ~t~c~ i.~~, ~, VA ) Lr .m4;
pif3 i:'..d Z3i3w a 96 v4f:,R piaf:`a. . .tfi i.3. dC`.T141t5` of 5,000
Ã;Gfl.:i.64 `,'"'.il and Fnt~.,.'.ub<.3:4ud t?'t`:=31.Iwx?E, or
until ~ = Z ~# 3f '~:=i>k~~l yu~.~<a acl." (
~~ ~ i~~~~i,:# i5:~?(..#.~ .~+ . i': ~~~~.. ~.=~25: a r ~ib:~~iuJ.~~ from
~."o:F:'wLl.." vf a1 i.4:~.i3.. i=~'::dG....6 :'L:pls. .a'+
w1d=': 1003.#l_ of 0:01 TI`at' ;l"z.~,. IlaalopanIt:.'le 5oliit#t3n auii, thv
colls w+'.f;` stibset.,.E..zafl}'
iÃ.t l.l'e`?c#.~~.:~ ~1'F~i? ~.~i~ ~?LI?~it.~:~:~ ~C?i= A~ ~fti:.i~"S> f~t~a~:
~1ci11f3A`3~;~1~'i~.:u :~~iF~E~.~.t3`i~.,l~.'~r`i:'- .,.::i dw3::lSr3'wf;:,
y 4
:~~;~. L.=L?~a ~bi~:i.'~ '~~,,~~~=t'~. i~1:'`C f~ i;~~~sC"~:.: s2E~.:i
~~~t~f.~a ~..s:'>. ~a~~~ ~i3~ t:~: eI'C::i'4: 3 a,~~'(.;
lf).:A1(4'4hf3te: , via a FII,"4 alil4'a..
"t
?t~
~~
>'xaIa:pl*, 22: Ff?s3idl' 1t 'm E1~ N>iV(nt aÃi4 4id Lt~a~l3~it;~ S ~? ~ y
7?~~t34~{3 N<#no25f3I .1S l4~
nac à umo~? :'. erL' p3e~.'~<~~od by 6tÃ'3 emulSIoI'?=`si?l4 eÃlt:
ev.spE3raf?y>F. ;IZf,ffi,?t;,
fir1+.'tl'r p?i y(titi;wic acid was dissolved in 2() 11=11,
25 dissolved 1Ã.:: lm=0>?1l~ ~~idalE?!'oEnothat~c containing ePtl1o: I or 10
wt % i.`?aa.'l.ttExwl pw.i w6ght
tff pC?iyJ33S n Th`~'. ht)lutiC?#? S3 His poured iliti:3 a mt?'itL1TC'. of 200
1na., deionized wavr
i,.txat<tIT:1lig ;v.+`6 SDS. Ti1C?c-a:1ul3ioiI1'S~yas 1,0""5 m.+.nuti-".`s
bu:~3Y`4 "l.o.iTz#.?.
. ~~,~ nninutes, and xina.lly dialyzed for apprs?xun ..:,
~,f}i ; 3(# W ~~)
S.
97
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Nanoparticle ESj2itilF.illlg In Az #` B-Ll~ Not Nt..Ea ?" d CY+}#
:; ~~.r? , ,,,,..:,<=
.A S 'tl..n of ~.. ~. #~ ;at43t3z#~.Zi ~. r ~Ãil~;; C from i#l~>.:~... ¾;~ y
##? ~:?~. vf' '.} u;~~ v ~i.'Z
.~ ~c::#-~:3. a..>~i.:##3'~~7~~ ~~5 t.~. v ~#` t# 4,
.
oa ~.. 37 pC. TIw ~.~1umCltt'i' of the pa;tiz:lt,s ~~ <1w .hL'.:l I-
Ã:t.z'sÃ:"s'C'.'d a"
:, regular i:i:-nc iIA ,t.rval:i .:,yni? dvt#i,,a3'ili; 11,0pt
:it:'afti':'FIn:; (DLS), showing ht?w the pa.,A.#.dos
ncr4~<>c":-~~~ d .11 ' S q} za5 ~+a~1 J.z> 373 to ' ?+r v't each + : `. 3 {~~
~'tJ ~~~ 5~= ,a'}~ ~F ~ 4 !. Li j kt Sr~~~'r y
y.: ~~ L. ! ~i..= {.~ ljv? ~S{4...=, D.,~~~~L'~~~Z::~I.L \=' a ii~.F.' 4 ~
r`Svd.t. s
rt.=
ro 5 5"L'. 1Ct3T Ai4 b,t'~..i;.~~;~ Particle 4L4i:llta. S^g x ; '~'Ã1~":t,. I
~~~+ v 1i#ii Ir La:{~~:1 't *1~:~'~.=C', to near
. ~s iS ~ 'sc~,.~a C~~.~ic:~. ~
I tt#';?.?Ã, arYara:.=;t.#' ?-vas i?~'~se? i'+'d ~sctr Fi r 9'3. 1.n
addalzz?.3., t:a3e rci:'<#:~e of fic,c.2,4:iF-
1#~~?[ 1'<<cl4 L; bzC:t'vcd #zSii?.- UV 'Vi,, 5pectro4co;?L s:t <:
wlvt.;oÃ,gd-f o~
292 also indit'.:Yt##1g iepri2tect:+J+3 of the posv23:('r ti#d4': ~,grcZl.p4
(s,C. Fig. `:.?),
a.iCse :`?at"t.c>.e. are u3:'fi~d for controlled rf;,lca5e. r3pphcciti:3t?s
_.S 1v..;I ;.~s foi-
C ~ : ~ in ~ the ~ o Z > c t;'c~. 4 .,t ~, y of ?i'c
~
~.t.~,p~a~.ax~#~. ~;;3~3~1CaÃ.#i?i.õ~ #:~3 '`~l#~.~~ ~aA~. #1.~;F~.. ~~SL' li~
vC?~~1a~_~. :~#..:~~ li,t..#i~.t;~~?., U;i:s`z;'se
tdii. Siza,'c> Oi"tassue in!O Whsch xbaw~ pol"~ms'rs i?:'L. ttiji.L=ti:d.
F"x1mA 4, Nz3no-mirt1ClL ilnd SLv-dil1 J el`i)mA SLFfx` 4mYo~;
r
/ t n
......:, ~,+~
~~ t+
.?!/~r,=%\~
'2 ro ~si, .t} this ..=f?i:~~lC?$oa?E3 pv +3 v- vc S ~ described i .cv ~
e a~t~ 4~5~?~i:3 .~x4,~ 1:'e`t. 11L'S.~ ~.3..~ as s':~s~?=>,~ by .~tc.~~: 4<.
s. .<a. si: is
f;~..~lt3+.;k et tX:,; .ioumal of the CheT:1Tt;tia ~'i#f Fdy. 4433-4 ~ 19:96
3 3.
20, Slui:ol- uran SG ( I .<''XI) g. 3.46 mmcl' and
CN.2Ahyd)`#t...W (12 Y.V.tAv, 1.2 gqC`.2 }3.2õi1ioSY were dissolved til
Z?;riil.ikne(5 ZiS.) L.a.wl.. ww\..~\~W~i. ~:..`.
98
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
S_ .~I' 15 ra+3l'zrs. Then iv;l;o. (K<S M) k=vc,s 2Tld#:d, and Jki#a#`3 :aa.
65 (-,' ~' .I.`: :..+::)iltitl?w-:a
:>E?I :aai:?thLr .,'J .C?l3zs :aÃ'li", tl?oS1 at ':'L`.'td3m ie1nporrata.e3'e
i?1Cm#.ga'tt. 3hi mixture :'i 3s extF'.i]i_wd
with he:S.akf.cs i 7 .3!.L X 3,1 .,.d the combined hi'Ya:le:>
'w..>..#'c..ti.'ts vL eI'o tz?e#] -washE'd I M."
MO.. i: (15 ??1L X 33) iLI?Y.Ã. dic1E5nÃ:::4=d water (15 I31L), xbfl(ti,~iml
by d3"?,A#1N tFi'{ Y~'hc
Si?li'C:lÃt :vc3 < ionl3v+ d is$Ã?,: 1`a?ti#..~' ' e=b'%lp9:3?"at1'ri#av and
tbt_= Ãt.`.aT:ai1Tn a?;Y `~.'13`I'#.pf:}u:`1d was dried
#?#:dz:3 i"#ig-1? v< ct3aa.i#?. Fhe product was E?.:sta#.ned as :~ c4L.u oil
:a.Ã. ,'^r, } a 4s
N.?>nibptl3:xS:ics z%,'e-i`.'. Ã>?3'aF?3#'Ld fir<4m d1s.`.' resul'Ã..ÃI'3g
p,"?dt#.C=t by Ãia#:;ht?:`s dL.`tit.J ,}3c=Ã.l
lioa"eÃz1. As:Ã3aap3e ?..?~ ~~oo nii-ni pci~~~:1dvS was Cifl1:Ãted i31 0. 1 NI
~ICa anf3 mua1.1i ,.;Ã.Ytet.E at 25 'i_',
The :f.?ci#,acÃL:":`,? fll.I% p saft?::=:Eez,3 was thi.=n,.E"i]ea5u:Ãi.d at
1`t g?.:#laT.' t.,Tl..c i't'a:a.,;.'v:a.lS {.SÃ:I.i.~ dyndmzc
l~`x=?t ``+~'<3t.~.'.#'a~. c~ t.~Y~'{:E.~ iõ ~'+~' 3;xii~~.~.} iY 1 particles
;~~c~.~.i~.~~:tD ~ ~ ~ t >Ã~ i='`" over ' t ~~2l5~i~ (Fig. ~~ ~,.~ .. 'S: ~r
.:~,e~'t'p h.~~'~.e ~G~~~wt.,v .~"... 1"'lg. 12, h.:ow:> .a?m 43t::a PIJ S>f
aboL3.0a the particle size f?a9t3? about 200 I?ta"? Ã:L?
about 1600 ?'.tTi> t?t'a'T flX L:t~;%il'S`v' t'#.{, f&d:3w 24 hs;)urs, whereas
M. pl'I of about 3.0s li`ae
panÃ::=1c size is stc3blL etvcr the si$II.~. ##1't?:L`: pcIEC?&
E5i ~?i:i?,i?~ >~`~:. ~ ~ C2~~iÃ4<~~.~C?~a Ct~ s.7:Ãa?~r~L i.~Z=i.# i~.R
Ã.~o~i~1
--....... = _________ _~_____~~.~. ........~
wi:l'#:'. 4:.'t:+r: t?I?t#3 glass by dt.p##41;.1ng a pL7lSttei'#
:iola.ÃÃ.at??> ct3;t7.a3r7si.'d (`f
tat? 1E:d;vW .#A osrpi.?ly?'?#C..a" #i'.i5.:l.?.d.ll?g baÃi. #a[?t hin3tZ:d
e:t) p33l,r~(stea-ri:<i aC`.d ~=i~Ã ~?~?f a~E ~=i? ,s
t`=apÃ"}?jeiLtsyrw). dissolved i37. E`s.ti':3hytaaFi?fI:1:a`::i.:?. or
tC=3lÃ..i,,.7.a;.'=, wMn"ii: ta
Ã:.3ÃL;C3yy3 ilip'<. ?.?i:= sobvcut was removed by 5la?w i'.','~:poza.tii.$32
overnight i3?:.` dtti ri placed
under #=LdooW :`,#'(;ss1. rc for 24 hours.
"'Un niaÃion of ~1Iti 1av.;s'ed Pa, F _#~;
}y}fyai:iicc?rit_'. ;:a#....d ucÃI'~ f}:lik~<` fa~c ~ >3~?t~?~ifCaCp~at'~
~I~iT?l~ Z~ Le'ci #.d;'2c:"ixl b[:"f-~,3"'r,.+=..`in
,a%Ãd3 A po(5(lÃsG:fii.'-i>t?-glt aol1i
solution w a., Cipi?s1t~-'"I :3iltl; gl<#.44 using a `.iT.aerC?Sbl'Ãtl {i. Io
fZ`Ifll sfihn, A pt?l5tt',b:I4=
q ~ si,'~l:Ã 3 j lt7 ' ' ~~*~..rt.;, r~ t~:~ ~-,..:;3.3#aix~.w L.tz
=^i:i3~1~F~s`~~.~C:Ã1f:,'i.~:Ã~,%z~~l.~E.33'Ãi.#~"#i:ii~~.= ~#E.~ .,.f~i
'txi.~:.,_,.1t.i; ,l.ao
<ÃC.sf3
~`ri;:~~?l,.c:as~:ÃE3) film FÃ.Si~ÃiF? a Ãz?1S:=ri3`s5~=a'ta t>G~ to
~:EyI'I]~ a `~.~.z;Ã?i.: ,s.~=~?i", i3
, r k.
p;?I t'
?:3t?l`r`(s`LC.,aazC: i3i.a41 i ei:t?~~~~tÃ.i=1~~~4r,^r;-S=i:~7I~?~Ã:li ~t?f3~
+, fihm a.:s#:li.? a .I?.LrosL if`g:: $t. .:U.E-I:i? -all11:E.E, =
lfi{`m
99
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Em3m pai 2 _DevE? :C)n of Pt}l`rm:1 FYl#i4 on a ti=2iF f t <'
F>ed~`"ik~~
,~e~-i~:a~-:~:. ~~~?a,. `l_'.~:.~t~,r . crr tit~~~~.~;.t.~i by
~.~:~~~ui~tÃ:~; ~Ã::~~~a~>~~ac,.~ I .~.~{}Tz a:.;~~;~11:..sici :~~ ~~a~
:'.z~:~i~'x1~-~.'<3l S:i)p:l~`F~'l%',E 1TES,'3~?~ but not i.itl:k#ted to
"}.33l5ÃsLC;iL?`iv :i. 1d Uc11:bE?n,x:E.e ~co ~>
<.::3p`>olii4:,t(`P~S'=:#, dissolved in d3chl"Ã}rw`E"s[~than`s'.,
tetT'c`=Il"lydr4.3i.uIi:i3i or $i 6F:~I1`.:`=Y. usÃng a
::ynagc, Ihe Zb<.E:3= :I'eI11oS'i'.'.d ar Slow Lvc:poii:tzE?n 83vC:1n5ghi and
f.h;:f3 plcicQG',
'.~ndei t'e<F~.~L k:%~ ~~'i e"es-~.C: di.):x ~N hl+urs,
~att~ ~EL 7i ai o pi^kr"ht_>on 13if# P33I41`na F#it;l`>
::.. ~ - .....:.::._a-_ . _. _ . .. , w ______,.~,~ ........ .........
.....,._____.........~ ,.... ...
:~ iag, loxided polyfla4ric, ~~~~~~~~~ ~~~~~~~e. cast or ,;Ira4e<l.>ziic#
gla55 by dozo4Ãiing a.
yry loy~. r< , ~va k' 'ri-1<~n 1l'~=(x
I .~i3~~.r of ~ 1~[:3'~.~-.c3 i(: :lF.A i:[!~`~?1.1:i1Li'. C.i.= Y, z _tp3-
#~C~~ 1 ~~a. ,~ ~_ .7. T'r G::3~ la ~ and
us! õg a iYiicl'o` vniTage or c3i:;t'osCll dei ive, T'1~= sÃ;#h e:z.,. :L =;:s
E'%.,T,os'ed by slow 1~.vs~pors3fion overnight aFtd Ghei3 pl:~~.~,~.`J,
ti.ideE ?'<;ilticed pressure fo,. 24
h$:3 -ors.
~151
E maiiv i 29 12Cs3M3~~`ÃtsTl ant` Patti.`n3fi> L ()flvdn3x ca Iotb. L a'i IF`
~ Pov'EnL F1hns
a3t.Il ,~ lfi.~S~ ~ "` ~, p`y : ~'l~.n'; i'~~.I'c gj#~sS ~>.. ~ :3.~sl~~k~ i:l
.{v.; .~.= ~:6.i ~Y~E.e :i~~'l+a . . .
?:t3 i'rop#:'a1lia or 1r.iL"r 1sy...iie:;it by dt.pi?4iÃi#lg a p()lyme?.'
tiORIl-is?#. of PolL(4t:.c.ifi.: acid
t':a .;bi3I1=:ite ci;..c-C(`tAsro Iad.n;.) }?rtchlC3romethcÃnc..1nd i.? :>
coi,Eroli,,.d -n:a:eu>!.'r to t`.I'm '"~+a.tto;ilS suF:<l3 as Stiip`ws :_ITW
ta#4s. The solvent Y` w~, rt`fzlt.Seii by
s-lS.;i' QvapoI<::`t1.1 i>:vG.Yn?gN c'si7d #1he.~ ~~act-d iittd['i
.i"sa:ducQ: pFes:~uIL` ti,#Ã`24 hcDt;.t';. 113.14
1-u,::`tl3#,?z3 i a 3:.#.k,y be L;Sod w>fl1 T]?mn:= than E?t-IC P(`.lyn1a
s1~z.?~"':3ltaawi3iI`;sl}%.
Exwnpl1 30'. Rilsr?4c 43f 0?-I-IyLt~xaa3'it#thtidnfri 1T3
_ r 4 = r~':~iS:::":~t?. ~r..
A~ ~`,S;~<3 paZ~~3~l1L. ,;#.I.3-~34 ~6 ~',.e Q<.s:: onto glass a'kv i~~.
7C#`~.1~i1~r.t. <` ~'#tzlE3'.T~.
i:{)RxA7T18W f?f a3<,33y`c'r¾'#:l.~I acE[;3ie) (5 f?Ia',hloro5.31effi.-.Ike
(50 aL)s a72d 10--
i3` (100, t-`g)9 usiYig a I 3icrotiv=~ungt`:=. The so:LC%n_ was :'
.Tn(?t.''.d by ^^.alFL'`%
s~.' z3p.?::.et#:.sn :?voI' liight and flaoa] plaL.~=d :radi'i r4dt3i'.ed
pb'c.Sslirf' l-z?r '24 h#3a,s. An initial
bL2#'si was :`. i''ti.' fli¾., ..,"e 1: two Ãac34s, .i'c<C:.aaiIlg <3t a
.'<3.tt of aK)o[I.i 5 p`;.'da`:'.
f3r\.g'v.io).aded poi\=rSni.2` films wek-e6(}so Ci<sC }ri.ff:o gY...a.`.s by
dilpA}4`tin\ \; p:#3`imeA;
~
Si.?l::udi;F: E.o>;-x> $a.~oc, of ,.`t}:y,(wtE.lnic CFa ~?<?.i¾i.i 4c, ~
f;'sF.~~<3~ ~ÃC? 3'~ (.5 mg)
l. 0 :,5
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
(50 i.fL). 3d paGI 1,.::Lxe:`z (100 .#g); using a mtcroti).i.i?ga.?: fPhe
solvent was i41:a#c~Q.i, by
slow i: i aPife 23.~.~;)Tl "7 .~r n`=?h,ft and Ik?Q3i placed tiÃil.t'Ã
ro;Fur`ed prL:s`,"rL.u LSor 24 .i.~O....:>. i`Ew: resulting ,.7lx7iS 5,3:,ri:
hoi"i]iitses?ot#:. ~.d opaqljc,'+vÃtb :yi:Z.?d adh.`: cÃ'?G.a`.~ to dhe
g..'zl~~ su.?,,,`.Ã"i3.3o.
The fii.ti?s ri:ha5.`d rwxi?l over ~
of I i r o.348 l[ax fl Ã3m.
vI4tG`k?"ic <Ã i{F
Dt..i;?~Ãi;aded pi~lyEY3or fibus were cast onto w?lc{sw by depositing a p:tlI'
si}lut1011
r 1 P A~~~.> 4~, \ { ...
~:o~x~~?r;so~.? ~.f'~,~~<lz~(~tca~~:~. :a~:i~: (5 ,(50
"0 it ), i3:3t~3 (1~~0
~tes) , using <31zl,LT'?SyI.nge. Tb:S si?lL'Cw, 1Y as
:t:i?':<3v(d, by slow o4'`lpora=ttci?2i (a)4'G; night iFÃ:?t'?tiZ.en piaC;<'=d
under redz:wed_ p.c;~s"ii..c fb:-'.w' 4
f~f3urs: A 5lÃgak r.~~~l.i~ ~~~Ã"St was ht::'I~`a over ~~?~'. ?`EI'+~. t~#`~?
CiIZ's IC:~u'sl`:g wt ?Ãi:#tf t?e 1343 3i 3
occurred 43vf.'I:4t least 30 days ciE ., l'.:C `b z 4 cE3Y?`t3.<l::3f- Ec?le
of
.:e. ~9~, ~~I~tt ~^`
15 "t ~ltL~'nnl?`Z g ?
~ . l~f:' ~ ~:? 3 films r~ ,~a tl~~Ã~~c.r i:~i ~>~:. rt, cast if:t ttc. ~ ~,1
uh,1 by da;~c.~ t ~z~; a
`3+1ls.li?t..t. ,. 3>u;,Z?.? comprised of pi3 4(stf;13I'.Ã4 .={It'~~[J?:i1~G
4f3-'cr i c:~:?#i?~cE~ ~s?Ãi~ ~ ~~ '..3:~:~1.
..?..,hlomF.ieffi:;Ãef' ('?i p.L), c?ndpaL,lftiaxt,=l (100 l.E s~. i,$siTÃg
a ? t?lcxoi t E :i3 g?:.`. I'T':e st?.l~'e#':t
W<.,s N.ML+; u'.:d by sltw evaporation (wt:2' t71gh:: w`Ãd th#3i1 placed
under t'eC$ll.ed prÃ,s~,f2rc tf:~r
24 r3~'r"L~FS. a':'is'. 1`11t.);; weI'e, h(}1F'#'3u:2?.i?i15 i?. .3Ca
izpFzq#1e ?s`:'#ii gi?<;d U.f?.iw<:'4=i?.>e ti? fb.;::
20 <;`.iss s:tbsar:Ãt.:=. :The :iAnis t0casid ia:x{.~t ws-cr time.
aJx{~.3~pjl~> ~ Rx;~eaye o 104_Iy'AmNaPtfy 1~ cirl arorA.
?
D.-L1g^lt?a.#.E>C:d poly~.nt.i .:Ã.lkT?s w:I'C, cast Fsl.tt} h~li3ss by
.~e1?E?~i3'~1#.y~ `c~. p 3.:5'?'?A..I JF?l"t:i:1.3:~"~
25 Q[falpni`.,sed of poly(hydroxy -;S'GcrL.'l 4~:.?~>dÃt~~4 Gt~ ,: L.i~} C3~
sE ~~)T~< t (?m# ),
>~a-=?~~>Ã?;d>a3?o (:)0 pL); and IN?j'`dt`t7Ns?a?"1ptE:3t:ho4Ã.1 00 ig),
`ydLi~^ Ã Ãx=~C?4~?'Ãi,;`~=.
. i' ;o,ivei?t 1v<>q removed by slow avg1po?"at.of? over ;?zgj1'C and '> >2i
i.?i:>od 1f: F a #~.',c;L?ct.':d
jptos5`si3'L for '24 ho1rS> AI?.i.dfti3l burst was se.Ie ;3vG;Ã' tbv first
day. Ã`t,.,iowdig at a Ãi.lti= E3~~4
F3bz?i1tl8 l:Ã#.=`ta<Ar', Ct`.,3.#3:'`i.itl.1S T4'Ees,ÃaC' i?Ã;e-l..1#Ted
over 'ekt I :a:ii )?} &yS, bt.?gi 3=lÃ?-<lt a 1:"t.iti:=
to less than I ;.tG.N+c~3t' at aoliF' -%VLLk<i
30 i3Ã 3 #iif day and ~lo~~ ly decreasing
10~~:
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Y R : In Prt= Lt Turaor Cytoxicity wich iFc~ i' :;L L
Pt?`4(StLt3FFt aLTiE GxtFt~3Flaf~t` 4f) # ~ i `F1~xx# ~>i3~t,~~i~ t{2 ~
~i.:EF.I~;~
.. - ----- -
Lewiw Ã. fF~~_ Cucinoinz.~ (LLC) ceEl~ 'were washed wiÃx1 st:::r.fÃ:
ph.i,,q)h..Ftc buEkn-ed
s"~?m4 (aI~'=~~S) szsd tr~j3sinIz's-':f. The cells were tn"1.'C=ki counted
u`.aingi? b,,. C_#W:C;f+ ool.`ef..tt::F" t3nd
Y
3<3 S.4`~'i~?~ ]t t. 1~ `~ j~s<tall plates. ~.'i:,~l i t4 t,~ c;
{li,<'.i`3'ai<s :C ::iF.F{.. Y then
~~ i~C,\3`i` .~.~.., A`. :~~3 .i.'F"!~ S~:#`~s~~~F ::3iL..t
F~3ii?E+~i~a
~.. tn~3~1\ LZ... i:~Gl ~r.~~ ~ t: ~\L ~.:GF}..= ~.~w
treated qYt i it`:l i~- ?, = +}qT= t~3z . ..~4L~n~~.ra.x~-l"~ ~
1:~.F1ti3~."~3'~ .~.t,.,es `r# 1i) ~lik'+ t~]K :,Fa:;:
n `
3?f..iFu:~cl^.``yf.Fin.aed ne3.1oputlt..les (I % Paclffi.aAel) fo: ez ~.t~ e
da SperFod. A r~a3sF.J?vÃ. 4.t}nr:ri.'s''^.
ci`.+nl't1.FnL.d IF134 <.3r the ;,a.l.Fa3e LoI]Sf:=TAFi.kt;.;3n of i'M
pFo\c'.dvZ'a ao# t;.L:#.Fwd 5.:03:`, 1vv-h,~'+l`~.'. a
;34:"gafive i:=o:iia'tsll kwked r' BS, At :hG U<1vipleÃIF,?i. of t,'fF.. assay
:he cells Ly'4."G .,?~=Ã ~?F[~ i~
zv ith 5 "0 ~ :;r o i x x , 1, 11 i . Fo l~~~ ~I u i.~ =I'et:az <-3I iLj m Bro
na ;d e (-N -tIT, S ' g=n zF) d'=~~~I v e ca i n 11 B S
at "', "C .ba3" :3i?l:fr,.>. - l7'L: Fx3i;=d3.a w: 4 then ~sp.F4.atG;d and
1,00 of DMSO was ..{dfaf:d Ã#->
each w:..l.F¾, 11hC =?i,:Ã'L''.<.`'s were then E3i3vedc7f. a s+3'ikal3,~~.~
det='ic5~=. 10F-nÃf?t`s:C.s t...3d Ã`.i4 Fra.'ells
>#..n;~:~d pÃfp.;4y ~.i>~Ã"s'=`~~>~~"?~~IIF~M ~ :Ã~~ the n+.n2?*-:e':]
iwj..v1;_Fblo, :TF t11t; Z%s'ell frili~.:
;?lati:s wi.n. ptui:t`.d wi an ELISA reader 'tJ3-ict scanned at a
w%FvC:rt:=r?lgt}x o1 5. :.t #i#.: .
\
1 J!\ `w.} SY ={ C 1+-\ w~=yÃt: t3]'~~fx3 i:~ia.~ \: to values ~~`;?~3'~ F~.
`i 1';t; ~.i'Ti~+~. ] C2, y~Sar1.:.#~<~ K~ t". ~ t .~ ~z;~ 4~Fi. ~'tii]
..r :'~~3~~,r~=~~,]õ~~.i: ~'~,:1~::~ T~:~11~3[=i''I. .
cvÃua:i:;:3SecFiv was ob:iQõ"v'%a,d L;'?tl3 g17-: t 1TZp#i4! nanoparticles
(a:* a Col-rt i1t whereas
:aFSn.. i. t~.. '~.. J C~ ~ e[y ~ ~ [ ` 1'Y J ¾5~~1 ~~i :~~ Ã~~ ~~C 4 tls?C~
5
t 1r ' 4~ T . . . t= . . . . ..
Exi~~~,,o.4 34 Czf
---- ..a:..- - ---=--__~ _ - _ ~ _, _ _ _ .-__ --------- --------
20 1:101A(lau;i?v zlffil2Ãi Ly sÃoa1F'Ic) t~l"~:4rti3l fl#~Ff ~F E~~~ "tc#-
y Y
:0,3':
~s~~ah...i~,i.Fi~~'.d ~~i7l~~'f`:l[:F- .i.ea7,i ~4'+~::F'3~.. cast onto
\,:.`.~~1s+ by ~ e~..t-:':~a~1 }~ ~.~`~?`~.'F`'31.T :]?~.+i.It=
f.omp:'i~'+cil of pst Y E.(Ic3 #:r:c' l.fy-#7sti . 2)iFlII]Ftii". or
:~te=<7:;F1)
(50 LF ~ .~= and ('100 t 4;t, : s; n43 c.i
Thw +?~Jb{ A~~ was rem'c3vcd ~.~y'CSlow ev<3PC`>Ic3110# O:''i`,t 11g1-a and
Ã:^t..ii placed
25 1F1..de1 :<.duceL. 3:'c4_.1Fre ;<);i' 24 h{1u3":'i. An ]IkFtI:'r1.l
b`iFr.:i: was soC n. over tliF:, first di3v.;
1uC over at least 49
day-,, beginniFs.g al i.~nilie of 1"3 gh/day ud slowly S..tecroasing to
aL=....L. :3~'++an I ug1RLa'vr tFE.
xc3cF.r -w..cks :: Lc l'.Ãg. 6). F:IG. 6 sÃiows tbF.t increasing t1he
h;'dr<~pbiob3; ;Ãy of the po:yui:v.r
C~~,t.3~~3:~G release 157om Ãhi' petlyn.lt a's. Intl:i.FT1ed#.atc .F'elCilqc
lTrofle:. .4: fluoS4.vhi7wn. bC:
30 obtained by F:32>.F#:g or bli el dI1.gihe a olZd~.'1L=:'s:
3
1021.
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
à ?aat # iyzÃ.Iol ( t~ a~1t321i3$~ 4i? .itoiig) i.111P4rÃLudi3.Em S:r# 4
D#u.Fa;-Ii>a4MC,:d po.ymS.:r i1311:1, ivi::rL''. C.'cl:st ,3F.tC;pL.'.?
#c:3:#'tiiu#ii by dr.,3o5,.t n`.~~, a PL#[ v#I?i::`
sC)Ei#t3C3?F C?T3`FÃ?~~tn~ of pt?ly(4t+:.i.}:l'Fc i3i:id
and ~ ., . s - . . v =,
.ichli3'Ã'o#F?i..tb:3#i~-r, i'S? ~d.), i3f:Ls (100 ix~. ~ ~ a t t t.
L.%3a17 7~[.~~r:L~.lz? ;.F,_, L# JF;.::; .i 1as1~=~' 35~ #.,..t.
x The si?rv,=a was ''LF~~i.i~~~~=Ã3 by slow e Lii~?C?r;31~i?Ã~ overnight and
Ci~s di ~3~ Ft=ti=C~ iF7 dea J~tai ~'Cr
p "i'=ssun, w ' ~~.<`~- >3lii:#:F'~. t~3:? ._iiit?i l ~ri.ftF'st was seen over
illa`.'. ~'#r~.. day, .FL+;t3~~ ~~ `~TF 'y; ' ~ t~'. of
_ 2~. ,.~i'~ a i i{.
about 10' #r.4 i biy. CE3n3.F. #m# ru.ie<34 <?i G ili`.F'i d over at lec1,-
,?. 40 days, be~,aF.et?F~a4: lk :~ rate
of 3 :.Ie+i Fv :ihn'* 3y C'F':'=vai.:a~.~'`+inÃ.? to less than I F.itx`l~e.F~,
a.t .fÃ?L1Ã''~~j~i.=~'is (s~Ã. F'ik.: 7),
~.
~ r~
,u
Ex:i.-pp1e?6. Ce1l CF~lture and Ct~1 Assays
M>,.;ar.t?Ã;lc`a ~'~I 6 Ca?lt1 6 (hC:xTI#.1Fi lEF,.:; i,:?#'i=>.?'is3rn'c#):
A549 ~ ~#F#a ~F7 lung
c<#.Fti:zT.iÃ?: c#)ti -rnd LLC (#?luf'.,.1C L5'.~v#s Lung Carcinoma)
Z~~C;"'S., d..+.;1:bi.~#.tt=:d #.~ 'C. 5,.:~~~???
w .:}F MEM ÃwA,h 10`. ra .eÃt~l bovi.itn soraFm (FBS) ;s:id M;) essential
anitÃ>;:3 aõid-"i. - <
Pn~.~iicz. Ws.s ~:,;1ca,t`. ;gi:" L?I.,a,.2" Z'.'L'.F'r :l-ti eC. ?~ayi,
WhC.:n '#FoE. Lah1.RF'C;.d, all cell ?IS:`seb x ..:e#'s... stzb:l'i:C> 3rf
~~~~IN-1 I {Ãi efinti. i:?okia~a al. -"'O'tY s WiÃb 501,1r. FB& 401% JUIM 1
aFAd 1:0% :-'alneth.,y} . u13bxiel~
(D~~SO)>F,. i . . 1 .. . i x and = x ~ aiF ~Y' ~ Z, \ Y~ t
. .: t ~. lines were ~iF~~~siz~,Xed fIUI~ A~ cm ~~cFt( ~ i;a.~: ~~:~.ÃaC=~a
F.xli.t~ ~ : ;~'~~ ~?;<~t'S
i:#.nd ci?Ã'At,..C.wF..fii.aF~iC;I` of 30(10 C:elN per T=3'C'll, All cell
II#.aE.s we.t'i% c#.2lti.1.Fa:(3 10#.' z:i Yt3oi."#od of at
least three days .?ez#L?. e b6t?g feStL=d in cell '`~~~kE?l1fi:F"eat#on
a:ss:iys-
2kJ Tumor (. ei,iw w'L."ro washed with, <\, ti%? 4 i Ã~ ph},`7`p-h.Z r. `'-
bal-TGiC'd.. ti. i # so(TIa': kY) and
~'4Z ,)43n:z+ E~:.. TaFt. cells wC::F'C~ tbuÃ3 C:<?l.#.FIted I.::ilTI~' .F
Coulter C.'<#LIF.t:<':=#' i~,.#d p~':iEtE:Ci ?,.00+1
"1 ?:.` `?r~ 5si ~t~.::^. ~ (;s~lls ti~~~:. ~: 5~.r',~ll ;.t'~~:'~:,~ ~?~tGF'1
I~c ;:.~a.t ~ ,.Ã.i.s_z~ ~_~ ~~ _ 4~'.#
C:t,~.;~` ik's... ~ ~'. .. _. i'l
+
pi!z"=fitÃ?x. , i::7nlIL) or pfai;l?la:1'l loaded azFerÃ.p,.inFC.xC<:: the
a>c,'.)::`i &Ey. A
posr9.`.vÃ. cLsx33-.t.'o. %':f;nt23aIFi,'Ca 1.0% F!,-',S or til`.'~ sz3.I3"lf'
concentration of F.B:"i t).,o}dCd fo>
i.et .#.'.:~ Ck.is, '>~ ifflÃ: a ?FC".'atiSc i:o#tty`C)t lacked Fi}SS. At
4=t.te~Vfli:fioF2 of ..ee c1~say, the
cells wz<-re.,M:;ubG.t:ed wi}ll 50 41 of 1 x Thiazolv( B1ix Tdr;i.f...Fus?'i
BF:;Ã,i-ldc (MTT.
S a 'ii7.<a) d?.,ti.3is'E:d FP, PB :r :Ft 3 7~. .+;#i two ht?1Frs. ~~'ht:
mccl?tl Xi=i{S ~h +.F, iaSp F`"E.F,wd a...id 100
kt ~ of DNISO wiis ad:dod to i.zxs:;b Y{ N~~. The pra[e. ~&=QF=c thicn. placed
on dt~V:CC 1-<3r
tt? 711.1,11utes amt the WcHs Ã:;~#rneÃ~ purple, cc?rrew~.~~.~ridxng witti
fria: aur.~be.,;; 3t ,iabl.e
b.iiewv#~l The plates wdirC: placed on a:?, :_:F..;ISA Tec#-dc.. `ii..
LrS.:ui`.3ed a. a
:i. wvi C F1 g h of 570 Iazn. J 1te absi7ti;c' V:.3.eC.iG:F were
"toF#elalFr.i..d to a lk:.2ii.svw?
103
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
Ã.E3#`.ihe? Z?fJ:` .i'#e~'? ccIls. ':l1c dt:3se ikfpC1el1'~c},.~ei at
bi''?'#.cia 50#t3 s.JfeF.;.s are a.th~Es, or i_,D50,
was (ai1c. #lani i~ to be 3C$wCei1 I = Ek Ã;<4 i23I:, : ~
pp~'Li:Y.zCklzif:~=ly 1 ':~,:;~~L~ ~3~.i*:..i.;~Ni:1 i<?c:Zei:=~?
3 . .^s > to "s~l'.~`YIi.= ;~~~. = similar `,i~?al+~::l.uRlot G<r t \
~I?LL.>nt:~~.ffiiÃ":s .,in
4'r~`^, i1~4.Ul.S~i~33~ ;~ e: :;t:l;
~~.~.`=R~~~#.
~
; ' a 15iz tt~ Y^tin - tt?~.< ~=~'~ ~. a R =~.~=Ãry of t.1 ltaS.~ 'C
x?~.~,~:.i.'s zi~ #.IsÃ~
i,~r :7.i~?i .,r..t'E3.~'#.is~l ~~~=<~ . : ~ ~?, ~:~r.~i..;~ a~ were
i.:'i13;; ?
three '>Ã.:tao; ci..x llaes, Le=wÃ'~a" LonS: Carcinoma (LLC),
NlehunGimi1..>,ld {.'a:z+3 (14iFlaili?
C ;Y.C.er) \.Q:3 l1nE.':i We3'e plated a. 3,000 cells/well `ead-kd whe:i7:
ostcabe1Shei3. :Neft..:'S3d .`,?1 iTac-df:tl.
p<ai`_I?taxo3. Sikil`.5..' ,k.Ii1lt#.ni''i:; wC<i`c miafllata?'.t.~iod with
f.p::#.Ã :i.E go`t\ ti3 ;4Lw`z"ti
(`Cr"'.Ãm) wht;na`u t?thwõb WC..1'e scS'illlm, s;aI'vGd. (ÃloI3wg7o}Z Ãt3t.x3
cEa4turLS4. R'i. ,xf`s f.cl".
E31mw3' C:`l ; m-sl.-f<.t.;:iflon, was asSessei1. via MTT cÃ.i7t3i4's.i`i.
Data was X?hoEtt;C3 bv
f`.tix.3.1ilir.ext_ii.?f3 w, 1}}c pt?s.ef?rc: xa*.z,.i.i7ti w3t1Vi;.
Con$'E?l i:ultua`es, as O~'t3 :lÃ0 100?e i~~lubitlod?,
respectively. 15 1 Y1 C) n;~'. m a. reliably l.nhib ,tS gTowd7 of .1c I.M
melanoma, .i#?d Ct.#.l :a6 WmE)I'. <:~..`l i.i#i`\'.> 3T.
p.t}lffZ'.Ã'.h`.io;:Ãw~ I.:ll* data wa-, C?btai.i3eis. 1:1s1I`tgmioC~i.i's.`t
eC?f.ta1r3:Ã`g I fs':~t. i'BS, tposxfivC'.=
CL,c.'i#.ti.a(?.S J.
Ct. , i - `> ~ t c'w.., Ea~' Jikn' ~ i .e~:~ic~ of :?.I.k~i:~i "r.~#.C3?1
were +~ to ;ii t¾,4' the i~ a
Ãu~ 1-: on tumor ~ow*h. J. Ã,Ãmor cells were pl.itc.~Iat. 3000 ,,.o11s;';i e>.
mad l?osiÃi, ~~
aTlÃci ztpa
.C.'Y.0- i w.. ;`'ze i P= af '~ r a > r+ i used [T'iti A~, J j ~~t.=..
I t>,;4ti,z ii=~ ~~.,?~z.:l~~ i3{?~~ cultures ~~'~.ii ai~<k ~.l >. 1 z~ z:'~Ej
i~
gww th .iÃhI;?il{<,n. F: sg)ec$13'~ ly z: wus found tll:a~ the addlFit?I7 ol
zix~~tC#tii~ `c t.~Yf#?}4'
results .i.`a i#.;.?:l>ivÃt?z: equal to PLiclit:axeS ~~~.~IaGeÃ"Et?tll1oÃ;s 0
~~L ~'>>s ~~ia i?"'i.,4Gn+,:~= ;5f se.luÃ7~:t ricl1 J11ed1<`x, lT3h.`bb#t1oil
i1f tutnto:" r;#':iswt1i'it':A'' i?.C}r. ~?T=uti4~?'2t
)i=2tli'+,.onit-mS$~1/]V].`-r~~~ ~iZ:~l.l?~?A2}.,{1Ax'4~.~1L1A~~ ~~\? ~.L1.?$,
4\~'S.~\iS.i ?. };!F'i'~vfw~~~.2~:>~ t ~~4=1~ .t.=t]L:~.L+~,3
2`5 d~#:2t
i.i_Iad s`i'.t,,Uh in :a23 effective Tc? Ã;e~:~.Ã~.?.mi. Vine kcnÃ..tics of
:fic tiÃ~?tÃwtuaÃc?r :-e~pmÃ4e ~1 ~:t:~=c: by p3i.:t.it<xm..l ~l<.:Ã:~ded
3?3 cI'i v'u: ..C`.J .Ãi%tx +., ,a4s%i w .R?A' a potential Ini"J. effect" of
dill>_ :iLlek:ofiN a cell
p3.3l1Aeicaldon a,,wsay i:=o#.il,%i'7i?gPaC.l.1tc:x~.~l li}ildcd
msa;=IC?p:3T'tii.les and DN;`^O E:,'iklst.',?l?
3c, I#a.C.id:spe.#tt..l.Fe:s .isÃ:t?.g the `s11el.ai3i?InL..i cell lIt?L:
w.i.. Itx,,~i f<?r fivt consecutive days Ev#~t~:. a
plate ,Ã\ ~o>. < ~ .1 ilJsi:t ~. =Xi~:la ~> ~~ )#. ~Ã~ days } ~~~ 2 ~`
~~a4'lÃtK.x~:l . { ~S.) =i~d,~Ã~'~~.w!
~~. wY?zF ~w~-. ~=~'"~ analysis V'~
104
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
&nd worf: :;d0ed Ã'il 5tri'urn rich modia -a{,d individually on
tziFiatar coIl-; of the smi.?e pl,:Ftc, 'l`~-le rz:stFfts domorlstrate a do-
zt:w dopu~~deni : t~~i~?~~:<3 ~ .=:~t:~:
i1.: ad.F'flilFfs:;:Nik?F.~ of s`cFds:a:Ye b-LÃt little t.fil"fl~FL;i1ei ti?
?:i3h?b4ii'sa; ft?...
vim dose on {s av 2 ~ s, i.iw {.1 3. {.~Ã1~..; .5. l~'f..~.9~~~ ~ ~'` j 3ti
colia.~~~rm thl:{. ;Ft~-~+l1~,[i,5:4l ! '>,i.~~v.rY"r~:{~~l~~o~ ~ ~Ã..-.
.Cle:`
~ iii}ixbià aÃ.unci~~=~ wr.3l;,vÃr3 qu>.ckly Wiih littlc diffcronce .ir.
oi3r:h
1Ãi..i1<3I C;=yipf} =aFÃ'1',. This is ctSÃ1S.sttv11t with u ii13:Ã11L3.i:;:Fe
rL'a#:'.:3se +Ff C~ Llg i? ld 1:W21"s.3`i~'t
bui?'St
3~ 'R '.~ic~.#~+G ~ic~ii3Cl~~ ~.+ p~:ci3~tC+. ~~,tYC1.sl~
....._ ~_ _ __ .....
;3imopii.F~ic,~-5 YvVle cI"C'.a{t'C?ct as ds:'st:.r`sbi:'<:E.eÃ"C'.?Il wI:li
tb?4 add::tÃE?s3 i?:~ Y.?
t?F4Zt% i;3` t .:L;o#'t.4ci.:.lt N+,7n-;inii3.~l QE'll .[Ing c:1.F5cof A"t^+ff-
.: ce.as were \S...L'd:',tÃ.
onto a 96 Z't u:l p.c:te (20t..#00 oi,.[N Fvt:>laf and H3E.LFbaed o~-
(:t`:tight ~.¾~ `7, 'C .3iJi~3 5`1+) c::::bo.ii.
(sioxidv, F`a`o mLd1;i wt3:~ th+.;: 3oÃ'ncnk:d fttT:[]1 rho W<`.HN .F11i? :'t
phiced 'FZ`iF:h c. b'xFs_ti..ad. St:Il,:';;
-ollÃI3o.n u4s?tlaini ÃgflE..(?i"Z:=Sc`1.'33~ niÃnC]p`c3rtÃt:lex at a
:ok7E:i.'~~'2trFft.<2{a of 0 5. 3 oa 5
1i3tJ'{1'a~ ,
IC43-;1tti3ls not S.tÃ`~tai.Ã17nff li's.3l1C7pr3 }1des 13'~C,Ãe also
poI'for13iod. Afti'. at YY 'C
tFÃi d 5% ~.b.3,;?~~~ dioxide ~.~~{~ 0.5j1 , 2, or 4 i~~s:}.F`~^, t~#::~r{
(~v {:{.`; and
the cells wcà :t .L :43'Ei:, weL~~lFffei'i.C3 >~Fl~Ã~~3~:'tkFlia
F.~ia.F;.~y4t:#.~ with 100 #<~.
`~ritaF#. X ..OWI{ in 0:.~.3. M sodfL3nn h 1tzri>l.Ãdo. Mfouhua1Ã1 , thC Qs.l;
;ysc3.e
;'sz.i m~.'~:~ ~c :+t,*,. ~~~ -.,.1FonW,,Fv+~~??4npth 470
x3iit,i'.nnd4Sao3{'Sts;C~i F?Ã.~. 5 18 nI..3 `ai3i>
20 coF~'.i3i,`-.F.{;:P.g it? a standard i:=taI L o g:ivi;. the concentration
t:& I3~{1~:~)3{Ã:E C~:. ahs'
Thc cells iiC3~F w[a ;.F~%F~ c$y:?IS upt.3.k^v over fim~= il%3d.'L'1`";tli
decreased z? m'..1~,~.?=-lrtlc_Fe
i,oncoitr Foot;. .:i the buffm
I-tal.F=o
25 Ceii aiiie (MSrl`O-211 1-1) is fniaub~,k:t>ia f _1" C' with NAR:M
,.
(w.Lt"i 10% f4sa..ba?-v::3c s4roÃ'11 (FBS), I% ossc.t7.t.tal a?nd 3c? :>cI&,
i3_[id. ,%
w.th ',. ~(giutami-n_G (Per-i, Strep), F-3.2 HAM (ixi:h 10'.:n .fiBS a.Fi
P~ I. w~Ã ~, . K s and ~,. :~z
f~ .~,.~:~) and LN,11.:~:~ (~~~It:~ t~~"k3S ;~~~~~. 1% en/St.ep) Ã;ne:al~F
ri~,,pczs:.ve ;~ wiffi,
:~lo~;i~i~ i.b.'1..Eli`;w=s C>.#:3o[; ovC,'.:`yr' .b!=oC' :]'<3ys,
4d,%hc::i1IlC?t cultured, iFil a,N.ls#nF:u~i tr Nn.. :i:oT.~F: i>`Ã
30 R'.t+W: .ÃAE.. fF:?g Ãi.odha at -80, 'C (wi1}? 40% RIFMI aF{d H)t,
daF.w.hyl s.31f}_~xiz:e.
(DMSO)) Col.. 3ir{eta W3:.ro t{ypsa{'{1.: od f1C}na 15 cm plt3te:a and
`'~.`.t'ded FI,ei1 9{`.F 3x<t.~: pl;Ãi.us
105
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
of z000 c6h, per wL.l1.. All cÃ:ll were cu:tn;red t'or a TI>L~nod of at
least lti,Ge &,ys bdfibrk bviag Iest,;>f; in oe1l pr,_ali#eration. aSsavl-".
z
-c ~ zf.i~~L.F'Ii:.3i.t;~t I#i ~`?iFt3 '~'~L `~~~~SE?Ã~~af.3ÃF?Y1 :~F1 I2C5I F
`c.al #i I itilh ~.e'i#~t ~lF ~i.s `~t~`?r`
Ex;:t~~ !~: ~ ~~
;_ .~
0:11, ~v>,.rt~ washed with sterile pht.Ysplhatz:hFiffired Sa~ rio t.PBSt and
t.yps#,Fized:
r11':ic cells were thC.`:Ã: colÃ#i:.C.`l~ ,asiÃlg a ('C.iF:Ftti.Ã'
i;t)IJ33_te#.` :aF3d plated 3,000 L;el;:5 wc-fl #$, 96
> ~, p:ÃF S~Ls. (,;~~ls :Vs.'IE.. ,c = \d ''.3~ i..t~1T .. a ;;Y~~t t13i= =
24f3 ~` ~'Y',~."., i, ? ~ci ~.?4:t3~., ~` =~'
4~:x~:~i~~'`.~'~:~:c.Ãz ~?'i.t3 :4.,4:ted,
6~~~..
con ..E.ti}õ~~(hy#.F'+.rxy #..3ycerol 4i$i~3t3t?s3~~'Ell 2,-
L:Ã#~sEl3~z~~~6s'iswi #F-i#cri3p,1;:ldE:s t3-r VwnIL;;Ãi3xed
:C?a`LF` ik `~EeI3z ~z: ~ ~
~: a , i, dzoxy ,1,lyF:~:,Ã'm?l ~.:~li~.tl~.~`:~ iÃ~ s:-~::?~?tC?~~~~C?,7t~=l
:x?F~;Y'f3~`ci`. ~~~~.i~~i ~a?~' ~I~,:~i iFay:
A po':rtus~ cQ-F3.'#ol #;<(?#:wI1?e:a IFBS iliGhe S3FTF:te 4mFcC
.'#ixai:o.Elof FBS p.i+v1:i:#.d >sji"
r;:l."zitÃ:.d + aw;ls. whiiv a TF+. f' <I.t:vC: [:537-ft3'(3l lacked FBS,
r=i.tilie of ,..$k a.is>iF3.y ti-3e
cells w~~rc IÃ:cWbaÃed with 50 xd of I x ..('h:azoI y: B1ue I ctrzrzo:;ui::F
~'-~rom.i: o
tP?F+:F) d ?S,.o, h'S.d IFz ~I B S at 3:"C Ios";t1x' o b <`,Fli~'s. The
F.T.]...dzC: w ;:ts ili F-ià w:j,cktt:d c3=3d a0 0
al #~A DNI'. +O ~; a1 ,`=,ld{t.W to oc.C=f# w03, I'l1e ni<1lti:.h were thie31
p,.,.,S..f. a ;?Ti .Ã shaking ds.Z 7:-:L'
~ x i#ru;~'. and ~~ ~d >l=: s t.~...~;xe~l ~. . 1le, =ps3t~~ ~iaG to ~tY ~c
tlF,.:,.~ ~. :~3~? ?~ ~..,. ~~"~~.y , ~ i#~li.
'~c'' Ã~a~~ , =+ ~ : F ~>~, ~ :~.:~1 1~t'~. ~#~-F~:. s;
:1? lE#i~.i t.~Ã1i~Ã"ii~ #-~# s~i,:' ~, ~..~z. .~'a.L'. ~7l:i:~S.:~i 3<'e.tÃ.
~:3l:~F ~~.~ f3x-F an ~..~.,.~ St~i 3`5:`i~~t # ~<~iI s~ <~v1F?. ~ i3.~ a
Wavf.'.l''~`.~Ã':g~1-F of 5 .'f? nam. .rh4 absi11`~.~iFnce 4'alF#,cs were
i;:Ã}c*~t,nahzs.,d to values fi:t?#.:; a k1"ls:3wa'#
nc~r~~~s~:~ of ~t: ~~>.?c~~ ce1l~. 1'li~ cioGL of per.~ietrea~~~ at: :ih#c;-F
5~~~; of cells ~<f,~~::~:Ãl1~.~a
LD50, dete'f7Fa'#?'ÃeZ> to bi.' ~.~a1~~'eGt1 0.1-1;0 pgrnl:. A~~3~3
i3'.IÃ;#~{:Ux~ .? ~~.i#.3 <x ?f1f,},f?Fkt!
pY'..na+..rY'e:fi"? :L?:FdC.'~d ili.vÃ'o~.?ti:rt`acli.s1well or -_.100 ;,22i
0"opFÃn t.;l e'o.'h:f.r,`.3zbr of l: .le're nv+..6.'stiarv
to EdnIc :t. pt.'..al%L.#'Q.YLd concentrations and ::eli CiC:i#:F:}2,
~::.cFp7 oxLec?1`?fi_tzeL; tF fFtsT?? l lhns3;.
tFn T:t3.f} .Iwr#3tv Cell P~'i?lifa::.rat#on .r~~~,tw;
3'i.`.Vint.T ffli~F1s a:(?i1i:iFI111:1`; 10- 3`,
ydY't?X\%t`_=:.IYt"#.ptof.hGci:1", vva:...` cast s,2``itz?
,wlFo4 by ..f.'.pi;'Ma1I`g a P(5>'+`:TFer bi3lu ..Fw? S,'.oll?p:lsEd of
poIy(:i':ec#.Ie 3Lim1 LarbtZF?sti . #;.C? ;k
5:-2?.p.i?l.3Litti,Ã.') Z"= mg3 $,50 ,.Alvf and ' i~00 J:i:;;)
Films we"I.'`v= l:?tpt}F>+.'d t}? *Ulttl<'si`.ia3let f:UIV,`o- radiation
ovem3g}Ft :?r1F?A
to 57+i.?.:g plc3.C:=ed F#?Fi? 12. õ'-w`:. plates containing 3,000 Lewis
LF`tbg F_;.FFc#.ni.3#2#3 (L3....;....) cells
3s.. '~ tLa z~~ ~, ~ `x:s Y a ~'x ..~. incubated 4 for . ~FiÃ:ay e:t~~4~FÃ`~:
.. " =Fi, 1) c~., # 2.:
~~~ = ,~~~;, z_~~iÃ~t ~il~~F: a~ ~~F~, -
h.sx.. (Fig. }) i`rLF'#i3iiti eFllm~ then i1.:asc'F.yvd fi3i viability
F:E:dnIF1F.H ~E~.`~.r~ T :~f,::i?.h ~r },3:F'~?tC3Ã:#.?x5. Both
4~
'i06
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
ix~~~su:-c: prov:ded c+~~ecfiive imbibition of t.un:or {.=c.'1 proIifer.a:aon
out to ~5 days
a#3:~ 1-b:c ,.mt..i#.du4zw= xpf`3:.im pefli+:)d co#a:inued to effts:nv4ly
k:3l., t:mi51 Leih, as late ~.~s, Day
30, B-t cE;#. Ar ctrisi3n,, exposure Ão films L<'3wa.1#eiFlg lit? dz wt,.',
ZuI.~t3:.3dt,d .:bna 3 '<.t31dea ':lAQ,
s4allfe exposure i;t?iid?1#C)n<i lp~. tlef:ltc:d I:FiJ {,.ytoir`jxic d'fcc.s
(tit(~ Fag. ; Ll"1a~ 3)These Fu4i.1l1s
#n{ii.~:~aaS.=thai;,`ur pol-YiiIei filF:ls cw:tliinit':g 10-=
4~f e.:=:n=i~,k :si.?,. w>:7.1a# ci.li;r for as long as Ãhi'ity days.
E"'l,it; 9 t. ~i2 .crrz ,' rrT{r T#.i#F s)T ~...N-tE~xiL~rt4'
~3i~~.~~c.14.a~~t~'.r.e ~(r~~G~.. ~~~li,i?.3i.t~'~.,.Ga~;n;
--- ------,~-.-
a"t. ` tualoi` z: tZ~{ a'..i~.f~;~ i,, ~'~~~3i'tÃ,t: ~_,~_.~.. ~~ and
1~.~...~~4rr .., ~ .~> :. ,~t~.~+-;c-x4~D0
?: =. ; #.ta~ Y' tkw:i
C3.e:';lÃ~
rn caI an~..~~ 3~ (I ~, -16); anus offichoma (~~~~~Ilan NA STC3-21I l. 1 '1),
b-r,:a~~ (b u1-n an M (" F") ] l-m Y.n,m,
'v4f'1pha:fea3. Ee3..:L.s1#nt:E (LMS05) t, ano5:r:i wer.: i=:uttur453 at 37
.'C./ 5% {O' ti. the aRpri;pr,.i`=.'C:=
in~.adia supp;anunt~.~ w-it;~ 10% I"e tl Bovine Ser~~in (FBS) and 1%
4;~th L-;;fi~ta;,nine, with Ãhe c=e,~-it:o~l. ot TVIEN"l ;~ic(fia wf~icli.
a:.of#ta'..i'icta I i~ssi:Ãlxlaj all:ino s?c1dt^; and I I~it~'IrIA.: of
bswi:'i`,' xeis'.:#fi.Y. 11..:wEi ..,~Jf :ezrt 'i"....
scc.ded at of IMOi) ; L:_.C. B 16; AJ,49MST~ 21 1114, NC'-1+460.), S.S`;?::
{NIM ) or 10,000 (UN4S05) col1s wJ1 i#-iti) {)6-wel1. aysmy plates -i.n,
f?.<I~~:A w ;.s:ab,tsla Oic
appt:;pr.atc it:.ntir etr.: ,iEattng dc=n4.ity. Cells ,~'c,rc;' :,'o-cul"utcd
fffit 7, days wiffi, paNliixt.SeE-
st7au~::.,a4 w;.Wd,{1nd;?aded :+-i]'ii=thyi ,~`^().4.;{3-t1 .iTi['t.F~4)xypl:
4i3vi }-i =3 dFZ>?<a#.e-5 i l :1l0$h,li
metha+'. -'late il,iÃtt?paificze:, ffalbI'1L:~2itioi:i, dS,.xit,-:1'1bf..d
t3b:#b=c',t. ~'~-4.fuZi'the 1ncubc~tiE3r, pLaI?_?d9
, e r v~ ~ = t ~ ~z-:~ Q
~t= z.~ ~ .~~4r.. ~.~y ; ~ xf~r viability :~.=~""1 :.~~~~~~'~~. .~~:~
~~~:~Ã':L~C, t .~=. ~ Ã~~~. ~~.W.u~..~~.agw of'v~ia~~le
cells using a P.. Sltftit. Co::i3'}t~ (culture cC?3?t.iai]ÃIbg no
n.x.iCxs1.A:tt+..ie4;) to, rep.a.` .#..:i3.t if.i 0 'u
vi :~.~ii.it4'.
~ i&, 1.6 4bo Js ;hw m;.c~lt for LLC and 17 Shows fc7r
cxpt;i'l#:ls:nts.?3'1d ÃndÃE.ate thzit pa..^=fitM.xtJl~lCIaCEtad, butnot
cell proliferation ior several dt-t_te-reait cancer Iitte~s at a
caÃ;.'cw=nÃ#'aÃÃonh as low l R+ mw<r#?;L
of A]~rA} t~#t A 1 Ei.a l3 32 ~IUaE 4 ((:={371ti1I!`:iig:ippr(.)xk.m<3tf'ly
100 Fig n.3..: of .E'<S:lv``aila;<~l, LAJ.Isf'.:~te1
witb, the IC.~(e of }?'. .<a peiL.=aft.tixt'l,+. 1`SG. IS :~bL?ws the
anta'ci:a`:icor activity o.C pat:l.iti~xei
l.,t<3dC:=d ?1<1:3opc3l..ciC': w"#ta7 LLC' cells in vft1`L?P =('ll(:s[;
i"#..sLalt: ;F:ld1c;3:te tA :1t. l3 #: po:STI i:?'`.^`.
~i..; c s e~i~e s(A e that c : ~ =,.l .i#$~ I an :~# ~ ~:.-i:c ` - `. can r
t~'v`>i v.`l,.<. F
~ C <xc, ~,='."i3'~,:.3 ~.t3t?l_C.~x'~#i` :~N?~. zi ~' :#l"
VrLfncVrr.ryell>>fo. .5uhta nt:ktp].+.t,to\!s of S.ti)..te, Ai*iy~a
w`:bV3:4=!~'4 }2{~yi#K.}.i\fit3Wt.unden43s.= offfic"
107
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
x xq>j 4 L3. Ql..ad]ti:E3gfitif3i1 of ml4,d'C) E~ k.....- ? ii
~ ^ ~....,., .. --- ~.
To ;L? ~'~ 5 '~~~<l~'L'. iÃal i"53~3iEi'~;i: =~1 `rkt:<icz3d71eltt to 1 lung
it silii, p%di`d c 1 cs s:v~=:
suEpLiIdi<.Ã. iii. Afimi?i3.i4 .:'vF-1 27 or water e1.11t~i f'=aci3 5t?(utl~al-
t was pad3dWd C;i?tt? th~o Ff3..~dc
7i#i.us4 R1# gs. h< t`.1e:<,3i..fingo,Y
~.r=~e' t y~.._õ j ~= ~ ~'~.a :'x
pleural ~~irdC~e ~iit cta'i~'+:' d.ltf r~t3:i~?C> ~t+,.r15.3+.~:~ ii:~i~ the
percent of i3't~f#~:..i.,~F diavi`{:3;3~#.itlt\ vl., 4
i3i.'ti.i'mx#le.d a.:#81.id..; a 'L`.+o.ilftfi,;; i:i.;vinier. Ati(;r a one
bot3..:' exposure tt5 PBS ~v$'ttiT?.w ilit' ?iAng,
thL' 4up~.'t"Ãaa';aÃ`z? ~'~Ss; rL'??dt?vi'd and cou.`itud foI' adhvs[',nt
m:cropartdc:es; wC'.rc
tht> t.fug;Ay fi?Esed tC? avoid cS)L1naT.:7gadRdE'.4d3'#"1 to f17i'a.
A73.3..e dc]t:~,.S..i flh4Yz lud.1,w, a:w i.?L` i.'tmt ,?i:P
?ruz<.rt?pa1"t.z.,S~- : dhoT.'#.'t?g to lui1`~ WaN ou,11d by 'cd`<aaoi;g tho
d'd?.FÃ:i~.~4:'1 of .n'icri?parE3.Jle:*
I rG`.G,..:iF'=d to .:he s3F,~e:i'~.lsZ$I.3.~1t. It was rdEfi.f~ that t}-
iGd'i; is a nnl#i;h .:1gl;.u pe7`4c.7t ~ft:ai..a3mon`~
~89.9 1 0) of :';?3.i1'r~,:,pa.tFcles loaded in .PlLii't3:71c NF12;
Y:.~,r.x3:t "vk#t..i tl:?w a? ~{?f`~1~ .Gti;
gel .
< ~.~... ~~
.i?` ` ` "~~~.~ if. :3 : (28.3 " 2~~~~. .a ~ ]a '~S'~'7~.` ?`~~
t~.?~o4L,~,.tkie.11.n:nti ~~t ~;t d~.3,,~
,~3 ~~''~3'~.s..:" }..S"``n'.l'~i'.5. ~ ~ f'z ~~(:i, in is
;tto-it#.5t#i::ally >;t,t?;#,`#m?i I ' 4051 and indicates that
:?..dfl'iS..:ii\'e:, such as NT>.27 g~.`l o_tn tÃssuo, Such as :tili<}
tiss.,:.
~~ ~ 4. 1'~,~ti Tii~t~~Ã + ~': ~'~~
=___==___ _._ , .... ...~.... ........~A ......... ~~___~__
~-__=_
( j(750,000) were .~~~ Y \ t
H Carcinoma cells (fF~~.S.,1 Vb:~~1+d wafla os v, ibmm.[51D
A14~=~.~,=.`3 i..1.~'n
a . - . `. ii']iz~~~ ~':.:t~:-3`a.~:Ãt~.~.~;l lf~?.<~.~~~c. ~ ~x~iGr,~p~i~-
Ãi~.le.s _<~i~ac:~~t<~:~c~?c~sl,~ ~:~-. ~.:~7e`~~,f~ ~~~l~ce. It is
:=itell i.;>aa:ei7.#.\ItL'`'d that this ;%tmi}r iit3Se I'C'sl\ilts :d1
a4bcE'slGdnct71:#:i tumor i.s:3dE3.1e. .v1$?7.II` 1
20 week wrt.l? Ã'::lpdd w;;'i?wah. requiring 4;~L%'#fii;e, witit7ed3 2- 33
wecks, tii t1'3e t3.ne following
.ir?,s.cfioii it 3r1i3'+ R)wid tt14tt t?aMor size Wck5 slgi7d#tcF. ,i;aly
dc'~.~.'e._.sex? in ..Eni.:r?<.hs Ymo;vii :~:.
LXX colihand vs. iirLi. s..ell5;2.oI3e. AE: c3.t.ai:cC;;
l`kiit~li}.;~ ~=~.'=?y~.~Ii,:~.~ 3.8 0-9 `~.[`3s sx'`i~~dt~bis ~.1:~:.3 i~
i,~~ ~: ~~a3~~7 P._'+vaA
, , ,.
y ~ r ~ =. ~ ~ -\ 1 \.,.. -} ~; ~ 1'~ - ..: '~ ~ l i~ ~y p 'S l (l
t3w.t ld..~? z..a ,+sx.#,:~.a~3 ~..1~.. (tt} d~iZ.~L~ j i~~ i~zli~t~ ~ .~~- ~
,~ ~I i3~1:~ (Day > : ~. i_ .05).
r
25 'I'~~c naajo..ty of PIT_tA-pac::.oxe~ loaded micropanicl:e treaml animals
developed
minimal ?<.vrdei'icc. f.5f :tm.aod or gyC?wrh. Nc; toxicity ffioi:f
ni. fE,'d. 'flhlts> the data suggests that locally df;li ; t,Ã {.G
ohe1;,isiht.T~:ipy
via d'I3i::ri3piSl3'<,lks Uan, deter ~~:Ã.'= gowa and i
.:ie:i.`~ab?1sha:i2C;1:t of 1i.mg ca3"+ ..i):< .d'..; :Jx ' e :oI:i".z.
: us3C . taz`i;=aiis I~dC~t Gi. C3f twmor b3`T3pSiit?EtAtii?f?,
30 Fc33Fd'dca .t.'C2 i)-11.ciEbpk1.i'taGi't':4 were 1 5 ~.i.:n in
d.1cEI:iC.te:`;, t:#,i?(?th, and 3aQk pu.io'~ity
'~ aiw~~'stix4 that they will ;Y1r3i11t{32Ã': i? d~:li3t# x'G`l~' l l?d3
5i3s3r fa;?=.LL? ii=aF <:i~4 a ~??~?y ~+~.iÃ~;.~a tJ~.
`~~
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
tFII;f:', If 1,. ..>itF3'?r'e1t4~ti tP?;i~. 4UI~.?ci t?-liF?t?r~:.d4~il I
s:;~'i'~ia~:s .:1 ti3e 5-10 zl?z .~~.?ii:l: :S
~. ~. .
;stEl:x<1.tC:d to be abF.gi. a .` .i?.icF`l}paitxc" {:s per cell, .{z,l a"
c{.Y_It *jwÃ;t:ià ; K
aF~~ nF of ':oiz...:tt; ueUs a:Id
r.:.
;~~.tÃ:..?#.~'.i?:ii..i .iei:AE:Ã~Ci, z'FiÃ~.i+3w343.1ti:i;::5
C~C.',F'F"#t51:i;~~..cit4~ 1~~]itt a C~C`,~~'. of 1i~~t: f.33#.ffiÃ3?;i
mF+.:i'z_Jp(I.dÃl :le,`~s
i't?.iil'pictL'I <` inhibits gÃ'mvth iunf4 iS1a.?l.;ii3;.11ent C?fÃ'FfffFt?a
Ã."cflk 71'1"a3I Ã&a;at3.on ta;s.zyS ..;,id z,r^;
~ Si'tJ i`?jixdEf.a:^ hc3ve iiz>o d`4'i.i3{3I?strai+'.d that the GC?iltaC?l
PLGA #.F-F1La{3'hSc rtFi ii <?iv. IFt.'~~:`~i and
~..
ti iffi{ywFt a k 4:Ã =.; vr, tumor 3?Fi.3wth.
E;Sis~~1 TaS ~, ~~.`~.na? TL1IF.zÃ)7 ~' q~7{?i7s4 C?f F3II?E3`ifAl'tl L~`r
if#ZSS~ ~clt?t# ~i3ij t# le 1k ~`E f I# t3
~--_ -- --- ------------ - ~--~-~---- ~------ -- -...___ .........,...
I.t`.I- fe..f'fii<:t`,S` of eftG:ÃTFf?t>1eF'G1py^lC?:id>õd F3imoptinJLles
f`>Es,n Exea..7Fple 3~
wer~ ~~valz.a"'vd i,: WÃ.l1-{~~tablistled sabcutaneou4 tumox models.
~.lot.s::. 11..C or hurn;:t:#
NIS''lO-2 _ 11-1, 0-atia::~T CeiÃ. 1:i-nek wore impiaiiz-<:d ii~~~i (,57BL6;~Y
a-espt.s.:Ã:ivelT.'.
S?.lsi?e}'1sF{?f?:", were with {ai11.m l?i? af.d
iFiu:3i?p._;::.AÃ.:`?L:s#iaii? tho
s:. w#t7Ã. .imans.:3tl i lFs.`.*iFes of the bc-.ck C3: :,?,i(:i:: 13t?ih
A3:t.". ` ,h"`2:5 Ã.:It`r `, Z,~ ti,?'i?$.~ ~?c'~~. :Ek,a.,?Sil;
~ ...; UFd
sli:?w" # 2.5 I.33L'F`53f4'7 i3 p.mr':'.d) 'llC?se~'_, of
'aiiÃ?oÃ:+e$z'tzLlE.\ `e .`L.ic e'4s.luia'tZ-'& A"ziii:'#EFh,
??jected W?~:,i: i,a.`#?i?r cczh-, a.oni,?.n PB~'s, tt3f?-if?T tv7fli
Iz.$E:I:.ficial dE-xie;, Ei;.e,.f?...z.,ed f::3I,ctic,:ni3i
Tumor Ã3~ lc?~iÃ~:~.~~ 3:~?1`. f.;#.i~l{:~~l.F,u~l
{;:~~1?~i~~~'1!:.~~}t71asI~f~C:_~ I:~G1nC:p3rirt~K ~ae:i k4,'.{ i:~`}z. ~i:~
controls. .r$:'`ir~
was m;3ni:i.;I'4d :?ÃtrL'i.#..lkly, and i:1.F-#.lfTlais wC:I`Ã; 1h ~:*.-
i.Il.>r~,h` r(.'clchcd 2 cm if? >. zÃ.:, As
2#ikmti.. aitf''.~d 'K#i.
~.
.' B bM3da :he high ilml I.{.~w doses oia pai: i.iiaxt`u`.E^3.63<ldE:<i
fid8.cbiE3llz$l
,?c.#1+3~3,.1`FL1~4 ,ikll#.~7?~ted w;:?'FÃ.FT gt'i~tt'ffi 1n flF?ii'e (~.3 =
~.~.}4?OS`?Y), and were F"?3i#if ?Ilt)"e
6FlCc`i2b e iF.:.?in even the pi3+,..,,ta?k.a:.l-loi:fdi:`,d b3.It Sat?Y?-'t
x;?.inSF%e Ã'z:li;ligp..1.fiG=les. Thi`=se d'c`#.t;.;
i.rctiTev dk.311.s`s.S;tA:3ts;~ that the v3t3 tu.?1C?r Ã..ffs'r.=t;> of
Piichiw".0-1Ã3:#-d6;;d a{F# :zi~???t:a
niFlli?;?{arlit.,:i:;j s~..i:? }:ss t ii.;'~? t#'aa=a3s:t;.tes to ~{k~7?~ ;,;
iG~ F~FÃ3 7~x ~#F ~#r~i t' <r #?1r`~~`# ii', F s~ (.<,
~ {
EC 1m3lu' 4i5' Ad7t;~,,.T Fl..7i ~a~' of St1beti~c~l7es.3~is ~~l~lyIF3k F
#fT3? n`.zi..#tsF e~zs f 3 ~~
,........~.--- ___
~._. _. ......... ........
i~.*,:: r+ "t ~ .'~:{-l > .~~.',.~ ~.i~a " 3Ã:"# '~ aà 2..,i3
2 :,lz 1'": ~ ~~.i-71'~t1. G2t i.C,t:~ f ?i iyE- ~ ci71+`..~`~Fi`, i~i~.~`y# F
'} :F '~t t'K`z] ~ .cl:`l t\ ;~``~'`~; ~.:;r
evaluated using i.Ã. Sub i,.3t.x:1{.[,ia:s ti]n14,?I` n?C}Q'.Ql, After lni-
~uobitsn . ..t ,..;~e..~r#aa.; ~..~:? + .Bi.<:E?
K ;
:il?#.~;i.'~ ~~C?a. \iaÃ~Z C:.i<z :F.J.d :?k:i~#'? EiF:i the back of the
F'I?.f e.::i(wiaw prC ;:'pod li, a ha s..FFon. .`al;.
i#?:.s;:{3:i z?: i,.:'`s :'.nz made bc:.weGn thC shoulders :iFe J.t#G :. 17.0
;S:\ 1 ti =.~{it'
d.li#'+'wA i.F;.ir. sY:tr, L?sz?c.'t @ed with ti pii3.d''C?f sterilized
tweezers t(? :t7.c3..'3."w a s.l.i`z.=t.#i>..,Fed.~t,E.:1
I?o2'kF:t. A }.4:ct;' of Gif#'ffI Ãzed" pttl ZiZ?s.:' fi I l'n dn{:d i.'+$? a
ps'.'E1~--iirda:.iy2e strip (i?,S x 08 cm)
wft~s inserted into the st1bÃ.:i..4a#?{:=Ãstts pC3e.ket with Fhu drug-loaded
sÃdt, Ã,Ffthe fiII>? }`,lnod
109
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ijpward .i.,nv:FrfYs ii-ic ,L,,d t~-ie IF.cisif?n was closed with 54) sutuF-
os. Nfi,x wen~
:110-nit~~red ~inz.~i futiv recÃ~~ven-A from anesthe5ia., given :wui.~gegic~
and w..:~0 housed un a
SPF ispe4~ific pAFl:-lorren 'guiudl4: "LFnirna.E facility. Two1}:zFYs worti
adF.(.fwCid healing KZs>,t: f4fi?ai 750,000 I~at~ilJt= LLC tL~iTlit# s~o=ll
`~"'T f~7~:`w` i~ C3 s17 = ~..:Fitixy i?:3 ti':q)
of t}ic 1mp1ara:~C'~ fi`f-t3 'i'#,, a 27-guage n4i'.dlL,
~ r . .
TF:.~i:si`i ;~i2::'i'c'~F5 iF';t3.F1tt33'~iF 3~~'s`.'t;3s~~' ~3=[3~~.
z.EF#iY.:Fl;~ ii~~.T~.z"#.tChec].I3Fz:f. Fl.tFl:i3õi?x'i
'2 a=f`? ff. 4 .{e. Funr39.i,F` .,1o~`rtb. didn<3t occur oL\w:c,p \?`
ap{.3I` moA :.flh":ts >.Cs<difod w.Fi.,1
30bllw L~ ~": ~ {5~~'~:i}i1~~?`~E~~;1~"=41~ (10 1-icPT) ÃI~' any of ffiÃ?:
C>.%p..:'Ãmon,.:i` m..u (:`s'i.o #` :-3g. 14).
Th:h is #.x ci37?t.a#.sa ~.t~~ the tlli7:31?Y g7"owti3 ihF3t ocC"L.rn':_l
directly on ~he 1..:11oi$ZieiE
pC3l4':x#tF fflam IF': over 7 -5;#:t3 of th:, aIa?lIl'c3ls tested. .. .,a:aU
\:fw'i' r
~(,"~'T ,.oFE cli~d polymer alli11s did develop tt#:I~..ois w.Ftii delayed
fbl,E)'Z:-up bF> theso EFF3n+3i"s
w4.:Ti. &Iwc t`ti .iF ti.le p,F FphC.#"=y of the pocket :iF,~d away ffim~.i
the filiFl it, ei'; ~s>.i` Fig. I.'~?).
:Fddit#t?:i tt:" '.b,. delay iF:: tumor appearance, Ih~.`'~s'C; F.i:Fl.F::t3TJ
W'L``,i `t. sFtx;i-1FfiCi.1.nt.,i. , iF..iS.l.,eF' in .#"I,e
(p ~~, 5K ui~Sx:':'i312~, ~s:1c`3.it) `t i 14~ :~ Ã-~: f> 3 "f~1ti; Y-l 5.~`
~Ã~-(~~ 3 films st;'>i=`~..I.L~:~ .Fi~:~~~ t =C?t ~ ;C.~~~.YÃ.~t.\
ÃA : ~Str y, l:l y"~ ~ 3`;La
13 Wni)r i-r1Z3d~.'l.
?`3r > ~ ' ?: N..3~ {.~.. ~'l~F.`' . x 4 In ti4'}`xt?~.~Ft~ Ht¾t2:~a~gI1~~~
tl~F~t~ 1'~`~.s:~'~.ca i) ~. S~~.~?w~' Ã ~~'ti1~t~=~> <~
~~~ .
PC`i.i'F:?#c: fihnS were subcutaneously <,.inplaF'::ied ;3'.'3 flir:i.= bi1&
of finFc~:=
3~ ~r ~ rc ~. ~ . .~~3` under %IFFt.~:;:F':t:.~3i3 as described ~`~Os~.1:1.
~`~t_c3li E:E1i ci~ :;sMe~;~~a[~ i:.3L~~fvC;E#.i?E,.:I: that
~:..
ccci~~~.t~ `. ~~ s{'II'l lt :~s~:d i~t~lyin:F -~ilFa?~, u>~1.~?a~3ec~
:~t~1yF~icr iil.Ã~s or s~~<2>3a . t, cFy ~xI~c.~
pockets ivi.re ~"',=['Ã:pwFF'('.(3 btJ.t Flt) film wi$.>i I3'F'1pliu]3.C'C.. 1-
~ll #.F-4. iJFt`.a3~i were
closed 1i Tta? 5-0 ;iut-u. ~,'. Th+`..# L`, was i1o t=,:4.Fduii.:t:'. t)f
w)EFnf.Si drõlul;.L;cx`.t.,~. early or lt3 w (::[l) to
s t.iq:;> :n u:iF.tF#':al's mat received lC?.:3ded or un:oi.:.dGd .iil.IT7s.
In adE..#ti~`f.]. ~.'1`~.`F"e w~'e~ Iz(?
25 dF.~".zL''re.Fai.:e ;r, 5"`."yfh`'I'f2%: or <L'ouF-id <r`,o-
3pC<i3:1:3.F2ci; ami3Ã:gc#.Flx"."11;3.l;s witi] r~'.Fhns 4CtÃ':sCIs s,.F.#nn,
Exc]ini~~~ ~~ Lote:il Dii1tF R<xe<zse of `>F 3eFxl.anc43us Pt7`ynFc 1`lffiF ~
F
.....,.. . . -- a... ... .. ...
, .#~` ii? ~a il drug .~.lft~.;ii1 of ~ .3Ek~~,: ti,~<?C~:=tz '
p:sl.,,:F`F3:=:w
. ~'~,, i'~Fti(:. ~g~. SEI.~i;=.l~i~'~~E~~~~' IT,1~"~~i3~1~:~ .x~ .
30 `Fi1m5 :'~~ 1'41,0 ;.x.Fs ex< ~~~ned. PolyFner fitrns were sF'abcutarwouSly
Fn .??.Am..z`. on ~~aeback
tsf C57BL/6 F1>iL'.5: LIFFfseT.':7;IleSt.ti.3eSF3:35 desL-t7bed abt')iCl. At
weekly ;,nteF r w:s
~ 10
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
implilntx3bon of t..ie.'; fllms, 4h,: s+.:rrt?uT1dL$'1g tissues Weis
?1a2"vf:swLa. Tlhe:L' #.3:~`~3.w;:r ?it..;':0 t:,::3::
in a filsi>iozl 's: w<? r ur+3_"+:I tA34 fi';FII and s`s?q,,il:i7(1a`.illy SC
gpli;I1.tt:d cl. 3::-rITri d#4taFlcÃ. .'i
, aY~ ..sYO 3`i \>m t.i Lb 2. k i d 2Sq thus pro} h 4.i F. L Atf i~ saw
fo[Si.J sc ts`me1 i F.at }ra}} oi:ts i.iii 1.f!_i r Lici)Ca.~ Ad
S_F1acefiYSn:. awriv fi.-L>na the dI33-3i;i3ded fii.E#n. ThC.> concentration
lF',, the w:?.I~ d1ilt<'.=d at tzi4~
t'a.`ik1;#s dusiafiLes was dheI% fx3+e:}i Iss[1o se FInL'..=Ilt L.#:?i:-Lg 1
. aPF_:C for t1hC:.
ti,?ct:Ãc i~I3i.:,; of fl `~"LL4~. The k'.`t"i:ldIt;$1t of drug
t.(3nm;2tr$i:=.#o!? Y-v1t:h1#> z. 2 cia'. t.iamnacF of
Y' > t Y '~+'Yr~,T = + ~{,Y
the :,La:~~.~.~ ~i3"t~~<~ film , ;<~~e tlaplotted to L..~Ã~~blisf~ t?~~.
ci~=ti~~ r.L,lL,xs.~ ~.r~~c.~ :~~.z~ ug,
<31st?,l?utim': zia;.o '.hi:= surrounding tissues in }'s'e'o.
1.:K.'t1mpIti. 4~-.~: _ t#.ML?3= Roc1:#1'?''moL Model of ~#3'Ã3L ~~~i z~4=~
Lfti L~II'i~3 R>.5~cfi%~~,'+13
J'J)o svqppt`cs.,_~joji of twnor rey.urronie, by drug..toarJc.d
nar,op.;r:iclz, an_~~ dlru~,:,_
loitded pol:.m~I fiims bit'C', also being examined a SsiF'#.g a well
L..s;..3~.`ll:.4wd .>t. 14ve,`r tE.J,ET:li>a:
to fA~4~ <~it~r( S1> ~'`~ >
mZ?C3i:i (Qc'r.Ci:3? ., .ai, A-n#aTho#'ai` Surg 80.1046'?i., 2005). ~?g1.,
Fl:ct; c3,1~=L: :a:.
4
tuA`.1oi' model w,.l..t,'w:=d if`: Iv7SiLLi1plC3 4,13, 750,000 Ã:Ã.1{ti' z_-
C.la`.s 4x'ac iitier..:'..=tsi
and i?flowl.'Yl to T ~p..e tumor wi3_ti 4,kC`3;'iL~lftL'..Aa y #"e:iZ:ctt+i fl-
1_I'mijL a LO
i,'.Ii1 #n~~:is.L?i3 p;...all~l ti, tils,'- tu711i3rand ght``. enuTc: ttu21o,
is removed and ¾}.''o-s; Fn4isiC3I1+.?z`.sefa
in control a$1in#:i.iks. Uffli..taded. or drug-loaded tlr.znopartli:le4 C)>
Po:ymer fi.tTis xl"S; applied
C).bÃL3 the I#...zl:,:i' bed Lt~ L ti~ ~ ~ i.illE=#l~r#~ animals and the skin
#:EaLis,<31.: `, :hiF2]_.3.a..y ?..Io,,wd.
Aniu-mada arc a..sL.sm1 b.wockIy.fL>> ele#ice of recu::-ent tumor gamwill
v;lAi ,..h our pil:z~
st.aL.#Qw h3! e di.=mof']s ratei, occurs aggressively in i_431ArC3l animals
"h.#t do nitt i`ew.t.'~fW
s~ru4,..}k,i,.sdod or P#.Zayme.#' fi9:~ls.
Exs_Lit7olu 50 +TFi IniFÃxJI1t~33#Ec7l '4~L sL~a}1~ ~iL)i~i~^ ~`~~~i# i # with
_ ________` :......... ._.---__T~
Pt3.vx~tax4''3"Loa'`l~F'4S.i Nl.
t ~' 3.h: abia~+` ~ i'~ r ~,~t #,A#~L~~ ~ c) v>`~ ;3r~~.~ed ?s #~L$s~t{3~
~.rfiUle :i to > ~ ` ii . ~.~.iit,=ii~ the Cr#'ow"i, ..r ?,{'..~,
. . wi#;am, tumL?;:
~~~
ca;IbS :lE t.i%o wilhii? 01"#e >.3iil'i3pe7'xii>I#.cal ii.lv7td' has altso
bot'.II us 11`", <l I~~i..3'lI1t~:
mo{.Ftii~of vi''olle'3iiabiished :!~i vivo t{.i,L,~$ nno~ ~?.#r~: : f=` t
.<..tr, J
t~L ~ ~1~.~I~.,:it>: ,
Tht'.fai:ca5.1i~vati4 SL1rK,. 1:32.117 9-88. 2006). Cultured
Y1iL:=sC,tuiG~~io#;.>i3u#.1:L`:: <;+,.il`~5
million M:? ,YO 21 11 ~'t .AY; :::o-iJ:tjGt .:d witl? '"a,.3a%=,tdtmt.l $ngc
dLd ftiF3a.oR"'Eal a`cini)pc3rfi.cli?S
6u1a3L?.Y ce.l5 alone in P13S L?. tEiT:I3r with identical dt5:,4:, of loaded
i1L3nf..nia.aZnz,# (1)t>z}--
? Y ~
CA 02653811 2008-11-27
WO 2007/140483 PCT/US2007/070159
: xpa1?sÃl+ a z3ai?opbl#fit res ;ie.i1'ed <i i i?iitif?li for ttl..Tit?iig
QF~ic>ty %1,,ml IIFmf?pafticle tt>x-jL'#.Ã'~~~
t-s;~~-s~:~::~i z~ ~:I >=.
1e 51: ~EMf?fFAÃ.~3s
L~-~y \?l~.._l;3aftW }.IoFfkiFc. fi.'f:.%.L=.F were cast otiiS..J gSLi4Js by
~~epL?sal.[ Zt.f .~i poL;,`iIiV't r;+oluhi\}I~
comprised ,?i'pUl,1(stC,.ik':.C ~u~~Ji??227~f` `dJ t. t ~~?C?~fl~~C?~<L~ i
?'#? ~~ C~; 4~~,~?,,:>Ã1?M:.1:.Ã1~= L ?~3 pt)~i:#Ci Ã~.v~~4Ca (100 ~#g).
t25EIru a llaliriivY"Ãrx~t
~,O. ~ a`.1+,: .`9ok-Qr.. 4u ?C. ~i'~ ('SÃ.
by il.t3w ev<$p<1:;Ãii3. over n7,+.,,ht, i1Ã'id then placed
Llnde;'.rL`ducei.,?xC.~s:".uI~fo.. 24 x:<3ua^s.
Prior ii;r. i'{Ti23Ela:g, the Fll`l1s wf?t'e, ci3:3l:i:d 't4>tl7 7 lIi-n of
At3lPd. The ;.3hms e4 erc #:;=?.aaged
is'^~?iYt` .1'#;,'ti .mi.11'... 01wi"o>? microscopy. f-l1e Starfal=C:s of the
fl~im i3.ppearQd 4`.zE~oEYkh atsi
~.`~oi'o1:i5 w,l~i fibrous-like i3'?ictm+Ni3:tu?'ff.'. As s}.lowt-}.iv'3 Fig,
S. cri.yS-:?Cddoal Ãnl":s;es tsEso
revealed a D0,11--POri3US il-Aer'iOr With Csfii;isÃent :hÃckiiusies tha'oi:ag -
.oW. dl.. l,:agxh
of 15 Examplo 52,~~
~~~~~~~~~~~~ IZzr scanning electron microscope ~SENP :n.,,a~.~mg were
prop4~rec by
w li Ãir~g a smp~e o~~`3' undSpa-mlicles, .s? a C:tni..eI:?,Ã.Tat.Ãor, :Jf U5
`Ã"'ig':alL waih dojE3Ã?iFed"11
wW.'e;a, A 10 ul. pd.?rt#i.Ã: of the d1h:Ã.Ld-sar-aplL rvil5 tht:n. placed
iSF:: a Clown ai?E.n.ÃI3:an "s-Au"Z
fl'#e sa3?'fpies were coated 4<.t}? 15 Ãiza# 1 t~,~~!' of
.: -
Au~"Pt. Sc7r?lpli.:-, we1'.i.. ;:hF:i3 1 .3. 'L;~'d~ i~.Ã~a a Zeiss ~?~,~P3.
40VP ~..,c:i~. ..~] ~ ;~~.i
L.
>~~f E.3C:d'ii.ltz~? t`i lt~.{t,:;:3: of ~l ~ r The image in ?. I ~i
;d~34'k~~s pz;.F.~i,:~f'\ fe<3'1'l''a abmi .C? ;'.~~Ã,=.`
microns SZl Ã:3G= pmt;:i t4S e3etwC;ei1 5 :3:[ld 20 `zI1lC:3.`i3ns.
N5i; Cf}x3t<3~~ ~i?.z} e~'~~~1~t1~`LÃ1c:?~
c glass t= ~ '' and . . .
p;3>y-ÃI?er films Weri`.- ust i#;at~> ~5:x~3:+t1".~.~~~ .~~#Ã~ the contact
c3:~7~rlt~ ;S~~~i';.s~:~~# ~'AI~~'i
W.Ã.'_e deÃei-mined i3.,,ÃEa4~ '3 L'nti}i.t .9.,:3'.t.?;~v
:~Ef;Ã~..7L?:.~~LÃ.1.~'`. ~.~:E.#ll~t.c.'~~. ranged .~:~4F#i:i 75 1J.:~~t'.
. . . .. +,- ~
i`or i ;iai?`P.ti=, `hc i ol'1Ã<1vb aF~,oõ1Ã' of p4.?~.y4`v't~.~1i'i4~ acid 4-
~.Ã"~~i31~i~tt.n. ::.;3 C C.a,4Ft~?c:LÃixe~~ i t3'il~
I i SK "Ã,aiw t:'Z?z3tt:C:t aiigiw~ of grl<.s':i is about 35r .
112
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t
._--- --~ --------- --------- --------- ------__
Th a':?-:ial trt.t:n.'s#.F.ioI:?s' of ead? Po:,``,dl??Cr were
mi.:i`bsu1't:Ã.3 iÃSIL?<~r t iftZ.ra'..' ..1a. 4t,aTin.S.ng
i=~low il2t"tI'N. P?lymii5 Q{ mpt?st'd of <: ca(?rf?Aai tt?tli- <?ird
beEl'!Zli??ti~v a1'~~c{~` tzI ~:Ã?rbz?maie
m[3nC)i.ne.iS we.n~ formed v.'1th t1`si:.= ~fi.~,lli,;wÃng carbonate mole
Iftc,ctFiTI? _. 0,05. 0. 0.20,
; V".~f ~ ~ v 0,401, r).J~( 4.1,.LL t ~f )s\t Yi itf zo1 k~i !c}=~+~ y~cj\~k.i
`q*~i.~s l. '} 41,c {<i~'4ta }[ C~~)={~ 'y .,i .) ~= t~~A E t~.l #. `~yF ()q ~
2
s~,,.' Sl~. 1.00. Y~{-'fliixy~ ¾ LV-4FS~~Z-:2.Cl.C y~k:t?.f}.~~~ `~i.l'~'~ l-
<i.i).Zl
>~"ejtlliw;~;oÃ;i~rt~I<?~.i..'~=> lc.ia`FG:~~. {~S"?~3I;;1 2! ~s~ti 5~'sC
::Usa:a?E#iL. and f3i..ha a,.i1x741l,s'Y:7cx ~1,~...4= a.Ttt?IphoI:I's.
0`rilER EMBODIME NTSS
It. is to i?e ui?:day>t #oif thF:twh.i>``.e the ~nvt:nt1o#` has .zi;m -
dest.Pibei. j.. ~. Lcl.l.t_:t?D.
E'e'i:':T t:xt; dci:ffliEt> theri.~C-yf, til-hf! lz?IF=gt?iS-1g descttpI"it?ta
is 1`:w: ded to iflustriite
and Il ~. If.:.,~?: t~>?~. ~iC~~:?~~t~ of tz?a, i>?~~'~s`I,l~t.?Ã?~~,
~tr~Yli:~'? Ã~ <~:;tin.t; by tiAc scope of dFo qlpeTtded
Cla:if;s. OÃ:#i;rt#*pect", 'wdvw%ts, and mi3d.ific'c?t7.or'iS
c#.i't;witl.i?.E? flIke swpe of :lw
1olIt?zvir?g claims.
113