CA2055086A1 - Cyclopentene derivatives and their use - Google Patents

Abstract

CYCLOPETENE DERIVATIVES AND THEIR USE

Abstract of the Disclosure A compound of the formula

Description

91~ 5~ 16~3~;TA~EDA PATENTS OSAKA Fetherst~n il ; 083006B01;$ 4/72 2 ~ iJ ~'~

~YC~OPBNT~NE D~RIV~TI~E~ AND THEI~ US~

FIE~D OF TH~ INVE~T~ON
~he pr~en~ invention relates to 4,5-di(hydroxymethyl)-2~cy~10pen~nyl derivati.vl~ which ar~
l~w in to~i~ity, ~tx~ngly inhi~it the growt:ll o~
rotro~ixu~ or r~troid~iru~ Qnd u~ul ~ nti~ir~l Age~æ .
BACK~ROUND OF ~HE INVEN~TC:IN
Silla~ th~ df3~elopment o~ ac~clovir, stlLdies on th~
~yntl~esi~ o~ alltl~lr~ enta or ~ucle~icie t~pe, and a ~u~Qb~r o~ u~ful ao~p~und~ hav~ ~o fa~ b~:n o~tai~d.

E~owe~v~r, a~3 ~he~:~ anti~riral ~gents o~ nuc: l~c~ide typ~

only inhib~Lt replic~tion o~ viruse~ but do ~ t 15 ~3~a~icate viru~es ~h~msel~r~s, virus~in~ect,s~:l p~tien~ -are required to take ~u~1~ o~ thi~ tyE~ fo;~ a p~olonged per~o~. Cil~c~næta~e~ bel~ ~uch, e~?loital.ion o~
orall~ admini~tr2ible antlretrovlr~l a~ents l:)f nu~leo3ide t~pe i~ de~irable for vir~ infe~ !te~
~a p2ltien~. Pexivative~ oJ~ c~r3:ocycli~ nu~ lde, pr~par~d ~ ~ub~tltutln~ oxyg~n atom~ c~ ~u~a~
portion of nucl~osi~e wlt:h ca~bon atom~ a:r~ ta~le ag~inst aci~. If ~ ~he~efore, compound~ ~ho~,~ing ~t~on~ly antivi~al activity are obtained ~:rc~m the~
~5 cArbocy~ nucl~o~id~1 the~ c~ b~ u~d i~l! ~r~
adm~nistrabl~ an~iviral ~gen~s.
~ mong vixal $n~ec~iou~ di~ses, acqu;ixe~
immunode~iciency synCI~Onle ~AID8~ due ~ in:E~ ion O~
the human imm~ne~ ci~nay viru~ ~HIV) aaue e~. ~e~ious depression c,~ nunît~ d i~ a lethal di6~ e.
Furthex,ep~clemic~ity of AIDS keeps c)n inc~rei~l ingl all over the world, call~in~ ~ serious socia1 p;ct~lem.
Studie~ on the ~herapy o~ A~S h~e bfa6.n activ~ly conducted all oveX the wc~rld, and several n~:cleo~ide 35 derivati~Te~ having ~C tlvi.ty to inhi~it propa gation of MIV h~ve b~en 3cnown, for example/ ~ide~xynllc: 140~icl~at 91~ 16~36~;TAKEDA PATENTS OSA~A Father~n i 063006601;# 5/72 2 .

~uch as azi~.othymi~ine (~Z~) ~ 2' ,3~ dideo~ deno3ine, 2 ' ~ 3 ' ~ eox~i~o~ine, 2 ~ r 3 ~ ~di~ehydro~
did~oxythymidine, 2 ~, 3 ~ -didehyd~o-2 ', 3 ' - .
~ideoxycyto~ e, 2 ', 3 ' -dldeoxy-2 ~ f luoroadeno~ine, 5 ~' ,3'-clideoxy-2' ,~r-difllloroaderlosine, ~ncl, e~p~cially azido~hymidine have been c:linically ~rovecl I;o ~how life-prol~nging e~e~t 1n p~tl~nt~ ~uff~r~.n~;t ~rom AIDS~

which is only one d~ug ~pproved for the~apy o~ AIDS
[Elio~heln, Pha~n. 37, 3534-35~7,. ~1988~, an~ others].
~t has ~oeen ~la~ hclt the~e di~es~xynuc..eoside~
~;uppxeæ~ ~he growth of vf.~lls by illhi~i~ing, in ho~t cell~, ~he aatlvi~y of ~v~r6e t~n~r~pta~ O~ H~V.

~d, it has al~o been recogniz~d tha~ they ~!lave the ~ctivit~r o~ inhi~iting the growth of re~roi~ ~ ~rlru~
15 havin~ ~lans~ip~e (~V), lil~e xe~xovlxu~ ~u~h a~
HIV .
With the aim at preparin~ an orall~ a.~rlini~tral~le anti-~IV ~ge~nt, searc:h for an an~iret:rov.ira:'. ag~nt~
f ro~ rbocyclic: nuclevsi.de derivlativ~s ha g J:: een 20 conducted. A~ a re~ult, it h~ eell ~vu~d l.hat ~ax~o~ir~ (lR, 4R ~ - 4 - ( hydro~ylne thyl ) - ~ ~
cyclopenteny1 ~s~uanin~, has the ~c:ti~ity of I nhibiting replicat~on o~ E~IV ~ 3iochem . Biophy~3 ~ Re~ . C'o~nun ., 15Ç, pp.1O4~Y1053, ~19~8~ 1 . Further, ik ha~ been 2~ cla~iied that nucl~o~ide!s havln~ ~~meniber~c cyclic su~ar and car~ocyclic analogs of oxetano~ ~ as well have antiretroviral acti~ity ~d a~ et~olc.vir~l ac~ivity, ~ore ~pecifically, in 2,3-di(hydroxyme~hyl~cyclo~ut~l deriva~ives ~ucl a~ 9- ~ 2, 3-~i~h~d~ox~mothyl)ayolobutyl]adenine~ 9-[~l3 di(h~droxymeth~l)cy~lo~ut;yl~guanine, etc, ~;PA
H2(1ggO)-~4~7) and 3~(h~d~ox~methyl)cyclob7l1:
derivativeg ~uch aB 9-[CiS 3-(hydroxymethyl)cyclobut~l.]a~enine, etc. (J7?P. H2~19~0)-3~ 73072), an~ire~ro~iral aativity and antiret3:0id~1ra~
acti~ity have bee~ ~Qn~i~med.

9~ 5~ 16~36~;TAKEDA PATENTS OSAI~A Fether~ton ; OB3006LiOl;# 5/72 ThP ~id~o~ynucl~aosf-~es d~?scribed a~o~ are, in general, very uns~able again~t acid ~ S~ nLI ,e ~ ~, pp . ~12-415, ( 1~ 3 J, antl their ~herzLpeu~i.c e~c s c~n hardly bs exlpe~k~3d by or~l admini~r~ion. And, whil~
5 AZT is lthe only clrug appxo~Ted a~ anti-AIr~S agent, it ha~ heen known to ~ILO~ serious unde~ le si~e a~ c~s suGh a~ y~3l0~uppre~ L o~ neu~rocy~ope!n~,! L - t~n. the other hLantl~ r~rl~o~ir is s~ agains~ ac~ l and ~an be adlrini~e~ed orall~, b~L~ s ~ntivi:r~l act...lrity is far 10 from ~eillg sati~3facto~ urth~rmore, c~ vir i~ very po~rly 301uble in w~te~ i~nd 1~ i~ hardly ,~]: ~o~l~ed o~al ~c~nini6~xa~10n t~n~imi~robi~l Ayen~ i!n~

~hemotherapy, 33, pp. 171.~175 ~ ( 19~g ) J . Fu:l~tllex, si~c~a 2 ~ 3-di ( hy~iroxylne~hyl ) c:yclobut~rl de~ivativ~. o~ 3-15 (h~roxymethyl)cyclobu~y~l deriva~ives are ~ o ~able against acid, the pos~ik~ y o~ their ora adbninl~ration i~ ~ug~sti~e, but thei~ a~l;'-viral acti~rity i6 nc:t sa~isfac~ory.
P~ying at~ention ~o the po~3ib~ lity ~i. using 21~ ~arbocyc~ ucleoside~ as or~ admini~t~ abl~
anti~rixal e~gsn~ the p~e~e:n~ i mr~nt~r:5 h~ cvnduc~qc~
re~a~c~ wo~k ~ox ~ynthe~izing ~vel car~oc:~clic nucl~oside ~e~iva~ive~. A~ ~ xesul~ he ~:r~ent . in~n~xs ha~e ~ound ~at 4,5-di~h~rox~met:hyl)-2-~y~lopentenyl deri~ati~es a~ l~w ln to~icl~y an~~t~ongly i~hib~t ~he ~rowth D~ r~trovir ~etroi~l~u~
SUM~RY 0~ T~E IN~NTION
The prs~ent i~ve~tio~ relate~ ~o 3~ (1) A ~pound r~p~ented b~ th~ ~OrmUlA
3r~ 2 4~ R' \ C13 ~2 wh2~ein B i~ a puri~e ~e r~idue bon~ed a~ th~ ~-., . ' 91~ 6~ 16~36~;TAREDA PATENTS OSAKA Fethe~t~ ; 06300B601;~ ~72 2 ~ ~ 50~
4 _ position thereo~, or a py:rimidine b~ r6~ .d l~ bon~esd at ~h~ l-po~l~lon ~A~3reo~, ~o ~he cy~;:lc7pent;e l~ rin~;
one of Rl and Ra is a hycl~og~n atom, ~,nd the! ~th6ar i~ a methyl grc~up ha~ing an optionally p~o~ectecl. ;Iyd~ox~rl S group; or a ~al~ ~hereo~, and ( 2 ) ~n an~iviral ~gent containing a com3?ousld c~f ~he .~ormula [ I ] or a ~al~ the:ceo~ .

I:)ETAILE;D ~ESCRIPTION OP THE PREFERt~ DI~N~
q!he fonnula [1~ re~sarlt~ ~he o~tlcall ~ actlv~
~rmula 11 ' ~ B
H t~3~ Z ¦
1 ' ]
1~

wherein 1~ ancl R2 a~e vf ~h~ sa~n~ meanin~ a~
men~ n~ad abo~; or ~he olp~ic*.ll~,ac~ re or:nula B
~I

~S whe:cein ~ nd R2 are o~ ~e sam~a meanincJ a mentloned abo~Y~ r C~~ r~m.ics m~ x~u~ and ~
In l:he ~ompouTI~s ~p:resente~ by ~h~ foY~nula rl] r - ~he confo~a~:Lon betw~en ~h~ }lyd:~oxymt~thyl g ~oup a~ the .
4-~o~i~ion ~ the cyclope.n~ne~ xing and the~ nethyl ~O g~oup havi~g a~ ~ption~lly protocted h~d~o~y l ~u~ a~
the 5~ ltion o~ th~ syclopenten~ rin~ is E ~ef~ably the E-c~n~ox1n~ion.
In the compound~ ~p:reser~ted ~y the o.rnula [1~
tht~ conf o~Sa~iorl between the group ~p~es~nt ~d by B at ~5 l-po~ lon Qf S~h~ cy~lo~entense Lin~ ~nd ~he neth~l g:roup having ~n Qptlonally pro~ec~e~ hydrox.y 1 g~up .
, 2 ~ 73~ V ~24205-911 the 5-position of cyclopentene ring is desirably the E-conformation.
In the compound of the formula [1], desirably B is adenin-9-yl, guanin-9-yl or thymin-l-yl; one of Rl and R2 is a hydrogen atom, and the other is a methyl group having an optionally protected hydroxyl group; provided that, when B is guanin-9-yl, Rl is a methyl group having a protected hydroxyl group and R2 is a hydrogen atom, and, when B is thymin-l-yl, R]~
is a hydrogen atom and R is a methyl group having an optionally protected hydroxyl group.
In the compound of the formula [1], preferably, B is a purine base residue bonded at the 9-position thereof to the cyclopentene ring.
Preferable examples of the purine base residue are adenine and guanine residues, more preferablyr an adenine residue.
Preferable examples of the pyrimidine base residue are thymine, cytosine and uracil residues, more preferably, a thymlne residue.
In the compound represented by the formula [1], the purine base residue or pyrimidine base residue shown by s can form a salt with an acid. Examples of the salt include pharma ceutically acceptable acid addition salts. Examples of the acid include an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid, and an organic acid such as acetic acid, malic acid, citric acid, ascorbic acid, mandelic acid or methanesulfonic acid.

- 5a -2 4 2 ~ r~

The present invention also relates to a process for producing the compounds represented by the formula [1] or salts thereof. The process includes the following methods.
A cyclopentenyladenine derivative represented by the formula [la]

2420!~ , i4 ._ I
H 0~3~ 2 ~ Ra,~ I ~la~

S R'~' whe~ein B~ L~ ~. purina bas~ r~sidue bondecl It th~ 9-pc~ition ~her~of, ~o ~}~e cyclop~3nton~ rin~, one o~
~nd ~4 i8 a hy~xogen aton~, and the o~he~ i~. a me~l~yl ~;~oup h~ving an opt~onall~y p~otect~d h~lrc~3~ ~OUp; o:~
0 ~1: 8~11; the~ pxodua~d by the me'cll~od ~;hich 1~
~h~ra~te~ized ~y xe~in~ ~ ~om~our~d ~3pxE3elented hy ~he ~o~nul~ ~ ~a ~ N H 8 ~3~ 2 41W [~3 wh0~ein one of R3 and R~ ~tand~ ~or ~ hydrot; en atom and th~ o~h~3r ia a me~yl gx~u~ h~v;Ln~ an o};~t;l.clnall~
20 pro~ectod hydroxyl gxoup, or ~ ~al~ ~h~30f' wlth 5 ~mino-~, 6~dih~logenoE;~yr:Lmidln~3, then r~3A~: t.i. ng th~a ul~a~t compound ~*lth ortho~ormic ~:e~r in th~3 pr~ nce o~ ~n ~cld ~o c~u~ ~orm~tlon o:E t; he pu~ine ~k~lo~on, then c:o~va:~ting th~ halogen on ~:h.~ ~u~llle.
25 rin~ n ~nlno s~roup, fGllOW6!C~ when n.~ s~ry, ~ub~o~ting th~3 amino grouE? to a el~proteat.i.c~n react~on, ~ ~y~:lop~an~a~-yl~ . d~arisratl~e xe~l~re6~nt~3d by .
th~ ~ormula ~ lb 3 B

~ [lb~

~' , wh~r~3in B2 i~s A .~urine bas~ ro~ due bc~nd~d e~t the 9-35 . l?o~ltlon ~hareo~ ~o th~s cy~ penten0 r~nS~J one o~ R5' ~nd ~6 i~ a hyclro~n atom ~nd t.h~ oth~x 1~l a 3n~3~hyl ..

group havi~g e~n op~lonLall~r p~ ected hydro~lyl s~roup; o~
a ~:lt ~ 3x~ produ~e~ by ~h~ m~3thod w}llch i~
charac~3ri~d by re~c~ln~ 8 compound r~pr~a~len~ed by the ~rmul~ f 2b ~ N H 3 c whexæin on~ o~ RJ ~nd ~e i~ ~ hydrogen a~o~ Rnd i;he oth~x ~ ~ a me~hyl ~ up h~ving ~n. optl~r~ ,y p~:oto~;i.e,d~
hydrox~l ~roup, or ~ ~alt thereo~ wit:h ~ ino~
dih~logQr~opyrlmldine, th~n aminat ~ ng the c; pO~ ~ tion on lS ~h~ pyrlmid~ne ring, and then reacting the resultant compou~d with ortho~o~mlc e~ ~e~ in the ~r~ e of an aaid ~o aau6~ rmation c~ a }~l3~in~ fikç31eton~ ~ollowad. -by con~rtlng th~3 halogen on the pu~ine r~ g ~o hydroxyl grou~.
20~ cyQlop~nt~nylth~mins d9rl~ v~ rl3p~sen~ed b~
the fo~mul~ ~ lo]
3~
HO~3~

2~ . 4~ 3 whereln B3 i~ 21 pyrimidin~3 ba3e re~ldue bo~ le~ a~ th~
l-po~ ion ~h~.reo~E, to the ~ lc-pentane~ ri.n ~, orle C~f 30 ~7 ~nd X~ a hydrogen atom and ~he o~c]le3: i~ a mq~thy:L gxou~? hA~r~g a~ optionally psot~ d. hydroxyl . groul?; dr ~ ~al~ th6~r~30~ iY pro~ucecl by th~ method which i~ ~h4ralc~ex~ize~ by xea~ .ng a aom~ou rtsp~e~n~ed by ~h~ ~onnul~ [~c]

91~5~ 16~736~;TAI~DA PAT~NTS OSAKA Fether3t~n . 063n06601;#11/72 H H

S ~5 ~ 2 ~ I

wherein X i~ a h~ro~n atom c)r a lo~er alk ~l grQup; Y
ii3 a lower allcoa~y group; on~ o~ R7 and Ra ;L~il a hydrogen 10 a~om anc~ ~he other is ~ methyl g~oup ha~rinsl an op~ionally p~ote~d hy~x~xyl group~ o~ a ~ hereo;E
with ~I b~se~ ~ollowed by~ w~ell ne~:e~ iubj~ ing the p~otecl;ecl group $o dep:rot~ç:tion.
Compounds ~ontaining the above-ment1c)n.sd formul,~e 15 C~a], C~b] ~nd ~Z~ or salt~ ~hereo ~re l?r~duc~d by ~he ~ol1owing reaction. M~e sp~ci~icz~
cyclopentes~ylarnin~ rivat~ v~ rep~3s~an~ y th~3 f o~ 2 ]
NH--Z' H~ J C2 3 ,~ , R~ .

wh~xe~n.Z~ is; a hydro~3n ~tom or an ac~ r~up, on~ ~ -~3 and R4 i~ a hydr~en e~om and th~ oth~ a meth~l ~ou~ havinsT a protect~ h5,t~rox~rl group, e~r a ~alt ther~o~ i8 p~nduced by th6~ m~h~d whl~h i~
30 ch~ract~ri~;~d l~y æu~ t.;~g z~ ~-n~ ic~clo~ 2 . ~ hept-5-~n~3-one ~ riv~ti~e r~resen~ad hy thç~: i50 ~nula t 3 ~

J ~ J ~
9 _ ~ -- --N ~ Z
3~ z 4 ~ C~
S lfi wh~:raLn ~ n acyl ~roupt one o~ nd R ~nd~ ;eO:~
a hy~ gen ,~om and ~h~ o~her.ls ~ me~yl clroup h~vlng a pro~a~ed hyrdroxy1 Çiroup ~ ~ a salt ther~o~ ~o 10 red~lc~ 3 rlng cleavAg~3 rea~til~n, .~ollow~cl by, whan nec~ ry; ~b~as::~ing the reEIction m~ctu;~e to daacyl~tion .
A~ th~s 8~l1t ~nention~ad abov~ UB~ ma:le 0~ the same salt a~ ~h~ ~lt o~ compound ~
lS In tha compound~ o~ the ~ el9 E 1~, 11a ~ ~nd ~lbl, ox ~ ~alt th~r~ao:e~ ex~npl~ o~ th0 p~lrine ba~
re~nid~ he~wn by s, Bl or T32 inalu~ g~o~p~
r~p;r~3nt~d 13y ~h~ ~nula [4,]

~ 1 4 ]
N ~ s .
25 wh~r~1n S~ 3 an amtno ~rQup, halog~n, ~ h~o~l gr~upf Q 18 ~ h~d~o~e~ o.~om~ A;~ O ~r~ r h~lo~n. Wh~n Q and Q in th~ ~o~ulA [~ J i~ halogen, ~h~ halogen ~ nalu~ luorine I chl~lne, ~b~ omln~3 a~
lodinQ.
In ~e~ compounds o~ ~he ~ormula~ [ 1 ] ~ nd t ~a ~5 C~ e thQ py~lmid$n~ ba~ r~3 id~ ~hcl ,m by B o~
B3 inc:lude S7roup~ repre~onted by ~hl3 f'O~ltUllL 1 5 ~a ~X ' .
, ';
.
...

91~ 6~ lB~36~;TA~EDA PATENTS OSAKA Fether~ton ; OB3006601;#13/7~

- 10 - ' . %~r.~ i, wherein Q3 i~ a h~droxyl gr~up or an amino çlr~upî X î~
a h~drogen ~tom, a low~r alkyl group or ~ lower ~lke~l ~roup. When X in th~ fo~ula ~ a lower alkyl g~oup, the l~wsr alkyl group mean~ ~l5 alk~:l group, S exemplified by methyl, e1;hyl, isopropyl, cy~lopropylmethyl, cyc~loprop~lr bu~yl, l~ob~ yl, ~ec-~ut~ te~t-but~l or pem:yl. And, w~e~ ~ a lower alkenyl, th~ alkenyl group me~ns C2~4 al~en~:l group opkionally sub~itu~ed with a halogen ~uch l!~S fiUOXi~h, chlorine, ~romine ~x iodine, a3 ~pec~i~ically exemplifi~d by v~nyl, ~r~ chloro~in~l, c~
chlorovlnyl, tran~~2-b~ovinyl, cis-2-~ m~;~vin~l, 1-propenyl, l-~utenyl 0~ ~ethyl-l-prop~n~l..

The ~u~tltuent~ shown by X in the Gom]j~ound~
repres~nted ~y ~he for~u~.a [2c] are ~he ~aml l ~8 tho~Q
~hown by X in th~ comp~und~ xe~ee~ntod b~ l:h~ g~n~ral $ormula 15~. Further, i~ the qen~ral forrhu:.a r~c3, exampl~3s o~ the lower all;oxy group ~hown ~y Y include 20 me~hoxy~ ethoxyr pr~poxyr bu~oxy, sec-bu~o~, tert~
}:u~oxy or cl 5 alko~r group~ optlonall~ ~ub~;l;itu~e~ wi~h a phenyl group ~uah a~ b~nzyl ~xy .
~ e amino group of t:he purin2 base res.ldue o~ ~he pyr~midi~e ba~e residue of the ~oxmula~ and ~5~ may ~p~ion~lly ~e pro~ected. Exampl~ o~ ~he p;lotective group Lnclu~e ~ho~ ~or pu~ino-ty~e ba~e o:r ~rimidin~-type base in the chemi~try o nucleic aaid, mor~
speaifically alk~l-t~pe p~ot~ctive group~ 2lk~1-type p~otective ~oups, ~llyl-t~p~ protective gri;lup~ an~
3~ ac~l-t~pe protective group~.
~ xampl~ f th~ alky~-typ~ prot~ti~ ~u~

include C~ low~r alkyl group~; ~ri- ub~ ed ~ilyl groups ~ubJ3~ute~ with e.g. Cl s lower alky]. ~xoup~ or ~enzyl g~oup; and tetrahydropyranyl g~oup. ~vre ~p~ci~lcally~ methyl~ et~ propyl~ is~pr~ yl~ bu~yl~

sec-butyl, ter~but~ 6!ntyl: t~imethyl~ ,l, t.ert- .

91~ 16~6~;TAKEDA PATENTS OSAKA Fether3ton ; 063~0~601j~14~2 butyldime~hylsil~l~ tetr~lhyclx~pyran~l, t~trahydro~ur~nyl, etcO are mentione~.
Aæ the aralkyl-t~pe pLo~ec~i~e groUpS r use is advanta~eougly made o~, ~or examplet b~nzyl group o~
5 triphenylmethyl group opt:Lonally subs~itu~e~l with h~logen, Cl_5 l~wer ~lkoxy groups an~ nitro- ~pe~i~ic e~amples o~ ~he~ include benzyl, ~iphenylme~lhy~, triphenyl~e~hyl, p-methw~yphenyldiphenylm~t]lyl, p-ni~robenzyl, ~nd p-chlorobenzyl~
Exa~ple~ of the allyl-type protective ~;lroups includra phen~l ~roups such a~ phenyl, p-m~ ox~phenyl and p-c,hl~xophen~l9 ~ptic~nally ~u~stitu~ iri~h ~logen or Cl5 lower alkoxy g~uE~
As a Schiff base-~ype prot~ctive grou;p, ~se i~
1~ made o~, fo~ ~xample, di~eth~lamino group~ ,!lUGh as methylidene, ~,N-di.me~hyla~i~ome~h~liden~ nzylidene~
e~hylidene, pxopylidene~ b~tyll~e.n~ an~ nl;yll~e~
~nd Cl5 lowo~ ~lkylidene groups optlo~all~ l!ubstituted with ph~n~l group.
~0 A~ the acyl-typ~ p~otective group6, t.~ se in the prote~ive gr~up~ ~o~ hyclroxyl group of the hydro~ym~thyl gr~p to b~ d~3saribed her~ina l't~r ~an he ~imilarly employed.
And, the hydroxyl gr~up on the ~urine ~i~a~e ~e~idu~
or pyrimirline ~ase re~idue shc~wn.b~ the ~on;lula~ ~4]
and C5] may alj~ vpti~ lr ~e protected. .IL~ th~
protective grou~ Q~ hydro~l grou~, u~e is ~imil~rly ma~ o~ ether-~ype or acyl~type prote~tiv~ roup~ for hydroxyl group o~ hydro~ym~thyl ~roup to he de cribed hereinafter.
. In ~h~ ~oxmula~ [l]~ ~l~J~ llb~ [l~], t~ aJr [2b;1, E2c~ ancl ~3Jr when the hyàrv~yl gro~p at the methyl group, havin~ an optionall~ pxote~t~d hy~ro~yl yroup, ~hown b~ Rl, R2~ R3, R4 R5 ~6 R7 R~ ~3~ R4 ~5 kS ~ R6 / R7 ~r R6 i~ p;~vte~ct~d~ exQmple~ w~ the~
pr~te~tive gr~up o~ the hydroxyl ~roup incl~,lde 91~ 5~ 16~36~,TA~EDA PATENTS OSAKA Fethsrst~n . 063006601;#15/72 ~ ``J.

prot~ctive groups u~ed a~ those the hydroxy:l. g~oup in the ~i~ald c~f su~ar an~ n-lcleic ac;Ld che~misC:Iy~ ~ah as et~er-typQ protective glrs)ups an~ acyl-type v ne~;, when r~ece$~ary, aaet~l-t3!pe ones, ketal-~ypo onel: and 5 ~rtheester-type one~.
Examples of ether-t~Fpe prot~ti~r~ groul.~6 inalude Cl 5 lower alkyl g~oup~ op~ionally 3iub~ u~ed with halogen, C~.5 lower al~c~xy gxollp, ~enzyloxy t'roup or phenyl grou~; C2 4 lower a.lkenyl group~; tX:i~ stib8tituted 10 ~ilyl groups he.ving, as t:he ~ub~ti~u~nt~, Cl 5 lower alkyl ~roups, phenyl group, ~e~yl group, el;ç.; ~enzyl S~roup optionally s~l~stitu~ed with Cl 5 lowex a1lco~y gro~ps or nitro gxoup; Cl 5 lower alkox~ grot~p~;; and tetrahydropyranyl group optionally ~ub~titul;ed wit~.t 15 haloyen, ~ xampl~ o ~he abov~-mentioned halo~ell~ includ~3 ~luori3rlet ~hlorine, bromLne and iodine, examples o~ the Cl~9 alkyl groups include m~thyl, ~h~l, prv~
iso~xopyl, butyl, isobukyl. se~-but~l, tert butyl, pentyl~ i~opentyl and ne~pent~ nd exampl~5 of the Cl5 alkoxy ~roup~ include methoxy optional~
substituted wi~h halo~enr ethoxy, propoxy, ;l~utoxy, vinylo~ ~nd allyloxy. ~d, in th~ prote~..ve gxoup~
of the abovo-~en~ioned amino group, a~ 5 ~! lkyl ~roup, C~s al~ox~ group and halogen, ~se i~ ma~e o~! ~ho~e e~emplified a~ ether-type pro~ective group~ of the hydroxyl g~oup~
Mor~ spe~ific example~ o~ ~he e~he~ e protec~ive groups of hydxoxyl group inc~u~e m~hyl, m~thoxym~thyl, benzyloxy~ethyl/ tert-~utox~lethyl, ~-methoxyetho~methyl, 2 r 2,~~t~chlorometho~ ethyl, 1-eth~xyethyl, l-m~thyl-l~m~th~xye~hyl, ~,2,2 txichloroethyl, propyl, i.sop~opyl, butyl, i.! ~o~utyl, s~c-butyl, ~e~t~butyl, e1:ho~ethyl, ~riphe!nylm~hyl, p-~etho~yph~nyldiphenylmethyli ~rim~thyl~ilyl te~t-bu~yl~l~ethyl~ er~-bu~yldlphenyl 811~ ,3,3 91~ 16~5~;TAI~EDA PATENTS OSA~A Fether3t~n ; 083006~01;#16/~2 7, ~ i.; V
- 13 ~

tetraisopxopyl-l, 3-di~iloxane-dl-yl; ~en2~.1, p-m~hoxy}~enzyl, p-nit~oben2yl, p~chlorobenz y;l;
tetrah~opyra~yl, 4-me~h4x~etr2lh~clLopyr~x~; l, te~trahydrofu~nyl, e~c~
Examplea o~ the acyl-t~pe prote~tive g:l oups in~lude CL 5 alkanoyl grou.~ option~ sub~J.~uted with halo~n, Cl 5 lower alkoxy ~Txoup or pheno~y cl roup op~ionally ha~ring haloçlen; ben20~1 group Op1l.ionally sub~titu~ed. with nitro gXGup, phenyl ~roupt Cl 5 low2r 10 alk~l group optionally .;ubstituted with halogen benzoyl group optionally sub~ituted wi~h C ! .6 lower alkyloa~y~*.xbonyl group7 Ca 6 alkylo~ycarl~on~]; s~oup optionally Ru~stituted ~,41th halo~en; C3 5 alken~,rloxycar~onyl grou~, ~en~yloxycarho~yl 6~rouP
15 optionally suk~stituted with Cl_5 lowex alkoxy group O~
nitro group; and phenoxyc:arbonyl g~oup su~sl.i~u~ed with nitro grou~.
As the abov~s-me~ntio~led h~logen~ Cl 5 1~1er alkyl gx:oup~, C~ 5 low~r alkoxy groups and C2~ alkenyl g~PUl;~8, use i~ mad~ o~ thos~ ~xeMpllfl~d :Ln ~he cas/i~ o~ t~e ether-type protective gr~up~.
More ~pecific example~ ~ the acyl-typ~:~ p~o~tive gr~up i~cl~o ~o~myl, acetyl, ~hloxoacet~l, dichloroacet~l, trichlorvac~tyl, t~i~luoroa~:~ yl, m~thoxyace~yl, kri~heny].m~thoxyacetyl/ phe.nl:~xyac~yl, p-chloropheno~yacetyl, pr.opionyl, i~opro~iol~yl, 3~
ph~n~lpropionyl, i~obutyl~l, pivaloyl; ben.z~;~yl, p-nitrobenzoyl, o-(methoxyc~r~on~l)benzoyl;
methox~carbonyl, ethoxyc~rbonyl, t~rt-bu~o~ carbonyl, ~t4,~-~ri~hloroethoxYc~rb~n~ on~utylylo:!;yc~xbonyl;
~enzyloxy~arbon~l, p-met}lvxybsnzyloxycarbon~;yl r 3 t 4 dimethoxybenzylo~yc~rh~nyl~ p-nitro~en ylo;K~ rb~nyl~
p-nitrophono$~car~onyl, etc.
~nd, ~ ~a~tal-~ype, ke~al-type and o;rl;ho~ter-type px~tectiv~ groupsr u~e i~ advantag~ou.~.:.y ma~e oftho~ h~ y 1 t~ 10 cQrbon ~tom~ whi~h ~r.!~

6~ 36~;TA~EDA P~TENTS OSAKA Fetherston ; 063006601;#17J72 r r ~ ~, .3 ~ 14 -speci~ically ex~?mpli~ie~ by m~thylen~e, l-~:elrt-butylethyliden~ phenyl~3~hylid~n~, 2, 2, ~
~i chloroeth~rlidene; i sopropylidene "3uty.~i. den~, c~yol~h~p~yli~n~ oynloh~ylid~n~, cyclbp~rltyll~ene, p~
5 methoxybenzylide~e, 2, 4-dilne~ho~:ybellzy~ c~rle, 3, 5-~imeth~yb~n~lidene, p-dim~thyl~minobenzylid~ne t -nit~ob~nzylid6ar~e; metho~ymeth~len~3, etho:~yn etl~ylene, din~3thox~n6~thyl~3ne ~ 1 -methoxyethyliden~
dime~hoxy~ thylidene, e~ .
St~nnoxane-type prote?c~iv6! groups ~u~l a~
dibutyls~annyl or tributyls~annyl, cyclic c a~b~nate type pr~tec~i~re groups and c~ cllc: ~orona~e type prot~ativ~ grou~ c~n al~o ~ ~imilarly u~eld ~ep~nding on kindx of those c: ompound~ .
lS In these prot~act~ ve groups o~ the h~l~ oxyl gr'oup, ~he kin~ls ~ protecti~ groups oi~ ~wo hyd.rc xyl groups ~nay be the ~ne or ~iff~ront. A~l~, like ~ tha ~:A3e ~uc:h p;rote!c!tive gr~o~lp~ a~ , 3 r 3-~etraiso~ ~pyl-l, 3-~isilo~an~?di~rl, cyc~ic ace~ ype ~n~ cyc3.i::: ketal-2 O 'c~?e, two hy~roxyl groups may be p~o~ec:tecl with on~
pro~ec:~ve gr~upA
Xn thq~ c~npound of th4 ~ons~ula ~ ydroxyl g~oups of ~he hydroxymethyl ~roll~? shown l: y Rl a~d Fl~ o~
R may b~ phosph~d. A.s ~he p~ospha~e r~ idue in ~h~t 25 ~ase, mention is made /~f ~L group r~presenl:~ld by the oxmula ~ ~1 ~ R
30 . tll ~
wher~ n denote~; an in~ge~ o~ 1 to 3, R s~nd~ ~or a hydrogen atom ~r a 1-14 C: hyclro~a~cbon ~e~; ;.cl ue, or a gI~oup ~o~n~ b~ combination o~ hydroxyl g rc, up~ a~
3S hyd~o~sy;nethyl gro~p~ of ~ and E~ or ~, whic!h i~
represen~e~ by ~he :~ormula C6 9.

91~11,9 6~ lB~36~;TAKE~A PATENTS OSAKA Feth~r~ton , 063006601;#18/72 .3 ~

l ' ~ R 7 ~ ~3 wherein ~7 is o~ the ~ame meanin~ as d~iEin~!~ above~
5 ~x~nple~ ~f h~droca:~on residuee sl~.ow~ by ~ 7 include C 1-5 lo~qer alkyl group~ ~uch a~3 methyl, el~h.~ L, propy~l, isopropyl, ~utyl, iso~u~yl, ~cn~u~yl, te:rt:-but~rl or pentyl, ar~lk~l groups ~uch as 13~n~1, p-m6l thox~rbenzyl, p-m~3~h~1ben~yl, etc. "phenyl ~roup, ~ ~.
~s ~he acyL grollp ~hown by Z in the ~clmpound r~pr~sen~3d b~r the f ormula [ 3 ~, and , as t~ acyl ~roup ~n .the ca~e wher~ Z' in ~he c~mp~un~ x~pr~;ont~d b~
general fOI~nUla ~ cyl yroup, uæe ls ~ e of 2-6C

alkyloxycarb~nyl group~ or caxhaunoyl s~roup ~tlonally 15 substi~uted with a 2-~C alkellvyl ~.~oup op-t;i.~nally ~u~tituted wi~h a Cl 5 low~r alkoxy group..
9pec:if ic: ea;~mple~ o~ ~h~ c~cyl grou~ 3,u~
methc~xycar~vnyl, ethoxyca~on~l, t~art-bu~a: yc~ onyl S
~arbamoyl, N- ( 3-methoxyacryloyl ) c~xba~no~l, N ( 3-20 m~3~hoxy-methylacryloyl)ca~bamo~l, N-~3 -~IthCI~y- 2-vinylac~ylvy~ ) ca~a~o~rl, ra- ~ 3-me~hoxy- Z-~o~l~yl)a~I~ylo~Jcaxbamoyl, ~t~.

In ~he com~o~nd ~eprf~sent~d by thg~ fc~I ~ula ~ 2~ l ~example~s of ~he lower ~lkoxy group ~how~ k~ include ~S ~1-5 alkoxy ~oup~ optionall~ su~sti~uted ~ h phonyl yroup, such as m~3~hoxy, ethoxy, propc~xyr ~ t~r butoxy, ~ec-butoxy or benzylox~ ~oU~, O~

Sp6aci ~i~ examples o~ th~s comp~un~ ~el;~r_sen~ec~ by the ~ormula [ 1 ] ~e ~ ~0710~8 . ( 1 ) ( ~ ~ -9- [ 4~S, S~L-d.i ( hydroæym~ yclope~t; ~2~3n~
ade~s~in~
( 2 ) ( ~ - 9 - t 4~, S~-d.i ( hydroxyme~h~l ) cyclopent - ~-e;~ yl ]
a~e~ e ~3) ()~ s~-ben~:yloxym~hyl-4~ hydroxy3llelthyl3 cyclop~nt-2~ yl~G~enin~

( 4 ~ ( + ~ t S~;-ben2~10xym ~ 4~- (.hydroxy~ thyl 3 .. . . .

91~ 5~ 16~36~;TA~EDA PATENTS OSAI~A Feth~rst~n ; 06300~601;#19/~2 's~ $

~clopent~en~ yl]aden.ine (5) (~)-9-[(lS,4R,5S)-5~ben~10xy~ethyl~4-(hyd~ex~ethyl~cyclopent-2-en~ l]~deni~e (6) ~ [(lS,4R,5~)-5-~enzylc~yme~hyl-4-~hy~o~methyl)cyclopent-~-en~1-yl~3denine (7) (~)-9-~(lS,4~,5S)-4/5-di(hydrox~methyl)cy~lopent-2~
en~ l]adenine (8) (~ C(1R,4S.5R)-~,5-di(hy~oxym~thyl)tyclopen~
e~ L~adenine (9) (~)-9-[4~,$~-di(hydrclxy~ethyl~cy~lopa~t-2-en-1~-yl~adenin~
tlO) ~~)-9~~4,~f5,1~-di(h~dr~xyme~thyl~c:ycls:~pen1;~-2-en l,B-yl ] adenillQ
t'll) (~)-9-~5,1~enzyloxymethyl~4,13-(h~droxyme~hyl)~yclopen~-2-~n~ yl]~uanin~
(12) (~)-9-[~-benæy10xymeth~
thydro~ym~hy1)aya1Op~nt~2-on-1~-y1]g~ninl~
(13) (~ 4~,5a-di~hydroxymeth~ yaL~penl~ -en-1~-y1]guanine (14) (i)-9~ 5~-di(hydrox~methyl)cyclope~ 2-~n y1]~uan1ne ( 15 ) ( + ) -~1 4B,5~-di(hydroxy~ethyl)c~clopenl: 2-en~
y1~uanine 9-[4~5~-di(~ydI~o~me~hyl~c~ pe~l-2-e~
~5 ~1~guanine ~17~ 9-t4~5~-di(h~dro~ym~thyl~y~
y1~uanine (10~ 9-[~,5~-di(hydroxymethy1)~ya10p~nl,.-~-en-1~-ylJ~uanine ~19~ 9-[5a-benzy10xyn~eth~1-4~-(hydroxymethy1)cyc10p~nt-2-en-1~ yll-6-ch10:lopurine (20) (~)-g-[5~-benzy10xy~ethy1-4~-(hyd~ox~me~hyl)cyclopa~t~2-en-l,B-yl3-6-chlo:lop~rine t 21 ~ ( + ) -1- [ 5c~-benzy10~cy~ethy1_4 3 5 ( hyclro~m~thyl ) ayo l~en~ n- 1 ,B-yl ~ - 5 -meth~
Z, 4 1 lH, 3~J ~py~imidinedione 91~ 3B~;TAK~DA PATENTS OSAKA Feth~r~ton ; 0~300B601;#20/~2 ~ 17 --(22) ~ r 4p,5~-di(h~droxymethyl)cyclopent: ~-en~
yl~ meth~1-2,4~1H,3~3-py~imi~lnedion~
~23~ ~+)~ 4~,$~-di(hy~roxymethyl~yclope~ en~
yll-5-me~hyl-2,4[lH,3H~ pyrimidinedione (24) (~ 40,5a-di(hyd~ox~methyl~yclopen~2-e ylj-5-me~hyl-~,4[1H,3HJ-~y~imidinedio~e t25) t~ 4~ 5c~di(h~d~ox~tlethyl)cyc:lopellt~ n~
yl]-2,4[1H,3H]-pyrimidine.~ione ~26) ~+)~ 4~,$a~dl(hydrox~methyl)cy~10p~ 2-enwl~-yl]-2,4~1H,3H]-pyximidine~ione ~2~ 4~,5~-di~hydroxyme~h~l)cycl~pen1~ en-1~-yl ~ 4 1 lH ~ 3H ] -py~i~nidln~1~ion~
t28) (i)-4-amino-l-~4~5~ i(h~ roxymethyl)(;yclopent en l~yl~-[lH~-pyrimi~in~!

1~ (2~) (+)-4~am~ [4~,5~ i(hy~rox~me~hyl)cy~lopent-2-~n~l~-y~ ]-pyrimidine ~30) (-)-4-~mino~ 4~,5~,-dl(hydroxym~hyl~yclop~nt -yl]-2[lHI-pyrimi~i~e D~scr~ption i~ ~iven a~ follows ~ to 1he metho~

~ p~odu~in~ the ~ompound ~presellt~d by tl~. formula ~1] or a ~alt th~rao~.
At ir~t, a co~pound of ~he formula [~ n which ~ i~ a purine ba~e ~es~du2, i.e. a co~pound r0prese~ted by the ~xmula ~la~, or ~ salt thereof can ~:e ~ynthes~zed by, for exampl~, ~h~ ~ollowin~ nethod ~arting f~ a aompound o~ th~ ~nmula r 2~

Namel~ ~ compound rep~e~ented ~y ~h~ loxmula [7a]

91~ 6~ 16~36~;TAr~EDA PATzNTS OSAE~A Fether~ton i 06~00660~ 2 Qi H2N~N

NH
HO~ [7a]

10 whe~ein R3 ~n~ R4 are of ~he ~ame maani~g aL men~ione~
~bo~; and Q4 i~ halog~n ~uch as ~luori~ r ~, hlorin~, ~7romine or iodine, can ha p~od~ce~ by :roac:t.inS~ a c~clopen~anylamina d~rivativ~ r~pres~n~e~ hy ~-h~
~ormula ~ 2a ~ with S~amino-4, 6-dihalo~e~o~y~ idine ~uch 15 as 5-amino-4~6-diahlorop~yrimidin~, 5-aminc~-~,6-dibr~omo~yr~mi;line, 5-ami~.lo-4, 6-diiodopyximllline ox ~-~ml~o-4-fluo~v~6-chlo~op~rimldine in th~ p~ enc~ ~ u ba~e.
5~Amino-4,6-dih~logenop~rimidin~ ~o be reac~ed ~0 with a cy~lop~ntenyl~min~ d~rivativ~ ~epr~ nted by the fo~mula ~2a~ i~ used a~ uivalen~ or mor~, u~uall~
l o S ko 5 ~3~ui~ valq~lnt~ ~ ~elati~ro ~o [ 2a ] .. A~3 th~ ba~ to be employed for tho reac~ion~ m~ntlon i~ mall~ o~ an ~r~anic base ~uch as py~;idine, t~ie~hy~a~.nl3, ~,N-25 dimethylaminopyridin~, 1,8-diazabi~yclo~5~4,0]-7 und~cene~ etc. and ~n lnorganlc ~a~ ~uch a,l so~ium hy~xide, po~as~ium hy~oxl~e~ so~ium ~ar.bl~n~
po~a~lum car~on~te, sod:ium hydrogen~ar~o~ e, etc., and, pr~f~r~bly, an organLc bas~ su¢h ~ kr.!ethyl~mine 30 ~nd N,N-dimeth~l~minop~ridine ~he rea~tic~ aondua~cl ~leuall~ in a ;c:llv~n~, and examples of pr~ra~;Le ~olv~t~ inclucl~ water, alcohol~ (e.g. methanol, ethanol, propanol, butanol, etc.), acetonitrile, N,N--dime~hyl~o~mamid~
3S dim~thyl~sul~c~ide, ~n~ ethe~ .g~ dic~x~rle, ~etrah~d~ofuran, ~tc.~. While the ~eaction tQmp~ra~r~

91~ 5~ 16~36~jTAKE~A PATENTS OSAKA Fetherston ; 063006601;#22/72 -- i9 --varies wikh the kinds o~ compound~ repre~e!:nl ecl by the :formul~L [ 2a], 5-amino-4, 6-dihalo~eIIopyximi.~ .ne and bas~s employed fo;~ th~ r~!action, i~ u~u~lly ~ange~ ~rom rooln temper~ture ~o about: 200C. ~hen it il~ nec~ary 5 t~ Con~ua~ the reac~ion e~t tempe~atu~es hi.~ r than ~he boiling point of the sc~lvent, th~ r~aac~ion :l~y be condu~t~d in a sieaLed ~ube. Whil~ ~h~ reacl:ion ~ime ~lso v~e9 with the kinds oi~ reagent~ empl~;~yed OI`
~e~c~ion temp~rature6, i1: ran~es ~rom ~OUIt 1 hour to l ~ about 4 days .
~ hen/ a c~clopentenyl~?urine derivatlv~ apresented by th~ ~ormula [ 8a ] ~2 ~

~N$
H ~ a~

~0 R'' wh~;~ein R3, R4 and Qq ~r~ o the ~nme m~nin~ :1 no~
~bc:ve, can bc2 produ~ecl ~y ;~e~ct.~n~ ~ comp~u~
represented by the ~onnula ~7a] wi~h c~::tho~unni~ es~e~
su~h as met~l or~ho~ormate, ethyl ortho;~or.~la~e ur ~5 butyl or~ho~o:~mate in ~h6~ pr~:sen~e c~f an ac.:.d.
While orth~or~i~ e;~ i~ u~ed ~ n la n)l~ of or e e~ulvalellt ar more relat; ve to ~he com~ound represent~d by the ~o~mula ~7a~ is usl~ally u~e~ in ,!l large exce~ volume ~o be al00 used ag ~he reacti~ )n solven~.
3~ Examples o~ ~he acid to ~e em};)loyed ~or the reaction in~:lud~ in~rg~nic: ac~icls2 s~u::h a~ pho~phc:ric! ,!Lc~d~
hydroc:hlc~ric acid, hyd~obromic ac:id zlnd ~ u~ic acid, or organic sul~o~i~ a~id~ ~uch as benzen~u:.fonic ~cid, p-tc: luene~ul~oni.c acid, methanesul~oni~ a~ l and 35 txi~luoxom~3t;han~ul~0nic aci~. Th~ id~ ar~ used u~u~lly in an amount of 0.01 to 0.2 e~ui~ nt rel~
~.

9~ 6~ 16~36~;TAKEDA PATENTS OSAKA Fether3t~n ; 063006601;#23/72 20 -- , ~o the compound represellt~d by ~he formula 1~ ia~
the ~ea~tlon ~lve!nt, th~ ortho~ t~ ?loy~d for ~he r~3as~tlon is used al~o as the æol~nt" ~ut, when necessa~y, by taking the ~:olu~ y of ~h~s c~:mpoux~d 5 repr63 sented by the ~or~ la. [ 7a ~ ~ n orthv;fc~rm i o ~e~
into con~ideration, a solv~nt such as al~oho:l s e . g .
meth~nol ox ethanol, eth~ . ç~ at.r~ahydro:El; x~n, dioxane ~ or ethy le~her, and ~, N-dimethylf o:~lni! mide ~ The reacti~n tempe~ature rang~ fr~m 0C ~o lOO~t:, usually 10 from 10C to 50C~ While the reaction tin~e ~; arie~ with ~he kln~s o~ r~agent~ u5~d and ~ tion te~CIX~tu~
th~ emplo~,red, i~ usually ran~e~ xom a};~out ~: ne hvur to about 24 hour~.
Fur~he~, a cyclopentenyla~enine de~ivat:i.v~
15 repr~sent~ by ~h~ formula ~la~ can b~ p~od~ e~ ~y allowing ~ çc)mpound shown by ~ ko r~ac~ w:l.th ammoni~
to th~re;l;~y subs~ituking tha halo~ell in ~he pl..rine pnrtivn of ~a~ with an a~ino group, foll~ec. by, when nece~ary, removing the pr~ot6~cti~a ~roup o~ ~.he 2 0 hydroxyl group in tht~ methyl g~c7~p h~ing ~ ]"rote~3ted hydroxyl group ~ho~n by R3 ox ~4.
The reac~ion ~or ~u10~ ut~ns the halog~i~n on the purine ri~ç~ is conducted }:~y allowing ~. lax~e exce volum~ a~nonia ~o r~ct; u~u~ r in a pol~;l sol~ren~
~5 includin~ watRr ~ncl ~ c7hol~ ~3u~:h tA~ meth~no::. ar~d qthanol. The reac:tion ~empexature rang~3~ u.s~ lly from room temperature to l~O~Ct and ~he reaction ;i.
preferably ~on~ucted in a ~e~led tube ~or avclidin~
e~r~poration of ~mrnollla. ~hil~ ~he ra~ction I,ime tr~rie~
30 with th~3 ~eaa~lon t~3mperat;u~ usually ~.arlg~e! from. 5 hou~ tc> ~bout 50 hours.
A compound o~ t~ fo3~nula [lJ, ~her~in ~

purine base ~e~id~ae, i . e . a ao~pound ~hown ~ the purine ~ormula ~ lh~, can b~ synthe~lzed ~y, ;I o~

35 example, the ~ollowing proce~æ, ~arting flo~l a compound ~hown b~ the ~ormu~a ~ 2b 1 or a ~al t t:hereo~ .

gl~ 5~ 16~36~;TAKEDA PATENTS OSAKA Fetherq~on ; 063006601;#24/72 ~ amel~, by allowing a ~ycl~pentenylam.il.e cl~3rl~rative xepre~;en~ed })y the fox~ 2bJ ~r a sal~
tllereo~ tc~ ~ea~t wi~h a ~-amino-4 ~ ~-dih~lG~nop~imld~ ~ 6~ah a~ 2-~m~ 4 dichloropyrimicline, 2-~ni no-4, ~-dibro~nopyri~ lidin~
amino-4 ~ 6-dii~dc~pyrimidirLe or 2-am3.n,o~~1 uoro-~-chloropyrimidine in th~ pre~;nC~ of ~i ba~, a com~?ound ~ obtained represented b~ the ~ormula ~ 7b~

~N

N~I~N~a H 0-~ [ 7 bl whe::~in R5 and R5 ar~ of th~ same meaning clæ defin0d a3~ove; an~ ~4 i~3 halogen su~ a~ l luo:rin~ c,hloI~ine, ~0 bromine and iodine . The r~action of ~he cox Ipound of the formula [2a] or ~ ~}~ ~h~i3r~0f wi~ ino-4,6-~ h~alog~nt~py~ mldines ~ ~ 8~1t th~ eol~ 1~ aonductad under c:ondi~ions simil~ to tho~ 3 th~ z~f~:~re-described reac~ion between t~ c~mpoun~ he f ormula 2~ ~ 2a ~ or ~ salt thereof and S-amino-4, 6-~ih~loQIe~ ?py~imicline or ~1 ~al~ t~rec)~.
~hon~ a~t~r aunin~it~n o~ ~ho 5 poei~ on the pyr~midine ring, orthofo~.~nic est~3r ~uqh a~ hyl orthof o:l:mate~, e~h~l or~ho~ormat~ or butyl o . thoo~mate 30 is rea~t6a~ in kha pr~nce o~ an a~;ld to p~.)du~ a a~alopenten~l~uri~e d~riva~ive re~r~nt~d :l~y tl~

~ormula ~ ~b ]

91i~11,q 5~ l6~q36s~;TAK~A PATENTS OSAKA Feth~r~tcn ; 063006601;#~.5/7~

2 ~
.

~N
~ Nl~J H 2 R~
10 whe~ein R5/ R6 and Q are ~;f the same meaning a~ d~in~d abo~a, or a sal~ thareo~
The ml n~tlon o the 5-po~L~ion on l--h~ ml~lne rinS3 i~ conduct~d by allowing a coml?ound r~)r~sent~cl by th~ ~onnula ~ 71~ ] or a sa~ hereof to reac ~ wi~h a lS ~iazon~ wQ sal~ such as b~nzene dia20nium ch;:.o:ride or p-chloxobenzen~ d~azoniuln chlorlde to th~ e~ caus~
RZOt~ZQtion O:e the 5-po~itios~ on the pyrim~i~;,i~e~ xLng, followed by a }2~ s~a kno~m p~ocesl3, i.~3. hy~;.ro~enolysig b~ ~he use o~ e.~. zinc-cl~et1c ac:id~ ~he ~!,action o~
~0 all~win~ i~. pur~.ne ~keletc)n to be ;Eorm~d by ,.he reac~ion o~ ortho~or~lc ester ls :~ndu~te~ un~e~ con~.ltion~
61mlla~ to ~hoso ~or th~ r~a~tion bQtw~aæn tl.E~ o~cl oi~ the ~o~mula [8a] or a salt ther~o~ and ~:lthofo~
acicl descri~ed above.
~5 Further, a cyclop~ntenylguanlne de~ 3 3hown by t~ nulA rlb~ or R ~al~ ~hor~o~ prodused l~y ~ ~er se known proce3~ which s:ompr~es a;l lowing a compoun~ represent~d by t:he ~o;rmula ~b3 or a 5~l~
~hexeof ~o re~ wl~h ~ b~se ~u~h a~ sodiwn h~xoxide 30 or pot~ss:Lum ~droxide ~o th~r~by convç~ he h~ gen on the puxlne x~in~ t~ hyflroxyl ~r~
A compound r~pre~ent,~d by ~he ~ormula 1 1~ whe~oin B i~ a py~ ln~ ba~o r~!~idue, i.e., th~ coIIpound ~hown ~y ~he f ormula ~ 1c 1, or ~ ~alt ~hereoi~ can 1; 13 3S ~ynth~ by, for e,x~ 3, ~114w~ng a c~Q;n}, ~llnd ~:hao~
~ th~ general ~ormula [ ~c ] or a s~ he~c ~ to r~ct ... .

.(~,., 91~ 6~ 16~3~;TA~E~A PATENTS OSAI~A Fetn~rston i C63006601;~87 ~ 23 -with a ~a~e, followed by, wklen neces~ary, r elnoving khe protective grc~up o~ the h~ydroxyl g:roup ~ron;~ ;he me~hyl ~rouE;~ ha~ring prote~d h~roxyl Ç1~0Up ~hown :~y ~7 or R~. B~so~ to be used for ~he ~ea~tion incluc.e 5 inorg~nic l~a~e~ suc:h as almnoni~, ~odi~n h~rax~d~, pota~ium hydro~i~e, ~odium carhonate, po~e~ ~ium ~a~bonate alldl so~ium hydro~en~arbon~te, ~ncl ,~ganlc basc~ ch ~8 pyridine and t~iekh~lamin~, p~ ~f era~ly ~e~k l:~a~e~ . u~h aæ ammoni~ and pyr~dine . Th,3 ~eactian l5 u~ually ~onduc~ed in a sol~ren~, e, ~. wa1:e ~, alcohols such a~ m~athanol, e~anol r propanol or but~nal, and dimethy~rormamlde, c~ a mlx~ure Or ~ees~3 pola~ .
~olvenl;~. While the reaction tempe~ture va :ie~ with th~ kind~ of ba~e~ then used, it usually ran J~ rom 15 ~oom temperAtur~ ~o l50~C. Wh~n ammonium i8 employsd a~ the base~ preferable to con~uC~ th.e r~action in A :gseelled tu~e) to pre~ent eYapo;~a~ion o~ a:nsnos~ a .
While the reac:tic:~ tilna ~r~rie~ wit.h the kind 3 O:e base6 and reaction temp~3ra~ure then employed, it x ~nge~
20 usually ~rom S hour~ to about S0 hour~.
Compound~ repr~senteCI by th~ ~ormula 121t ~naluding khos;o ~hown ~y :~orm~la~ [ 2a ~ ] and ~ 2c ]
o~ ~alts thereo~, are iln~o~tant intermediat;e ~ or ~thes~zins~ a cc~mpound repre~en~d ~y ~he for~ula ~5 ~l~or a ~lt ther~o~, and these co3cnpound~ ca:~ be ~y~t~e~aed by~ ~or ~x~mple~ a m~thod d~ ~d bolow.

~aniely, a cyclo~ente?nYlamine der~ v~tl~re ~hv~ l by the ~ormula ~2a~ or C2b] or ~ sal~ ~hexeo~ b~r ~3u:~je~tin~ a compound shown b~ ~he ~ormula ~ 3 J ~x a ~alt ;here~f t~

3~ reduc~ rlng-openlng reaction, ~ollowe~l L~y deac~ylati~n . ~h~ ~ ~educ:t.iv~ ring-op0ning ~e I ::kicln ca be conciuated by using a metal boroh~drida ~3u~h a~
~ hium borohydridç, goclium ~orohy~ridç ~ p~ta~
borohydride, ~ Inetal cyanobors~hydride ~ oh a 3 sodiun~
~yano~orohydrLd~ o~ po~a~ium ~yano~orohy~a:i,i~, ~r a metal trialkyl borohydrlde ~u~h a~ hium t~ieth~l 91~36~;TAI~EDA PATENTS OSAKA F~therst~n ; Q63006a01;#27~72 J (~

.

bc~rohydride, pre~erably ~;odiu~ borohydri~. As th~
re~tion ~olvent, u~;e is mad~ o~ a polar so ~ nt ~u~h a~ water, n~e~hanol, ethanol, propanol, N,N-dim~thyl~ormamide or dimethylsul~ox.~ d~, o~ .!. mlxture 5 thereof, and alcc~hol~ suc:h a~ ml3~hanol , e~:hanol o~
p~opa~ xe ~v~tageou~ly employe~l. Whil~ ~ the xe~c:tioi~ is ~o~ductecl ~ually at room temp~ ature~ it m~y k~ ~on~uc~ed, depending on ca~es, und~;r cool ~n~
to -~0C or un~er heating up to the re~lux; I:em~era~ure 10 o~ the solvent. Nhile the r~action tl~ne va:l ies wit;h the kinds o~ reduciny agen~s and ~e~C~ion k( ~pe~a~ur~, it :canges ~m seve~ l mi.nute~i to ~bout 10 ~ ur~
Reactlon iEor removLng ~he ~cyl g~ollp i~ co:nc ucte~ by a E2~E se known proces5, foI~ exampl~, allowin~ a ba~e such 15 as triethylamiI~e, sodium hydroxicl~ o~a~ n h~clroxide oX ~odium me~hoxide ~o xe~ct for ~t~aining !he ~ur~o~e.
A ~o~npoL~Ild ~IOw~ l~y the~ form~lla t ~!a ] ,~li.n b~
producod by a E~ s knot~m method ~rom a co~llpound shoT,m b~ the fo~mula ~ ~a] or a ~alt th~reo~ . Fo:r example, i~
20 c~n be p~c)d~c~ r allowi.ng a compound shor~. by ~he ~or~nula ~ ~a ~ to react wlt;h a compound 3~epr~ nted by the ~orm~la ~ 9 ~
X
~ ~ C = i~ [ ! ~

whereln X and ~ re o~ ~he same meaning as s: .ef ined abo~
30 .And~ a comlp~und shoT~n by the ~ mula ~:ic~ hl~O
b~ ~roduced by allowin~ a com~vlmd re~resen~ e~ b~ ~h~
fo~mul~ ~ 10 91~F11,9 5~ lB;~3a~,TA~EDA P~T~MTS OSAI~A Fether~tdn ; Q~300~601;l~2~/7 r ;~
. ~ ~5 --~-- --NH

4~1 [10]

R~
~herein R7 anci R~ are o~ t:h~3 3ams meanln~ a~ de:~in~d above ~o rE~ t wlt~ a cs~lpuun~ ~how~ by ~he 3 ormula ~ 9 to cause N-~cyla~ion, then by subiec!tl~g ~ r~ul~ant ~o r~ductive ring-openin4 r~c~ion. ~his rç!ductive ring-opening reac~ion c~n be cvn~uated un~33 the conditions de~cribed a~o~e ~or at~.ining th~! ob~ect.
In th~ me~ch~ ro~lp h~ g e~n opt~on~
pro~e~tive hyclroxyl ~roup, shown by Rl or R~, o~
çompound represen~ed by the ~ormula ~1 ] or cl ~alt lS thereoP, when ~he hyd:co~yl ~rou;? i~ prc~ cl:~!d, elimination of the prote~tive yroup can ~e c o~ducted b~
a ~pa~ B4;1 knowr~ l?roc~6~. Pro~c~a~lv~ g~oupl3 ~;hich ar~ ~
elimin ble wi~h an a~id, for exa~npl~, t,rityl ~roup, p-me~hoxytri~yl group, t~r~. bukyl s~roup 0 ~0 tetrahy~rop~anyl group, ca~ be xomQved by h~rol}r wi th an ~ . o . g . hydrochlo~ c;;L~, ac:e~ s~:id, ~ri~luo~oacetic acid, ~-~olu~3ne~u~0nic acicl or ~ul onLc a~id type ion-3xchange resin, AGY3.-tYPe p~ot~ .i ve gxoupe;, f or ~xam~ , an acetyl ~ oup or z5 b~nzoyl group ~ can be ~6~mo~re~. by allowlng In ba3e e . ~ .
po~ l~n h~d3:0xide or ~dium m~hoxi~e ~o ~: f; act therewith. ~ typ~ prot~c~ive.groups, ~c.r example, a tert-~ui~ldilne~h~ ilyl group, can b~ el~lrin~ d 3 allowing te~r~buty~ an~nonium 1~oriide ~o r~ac~
therewl~:h. And, Benzyl-type prote~cti~re g:~c~ ps, ~o~
ex~npl~ ~ a benzyl ~roup or p-methoxyb~n~yl ~I roup, can ~e elimir~ated ~y allowin~ }~oron t~ichlo~ a~ to reac:~
~herewith, and, d~pending on CASes~ by h~dri.genolysi~
by mi~n~ o~ ~A~ly~ xeidui-tic7n.
Amon~ thi~ compounds :repr~ ntiad b~ this3 ;EQr~nUla.
ho~ in whl~h at liaask on~ o~ th~ hycl~: o~l groups ~.

91.1!11~1~ 5~ 36~;TA~;EI~A PATBNTS OSAKA Fetherston ; 06300~01;#2g/72 r of hy~rc~x~ thyl gro~p~ shc~ by Rl or R2, or a ~al t the~eof i~ phv~phated can l~e ol~taine~l by pho~phoryla~i4n o~ ~he co:rrespo~din~ hydroxy L g~o~p or gr~ups.
While th~3 phosphoric ~cicl compoun~ casl :~e produced b~ a ~E se kno~n method ~3nerally conduct~d in ~h~
chemi~try o~ nucleoticle, .it i8 produced us~la Lly by allowin~ a phosphorylatin~ agQnt 'co react, f ~Illow~d by, 10 wher~ r~quired, h~rolysis. ~xalnple~ o~ the phospho~yl~ing agen t ~he~ emplo~ed include pho~3phoryla~ing ~nt~ whieh mAy opt~n~lly ~r~duce:
oxidati.~n proc::ess, such a~ pho~phorus ~xy~hl ~ride, pyrol?ho~phoryl~e~rachlo~i~e, phosphorus tri~:lllo~lda, 15 polypho~phoric ~cid~ metaphosphoric ~ic3, ph 3spho~ic acid ~enz~rle~er.dich~ori~3, m~r~ollnopho~pll~ric a~id dich~orld~ , phç~nylph~ pho;r~ aaid dich1oricle, cyano e~hylpho~phoric a~ , dih~n~ylphosphor ic acid chloride, O-~e2~zylpho~phorou~ acid-O,O-~0 diphRnylpyxophos~horic ac.id, etc. The phos;p~ x~latin~
ag~nt 18 uaed ae~ on~ ulv~ nt or !nor~ r~ re to ~h~
aompound rel~res~nte~ b~ the ~aneral [ 1 3, pr~ E~rably 1 .
~o 10 a~ui~ralen~ he reaction i~ u~u~lly ~ dua~e~
in a polar ~olve~t i~cluding tri lkyl pho~ph lt~ su~h ~8 'criethyl phaspnate, trimethyl phosph~te, el:.c., phenols ~uah a~ ph~nol , n~or~a~ol , ~ta ., ~c~onltr~lo, N,N-di~ethyl~orm~mid~, dimethyl ~ulfoxide, et~; a non-pola~ s~l~rent ~uch ~s tol u~3ne, benæene, dichloromath~ns, chlorofo.nn, etc.; o~ a mixt lre sol~rent o~ tham~ The reactic:rl t~mper~ture~ r~n~ m -7~CC to ~he r~ uxins~ tempe~atur~ of ~he 601vent the 1 u~ed r pre~erably - 20C to room temp63ratllre, Whil.~ the reaction ~i~ne tle~aends on tha kind~ o:~ pho~ph ~rylating ~gen~ and ~eaction temp~rature~ then employ ad, i~
rang~s ~Erom 3.bo~ 10 mlr~ to aho~l~ 10 hou ~ .
Additionally to s~at~, a c11 pho~phori~ a ~id eæter ~ .

91~5~ lB~36~jTAKEDA PATENTS OSAKA Feth~r~t~n ; oa300~601;~30~72 2 ~

or ~ripho~phoric: aci~ ester can be produce~l by allowing, ~or exan~ple, l-~luoro-2, 4~dinitrob ~n~ne or ~arbodiimid~zole to react with a mo~ pho3pho ri~ ~ci~
e~;te~, according to a ~er 3e 3;nown pro~e~sy ~o gi~e an S ac~i~e l~ho~phoric acid e tex compound, whic~ is th~n subj2~ed ~o ~l3action wit~ ~ ~alt of orthoph ~sphoric acid or ~yroph~sphor1c ac.ld wlth an organio~ lmin~, ~uch as l?yr~dine, tri~a~hylamine, etc, Aativi~y o~ inhibiti:ng replication of H ~ 1 was :lete~minecl ~ th~ follow~ ng method .
( 1~ Prepara~ion oi~ triru~ ~olution HIV~ IIIB3 infeoted ~QLT 4 aQllB ~ l x 103 cells/ml ~ weX~ ina~b~ted for 3 ~ay~ . 'rhe ~0 Lls were main~ained in RPMI1640 co.n~aini~g lP9~ f~ ovine serum a~ 37 C in S% ~2~ A~er ~en~xi~uyatior. of the ~ell su~pen~ion, ~he supexnatant was f il~ere i b~r 0 . 4 5,um ~llt~r, ~nd w~ ~roz~:n Rt~ -70C U21'C~ 1 u~e. rhe tit~r o~ ~he supe~n~t~nt wa~ c 10~ PFrt/~l (PFUs ~ ~laqu~
<:~xmin~ uni'c ) .
Z0 (2) Pr~paratl~n ~ ampl~ solut:ion The ~ample compouncl was soluLbili~ed ln ~MSO
(di~ns3~hyl 63ul~oxids~ at ~0 mgJn~l, and ~hç~ Lu~ion was cllluted with DMS~} to 2000, 200, 20, 2, 0.2~, ~.0~ ~g/ml.
Irhen t;he~e solution~ wer~3 dilut~d to 200, .~0, ~, û . 2, 0.0~, 0~00~, O.ûO0~ llg/ml with P~PMI1640 coI~t~in~ng 10~6 fetal bovine 5erum, Io~pec~i~roly, The ~exi.e ~ ~e the ~olu~ion~ wa~ used for antil~IV a~say.
( 3 ) AntiYlral aati~rity o~ sample ~ompound a~ ~inst HIV-l ~T ~ cells were exposed ~o HIV~ r IE~ ) at ~n m . o . i . ~f 0 . 0~2 . ~hen 50 ,ul o:~ the cell st~.6 ~en~lon (1~6 x 10~ ml) wa~ inoaul~t~d i~ ~-w~ .l U-bottom plal;~ and 50 ,ul of ~he ~ample ~olutlon was a lded to the cw~ll suspen~ion and ~ultu~d for 6 d~y~ e c~lls were n~a~ ntain~d in RPMI1640 containing 10~ tal bo~r~ne 3S ~rum a~ 37~C in 5~ C~2. Go~rol cell~ wer~ tr~ted Elimilarly bu~ no~ ~x~ ed to the ~i~u~. CellL
.

91~5~ la~3~;TAKEDA PATENTS OSA~A Feth~r~n ; OB300BB01;$31/7t~
2 !r~ F~

prolifer~ion was as~ssed by ~he X~ (2,3--b.ls~
me~hoxy-4-nitro-5~ulf~phenyl]-s~
~(phen~lamino~car~nyl~-~H-tetrazolium hyd~o~ide~
mathod. Then 50 ~1 of xrr solution (0.5 ~c1/1nl XTT, 3 ~g~ml PMS (phenaæine methosul~ona~)) wa~ z~dlled to th~
~ell 6~spension an~ incub~t~d a~ 37C fo~
ab~orbanc~ at 450 nm w~ m~ur~. Th~ e~i.e~,ti~e do~e~
SO% (ED50~, rep~e~ent~ the concen~ra ion of c~mpound tha~ ease~ ~bsorbance in the infec~d c:uL~ure~ to 50~ ~f untxea~e~, unin~ec~ed ~ell cont~ols~
Sin~e anti~rir~l agent~ o~t~n ~how to~ci.c. t~ ag~ins~
ho~3~ qolls t the ~o~i~ity ~f tas~ ~mple~ a,qa. n~t th~
ho~t cell~ wa~ examined ~y the followin~ m~tl~od.
The.cytotoxity of the ~ampl~ compound tl~ MT~4 cell~ was ~easured b~ ~he similar ~ethod de~s~ribed a~ove. In a ~6~w~ U-bo~ttom platet 50 ~1 o:S the c~}l ~u&p~on (1.~ x 105 cQll~Jml) wa~ ulat~ld in a 96-well U-~ot~om plate ~nd 50 ~1 of the ~ample ;3~1ution wa~ added to th~ cell ~usp~nsion and cul~urelt for 6 days ~t 37~C in 5~ CO2. Cell proli~eration ~Oa9 as~ed b~ XTq' a~ay and I~50 wa~ determi~ed. The ln~lbl~ory doae, 50~ (IDso), r~pxe~n~ th~ toxi~ aon~nt~ti4n o~
~xu~ that reduc~s ab~orbance in uninfe~ed ~Illture~ to 5~
~he antl~i~l acti~it~ v~ 4,t3, 5a-~i~hydro~yme~h~l)cyolopen~-2-~n-l~-yl]adeni.nl3 ~the c:vmpound oi~ Example 3) d~t~rmin6~d by th~ m~tllod de~cribed abov~ wa~ a~ fo:Llow~.
Anki-~IV : E~50 .3S5 ~g/mL
cytotoxlaity s ID50 66.4 ~g/mL
A~ the oom~o~ xepre~ented by the ~o~ la Cl~ i~
weak ~n cyto~oxici~y and ~how~ ~t~ong anti~i:~al actl~ity, it can b~ ~ed ~or th~ therApy of.~ e~s due to viral in~e~tion and ~or prote~tion f'rom the 3S in~cti~n~ Pu~ther, tho l~mp~u~d ~lJ did no: ~how cytotoxici~y to vero cell~ at a concen~rati.ol~ o~ 100 91~ 5~ 16~36h`;TAl~E3A PATENTS OSAIIA Fethsr~ton ; 0a3008~01;#32/72 C~ J ~
~ 2g -- :

g/ml. In other words, the compound of thi~ kion can be widely used for the thorapy And proph ~l~xi~ o~
d~ ~eases due ~o vi ral in~eation in m~mmal~ clucling man. Especially, khe ~ompound o~ ~hi~ inv6~n~ion ox a 5 salt thereo~ i~ ef fective for the the~a~y an,l prophylaxi~i o~ di~a~a~es such a~ AIDS or 8~ruln hepatitis c~u~ed ~ i~f~c~ion o~ re~o~riru:s or r~xoi.dl~riru~s.
And, as ~he aoml?~und of ~his inven~ion or a ~alt .
thereof i8 stable again~t ~id, lt i~ u~e~ul for 10 p~ien~, like ~hose i~om ~I~S, xequiring admini~tration of a~ vi~e~l a~en~ ~o;r a long period tim~ .
Pharmacelltic: al~ coni~inin~ the colnpourld 11 ] or a salt the~eo~ as th~ eff~ative ~olnponent can I)e prepared 15 into suitable dosage ~ 3 ~uch ~ ~ap~ule~, t~blet~, ointm~n~s, in;ections, gr~mules, powder, solution, suspe~sion or elixir, optionall~ mixed with ~!L suitabl~
aJnount c~f pharmaceutlcally accepta}: le ad ~u~ran~cs ~uch as a c:arrier, dispar&~ant or e~ecipie!n,t/ ~hiah ca:lL be 20 administered uRually orally andl upon nece~s..t~
intrav~noue:ly or l~txamu~c~ularly.
Cap3ule~, pow~e~, ~r~nules and tabl~t~ I,o be used $o~ oral admln~st~atio~ may include an 2.d~uve,nt such . s ~yrup, ç{um arabica ,, gelati.n, ~orbitol, tragar ~ an ~um or 25 polyvinyl pyxxolidorl~, a ~iller such as laceo~, ~ugars, corn ~tarch, calcium phosphat6~ or s~ ol glycine~ ~ lubrican~ such~ a6 magnesium ~te~axe.te~ ~alc, poly&thylene glycol or ~ilic~ ~ d.i6integrat;l~ agen~
~IlCh a~; po~a*o ~tarch, or a ukilizable lubric ~nt ~uch 30 a~ ~odium lauryl ~ at~. Coatin~ Oæ *~bletli .aarl be conducted by a well-known meth~cl in th~ nt ~rt.
Liquld prepara~ions ~or or.al as:lministra~ion ll,a~ be~ in the forln o~ aqueolls or oil sus~pension, solut:ion, . q~u~ion, ayrup or elixLr, or a ~r~ produc~ l:o ~e ~issol~d in wat~ or any okher suita~lR so:L~tion extemporaneou~ly, These l.iquid p~epa~AtiOn~3 may 91~ 5~ 16~36~;TAKEDA PATENTS OSAKA Fether3ton ; 0a3006~01;#33/72 contain ~ ~u~p~3ndîn~ agent ~u~h as ~or~itol ~ yrup, meth~ lulo~;ç, glucoseJ~ugar ~yrup, gslat:l n, hydro~yeth~l callulo~e, carboxym~hyl c~ellulc ~e or alumnium ~;t~arate gel, a hydrc)gena~ed e~llble oil ~uch 5 IS alrnoncl oll, ~Er~actionall~ di~tilled c~on~ o~il or oily es~er, pxopy~ ene gl.yc:ol or ~3thyl alcoho:l, and a pre~e~Yati~ ~uch as methyl or propyl p-hyd~cc~xybenzoate, sorbi~ ~c:id, etc . The compoun~ ~ l ) or a sal~ thereof ~an also b~ u~d a~ a suppo~ ..0~y ~it~ a ~uit~ble base ~uch as ~aaao butter or other ~ lyceride.
In~ect~ 3 pre~paxatlon~ m~y be ~?~e~entec. ln uni~
d~be cont~iner~ ~or ~x~n~pl~, ~p~le~ or ~ ainex~ to which a pres~rva i~re i~ a~lded. ~he~ prepa:~.tion~ may sui~aJ:~ly contaln an ad~uv~nt such a~ a susp~r.din~ agent i~ t~e ol l or aqueou~ sol~v~3nt, a ~ al~ er c.ncl/or a dispar~ing ag~n~. ~d, the acti~a compo~nt m~ ~o p~p~rQd in~4 a p~wd~y ~or~n, which iS exteml;~oran~ou~ly re~onstituted with ~ ~uit~lble ~ol~en~ J o~ ~a.! :ample, sterile water containin~ ~lo p~ro~en.
And, the ~ompound ( 1 ) or a ~alt c~n be ~ eparedt in ~cc;o~d~nc~ with ~ con~ntion~:L pro~ea~, i nto a s~it~b1e form to ~e ~sorhed ~hrough a ~uit~ ~le route inclu~ing nasal ~d phar~n~eal membrane or ~ l onchial ti~sue, for example~ powde~r, a liquid ~pra~ r zs inhalant, lo~enge~ or paint ~o be applie~ on pharyngeal m~alnbrane .
~nd, in addition ~o t~he car~iexs ~ ~ny e-l.h6~r cc~mponent~ such a~ a staLbilizer, binder, ant.l.-oxLdant, pre~i~rvative, lubricanl:, t;hickening agant o:r flavc)ri~
age~. B~riid~ Qny oth~ ~c~i~e aomponen~ y be allowe~l to be c:ontai~ed in guch preparation.~ bove to give a broader meclicin~l use~.
Xn the~ preparationsi, ~he compound 1 l ~ or a ~alt thereof may l:)e ie~llowed to be cc: ntained, in a liquid ~o~ id do~a~e ~nit, in an amount of 0 . l to 9~ wei~ht~, pref erably about 10 to ~ O ~ ( weigh~ ) .

91~ 5~ 36~;TAKEDA PATENT~ OSAI~A Fe~h~r3t~n ; 0~3006601j#34/72 2 ~
-- 3~ ~

Th~ ~ntiviral agent o~ thi~ in~ention can be u~ed i~or the ~h~rap~ and prophylaxi~ o~ h-lman i~ununodeficlenc;:y, e~pecially AIDS, adult hum.. n ~-cell leukocy~hemia, e~G~ ~ a~3 an agent o~ inhibl~ g th~
S ~rowth and lnf ection o~ retroviru~ . A ~uit;~
ef~ec~ do~s o~ ~h~ ~c)mE~ound~ o~ this in~-~ tion i3 in th~3 ranqe of 20 to 2000 m~ (in term6 of th~3 ~ f:~ectiv~
~omponerlt) p63r day per a~ult person (body w~.ight al~out 60 lcg), p~eer~bly 50 to 100 mg, onc~3 or ~e~. ral ~ub~
10 do~e~ at appropria~e interv~ls . Prac~tical ~C ~e i~
d~te~nlnecl ~epe~ing on ~e age, ~o~y weigh~" ~ymptom of ~he pati~3nt and th~3 dc~age o~n ~nd adminii ~ration f requency .
[ Working Ex~mpla~ ]
The ~ollowing E~amplQæ ~nd R~feren~e Exclmples will d~rlbe the p:roduction of the compound ~1 ] Il ore 3~eaif icall~,r, R~3ference~ E~eample 1 1 -~enzylo~ne~hyl~2~aæ~bi~ hept~5~ n~, 20 7~nti benzylo~cymethyl-2-az~bicyclo~ ]h~ t~s~ 3~
one and 7-~yn-ben~yloxyme~hyl-2-A~abi~yal~ :a . 2 .1 3hep~-s-en-3~o~e . A ~u~p~n~ion of a~lopenta~ien$rl thallium (13.5 g, 50 mmol. ) in anhydrou~ ethyl ~3th~r (15 ml) ~ cooled 2~ ~o -~204C in argon stre2uns, to whlch wa~ add~E~cl ~ropwi~
a ~olu~ion of ben~yl(~hlo~e~nethyl~ether ~7. B g., 50 n~nol. ) in anhyd~ous ethyl ethe~ ~5 ~ The ~e~ ion mix~ure was stirred ~or 7 hou~s at th6~ same temperR~ure, ~hen precip~ta~e~ were separatli~cl ~y 30 ~iltrQtion un~er ~3u~king and wnshed with t~nlh~d~ou~
e~hyl e~her. Th~ fil~ra~e and the washing w~l~e combined and khere was added p-toluenesulf on~ yanide ~9.0 g, SO rnmol. ) . q~his ~olution ~a~ aOncerlt.rat under re~lu~ed preB~ure to ~ volume of abou~ ~5 InL, 35 whiah was left ~t~ndln~ for 12 hour~ ~t roo]n temp~rature . ~o ~he c4n~entrat6~ were added e hloro:Eo~m .

91~5~ 16~36~;TA~EDA PhTENTS OSAKA Fether3t~n ; 063006~01;~35/72 2 ~ v '~j ~, 3 _ 32 --(100 ml ) and silica gel (:lO c~), an~l the ml~:t.llre waæ
s~ ed ~or 3 hours ~t room ~e~np~rature. Si:.ic~ gel wa~ ~iltere~ of, anà the ~iltrate wa~ conc ~lltra~ed unc~r reduced pre~3su~e~ ~h~ con~entra~e wa~ sub~ect~d tc:~ a siliaa gel (400 g) ~ollllnn chromatograE)h~r. The aolumn wa~ sub jec~ed to elution wLth hex~.ne I !th~l ~ce~at~ ( 4; 1, 2 . 5 I~ ), h~ane-e~hyl ~.çe~ate ~ 1, 3~ ), h~3xane-ethyl acetate ( 1~1~ 3L ) and he~eane-0thyl aceta e 3, 3I. ), ~ucce~ ely to separate l-benz~ xyrne thyl r 2-azablc:yclc~t 2, ~ . 13he~pt 5--en-2-one, 7"-anti-b~n~ylo~y~eth~l-2-azabic:yelo~.2.1~hep~-5-e~n 3-one and 7~n-bena~loxy~thyl-2-~7~Abi~ycl~2.~.l]helpl;-5-en-3-one.
l-benzyoxyme~h~1-2-a~a~icyclo~ ,l]hept-5~e~ 2-one~
yiel~ 1.5 g (12~; c~lo~leæs oil; IR tC~Cl3) ~ 34S0, 1715 cmlslH~N~R (CDC13, 61) MHz)~ ; 2~20~2H, ~'lf 7 ~), 3.27~1EIt m, 4~ 3~83(2H~ nOCH~ 4.63 (2H~ e~
PhCH2~), S.28 to 5.71 (lH, broad ~, -NH- ~, 6 . 71 5~H ~nd.~H), 7.37 ~5H, 8~ C~Hg~).
MS s Calcd. ~or C14HlsNO2 (M ) M/Z~ 229. 1102~ Found 22~. lO9B.
7-anti~anzy1~x~me~hyl-2-~læa~y~1oc~.2.l~hel~t-5-en~3-one: yîeld 2.8 g (2~ lo~le~ ~morphous s;u~tan~
~cry~tallized ~rom ethy~ ether-h~an~); m.p. 70 to ~5 75~. IR (CHC13) : 3450, 1710 ~ NMR ~C~Cl~, 500 MHz)~ s ~.92 (lH, m, 7~ 3~0~ (lH, broad g 4~
3.~ (lH~ dd~ J~lO, 6Hz3 ~d ~6g (lH~ dd~ J~ 9Hz) (~nO~H2~ .2S (lH~ m~ 1-H)~ 4.50 (~Hf 8~ :I?hCH~
5.1~ (lH~ broad ~ -NH-), 6.71 (1~ 5-H)~ &.85 (lH~
dd~ J=6~ 2H~s~ 6-H), 7.30 t5H, m, CG~5_). .
MS : Cal~d. ~or ~14HlsNO2 ~ Z: ~2~. 1102~ Found ~tZ:
229. 1128.
7-3~n-b~nzyloxym~hyl-2-a~sabicy~1O~2.2.1~h~pl:-5-en-3-one : yi~ld 2.0 y (17%); ~olorle~s oil. IR tC'~13) :
3450~ 1710 cm~lS 1H-NMR (C~Cla, 500 ~Hz)6 s 3.~8 (1~
broad, s, ~-~), 3.21 (1~ m/ 7-H~, 3.39 ~ ddr ~10, 91~ 5~ 16~36~;TAKEDA PATENTS OSA~A Fethsr3~n ; o63oo66ol;#~e/72 &

HZ) and 3,~3 (lH~ dd, J-10, 7 Hz) (~nOC~ , 4.~7 (lH~ m, 1-~)/ 4.44 (~H~ s, Ph~ 6.21 (l~ road 8, -NH-), 6 .49 (1~/ m, 5-H~, 6~5 ~lH, ~d, J ~5, ~Hz, ~-H ) ~ 7, 3 0 ( S~ , C6H5- ) .
MS: ~alc~. f~ C~4~l5N~2(M ) M~z ~ 229~1102. ~uund N/Zt ~2g . 110~ .
P~eiEerenc~ Exampl~ 2 7-s~-Benzylo;R~nne~hyl-2-ethoxy~arbony~ z~t~ icyalo-~ 2 . ~ ~1 ]hepk-5-en-3-one A mlxtur~ o~ a ~oluti.on o~ 10~ hium t~ oprop~l nide ~n hexane ( 1~ m~) and anhydrou~; te~trall~,dro;Euran (20 mL) wa~ ~vol~d ~o 7~c and th~3re~ ~a~ lc.~
dxopwise~ slowly~ in Argon ~troam~ a ~oluticn OI 7-~yn-benzylo~ymeth~ azablcyclo[2,2.1]h~pt~ en~3~one (~25B mg, 5.4~ mmol.) in ~nhydrous tetr~hydrs:uran (10 mL), and the mixture w~ stirred ~ one hou~: at the ~me tempa~tur~ e reaoti4rl ~l~tu~a wa ~ added ethyl chl~roca~on~te (0.7 ~L, ~.3~ mmol.), then th~

çooli~ bath wa~ removed, followecl by ~irril.g until the re~ion temperatur~ w~t up to room tem~erature.
The r~a~tion mi~tura was stlrred ~o~ u~ther 12 hour~
a~ ~oom ~e~p~raturesv f~l low~d by c~ncentra~:ion under reduc~d pre6~ure. To the ~onc~nt~a~e wa# adc.ed chloro~c>xm, then ra~ultant lithiun~ c:hlor~ de l~as f~l~e~ed o~, and the ~ilt~ate! was concentral:.ed uncle~
~duc~d p~ur~. The Gorl~ntr~t~ ~QJ ~ub~a~!t~d to a ~ilica ~el (50 ~ colu~n c:hroma~ography, ~ol:l.owed ~

elution with hexa~e eth~l açeta~e (3~ h~ f~tion thu~ elut;ed wa concen~r~t,~d to dryne~s u~de:l re~u~ed pre~ure to a~ord 7-~yn-benzyloxym~thyl-2-ethoxyc:a~on~ as:abicyclo~,2.1~he~k~5-en.-;i-on~ as a colorle~ oil (g83 mg, yie1d 59%~, IR(CHC13) : 1790~ 17~1, 171~ cm ; l~_NMR (~ CL3, 60 MHz) ~i ~ 1.3~ (3H, t, J-7Hz), -CH2CH3), 3.13 ~1Hr 1~ 7 H)~
3.2~ (1H, m, 4 ~), 3.2 to 3.7 ~2~, m, snoc~:2-)~ 4~26 ~2~I, q, ~-7 Hz, -C~kCH3), ~,4b 12H, s, PhCH~-:I, $ 00 91~ 5~ la~36~;TA~EDA PATENTS OSA~A F~thergt~n ; 063006601;~37~2 2 ~ ~ ~ ~ S ~
-- ~4 --(1!H, In~ 1-H), 6.48 ~1HJ m~ 5-~1), Ç.73 (1~I, d~:l, J=6, ~HZ, 6 ~ 7 . 3 1 ( 5H, ~, CÇ~5_ ) -M~; CA~ o~ ~13~14~ ~M -(~4H5NO3) ~q~Z ~ 18~ 4 . FOUnd~ 6 . 1 ~ ~ 7 .
Reference Example 3 7 anti-ben~ylo~methyl~-etho~ycarbonyl 2-a~abic~clo~2.2~l]hep~-5weTl-3-one 7-an~i-henzylox~meth~1-2-a~a~icy~1~[~.2.13hept-S-en~3-one (1~05 mg~ was p~oce~sed in the samle m~nner as Re~ren~e ~am~le 2 to gi.~a 7-an~ enzyl~x,methyl-~-~thoxyc~rbonyl~ zabicyclo[2.2.1]hep~-5-en-.i-one (1163 m~, yield ~ a~ a ~olorl~s~ oll.
IR(CHCl3) : 1792, 1770, 1715 cm1; lH-NMR (Cl:l~ L3, 60 NEI~
~ 32 (3~, t, ~7Hz, -CH~C~b), 2.81 (lH, m, 7~
3~29 (lH, m, 4 ~), 3.2 ~u 3.8 (2HI m~ BnOCH~-~, 4026 ~2H, ~, J~7Hz), -C~C~3)r ~.4~ (2H, ~, PhCH2~'l, 4.g6 (l~, ~, l-~), 6.6~ (lH, dcld, J~5, 4, 2 Hæ, 5 H), ~.~4(1H, ~d, J=5, 3 Hz, 6-H~, 7.33 (S~ ,;H5~
MS : Calcd~ ~or Cl7HI~NO4 t~ 301. 1314. Found M~2:
~0 30~. 13~1.
Ref ex~nc~ E~mp~e 4 Bthyl (~ [S~-benz~lo~ym~thyl ~-(hydroxy~.~th~l)o~Glo pent-2-en-1~-yl~caxbama~e A ~olut~on o~ 7-~n~be~ylox~m~hyl-2-ethoxycarbony~ abi~ycl~t2~ ]h~pt-5-~n~;~ one (404 mg/ 1.34 mmol~ anh~drC)u~ ~ekhanol (10 mL' w~s cooled wlth lce-wate~, to whl~h w~s added oc.~um borohydrido ~255 my, 6~71 ~mol.), ~ollowed ~j ~tirr~
for one hou~ a~ room ~mp~r~ture. T~e re~ct:lon mixture was neutrallzed with acetlc acld - methanol ll;1), t~en ~he ~olven~ wa~ ~still~ of~ under redu~d ~,~re~sur~.
Tho ~ du~ wa~ ~ubj~ct~ to a ~ g~ oluunn ~h~o~atograph~, followed by elution wi~h he~ ne-eth ~cat~te (1~ he ~racti.on ~hus elu~ed wa~
concentr~ted to dryne~ undex xeduaed pr~Asu:le to ~ford e~ ~ 1 (i) N-~5a-b~nzyloxym~hyl-4 91~ 5~ 1&~6~;TAKE~A PATENTS OSAKA Feth~r~t~n ; 06300Ba01j~3g/72 - 35 - ~ ~ r~J ~; ~,", (hy~oxym~thyl~yalopent-~-~3n~ l]car~lna~ (35~ l:ng, yield ~5% ) ~s a colorles~
I~(C~ 34S0, 1715 c~ NMR (ClDC13, 60 MH~1.23 ~, t~ ~-7 E~ C~C;EI3), 2~3 to 3,0 (2E~ m, ~-H
and 5-H ), ~ . 2 to 3 . 9 ~ 5H, m, ~nOCH2~, ar~d -C'~ ~OH ~, 4 . 11 (2Hr S~l J=7 H~ CH3), ~.3 to 4.5 (lH, m, ;.-H~, 4.57 ( 2H, s ~ PhC~ ), 4 ~ 8 to 5 . ~ ( lH, bro 3.d d, J 1 3 H~, -NH-), 5.67 t~H, s, 2-~H and 3--H), 7.32 (SH, ~, C~jH5-)~
MS : Calcd. fo:c Cl7}i24N:)4 (~ +1) ~ 30~.1 10 M~Zs 30~.17S4.
R~îer~Pnc:e ~xamp~ e 5 Ethyl ( ~ ) -N- C 5.~ henzylo~ hyl- 4 ,B- ( hydroxyml. Ilkhyl ) -c~clop~nt~2~en-l,B-yl]car~zlma~ 7-antl-Benzy~ x~neth 2-~hoxya~bonyl-2-azabL~y~lot2~2.l]h~pt-5-~r--3~
15 (1132 m~, 3~76 mmol.~ wa~ proces~ed in ~he ~e,me ~anner a6 in ~efer~nce Examp1e 4 to ~fford ethyl (~ N-~5~-b~nzyloxymethyl-4~-(hydr~xymethyl)cyclopent-'!-en-1,~-yl~rbama~e (954 In5~,.yield 8~6) A~; a ,::olorle~
ui~ .
~0 ~CHCl3) ~ 3450, 1715 cm; lH-NlqR (~C13, 60 MH~
1~22 (3H, ~, J~7 H~, -CN2C~), 2.1 to ~.5 (lH, b~oad ~, -OH~, 2.~ to ~0 ~2H~ m, 4-~ and !S-H)~ 3.5 ~ 4H, m, BnOCHz- and -CH~,OH), 4.0~ (2~1, q~ J-7 H2r ~ C~3 4.S2 ~2~ ~ PhCH2-)/ 4.7 t4 5.0 ~1~, m, ~-:E~l.r 5.0 t~
25 5.55 (1~, b~oa~ ~, J=12 Hz, -NH~), 5.8~ , B, 2-H and 3-H)r 7.31 (5Hl sI C6Hs-).
MS ~ Calc~, for ~l7H24~ao4 (M +l) ~/Z s ~06 .170'i . ~ound M~2: 3D6.1701 Re~eren~ ~:xample 6 30 (~ )-t5c4-Benzylo~ thyI-4l3~(hyd~o~ymethyl)~yl~loperlt-2 ~n- 1~3-y~ 1 a~nlne ~rO ~ lutlon of eth~ N~[5c~-be~nz~l >xymethyl-4J~-(hydroxymeth~l)cyclopeallt-2-~3n-l~B-yl]~ar~!amat~ (510 ~ng, 1.~7 mmol. ) in meth~nol (lO ml) wa~ ad~Le~l a lO N
3~ ~olutiozl of potassium hydroxld~3 (lO n~)" ~r~d the 91~ 6F 16~36~;TAI~EDA PAT~NTS OSA~A Fether~ton ; 063006601j#39f~2 3 ~ $ ~

mix~u~3 was heated for 20 hours under reflux. The r~action mix~ur~e wa~ concelltrated uncler redu~ d pres3ure. To the conce~t~ ate wa~ added wat~s:l to gi~r~
an oily produc~ aIIcl was ~ t~acted wi~h ethyl acçtate.
5 The e~tract solution was clri~d over anh~rdrouli ~odium ~ulfa~e~ which wa~ then concent~ated unde~ r~lduced pxe~ure. ~he ~oncentrat~3 was sub~ect.ed to ;!. ~llic2l gel ~ 25 ~) column chxolnatography, follow~:d b,~r alution wi~h e~hyl aceta~e-~nethanol (1~1) . The fI~a~i ion ~hu~s 10 eluted wa~ con~entrated ~o d~nes~3 unde:~ ro~llc~d pressure to ai~for~ 5a-benzylo~yme~hyl- 41i;~
Ihyd~c~ neth~rl )Gyclopent-2-en~ yl]amine~ ~ 3:~ mg, yield ~696) a~ a colorl~ oll .
IR(C:HCl3) : 3~0 ~m ; E~-N~ (CDC13~ 60 MHz) ~ : 3~ ~8 to lS 3~87 (5Ht"n, -CH2- x 2 atld 4~ 4.5~ ~H, $~ :I?hCE~2-), 5 ~ 6 7 ~ 2H~ ~ S r ~ ~H zlnd 3-H ) ~ 7 . 3 3 ( ~H, ~, G6H~
MS ; ~alcd, ~or Cl4~ Oi(M~-l) M~; 23~138~ Poun~
~iJ$; 2~2 . 1333 ~er~nc:s Exampl~ 7 (t)-~ $~ 3nzyloxyme~hyl-4~3- (h~droxymethyl ) c~ lopen~-2 en- l ~-yl ] amine E~h~l (+)-~-~5~-bo~ylo~nethy~ hyd:~oxyqneth cyclopent~2~en~ yl~carbalmate (324~ lng, 10.l;4 Irunol.

wa~ proc:es~ed in th~ same manner aa in RefeIn~nc~

2 5 l~a~n;ple 6 ~o ~ f ~ord ( ~ ) ~ 313-b~nzylox~methyl~
(hydroxyqnethyl)~yclopent-2-en~ yl~a~in~ lorle~s ~ri~m~ (cry~talli~ed ~rom ~thyl ether)O Yi.e;.d lg~O mg ( 79~ ) m.p .: 73 to 74 ~C;
IR (CHCl~) ~ 3380 ~ H-NMR (CDCl3, 60 MH~ 6 to 3.00 ~2~, m, ~-H ~nd 4-H~, 3.63 (2H, d, J=3 ll~, BnOCHz-)~ 3.71 (2HI d~ 3~8 HZ~ O~)~ 3.36 (l~l~ dc!~ J-6~
) r 4 . 55 ~ PhCE~ ; . 91 t 2H~ ~3 ~ }I and 3~H)~ 7.34 (~H~ ~/ (6~5~)-MS s Calcd. ~o~ Cl4H~8NOa(~ /Z: 232~1338~ ' Found 3~Z: 2~2.1341.
R~3~eren~:e .~;xample ;~

9~ I;EI 16~36~;TAKEDA PATENTS OSAI~A FeCherqt~ll ; 0~3300~601;#40~7~

~ 5~Amino-4-C5~-b~nzylo~.yme~hyl~ (h~drox~,m~thyl) cyclop~n~ en~ yl~aminc--6~chloropyri~idin~i, To ~ ~olu~ion o~ [5a-~enzyloxymethy:l-4~-hydroXy-meth~l)cyclo~ent~ n~ l)amine (~2l'~ m~, ~.15 mmol.) in e~hanol (13 mL) were added 5-amino 4,6 dichloropyrimidine (378 ~c~, 2.3 mmol.) ~nd ~rle~hylamine (3~ mg, 3, e; mmol.)~ ~he mix:tl..re w~
h~ated for 48 hPur~ at 100C in a s~aled tu:be. The solvent wa~ illed off under redu~ed ~e~;ur~, then khe r~idue w~ s~bjected to a silic~ qel (1'l g) column chroma~ogr~ph~, eluking wi~h he~e-ethyl a~ ta~
( 1 :1 ) . The .fr~c~lon th~ ~lut~d w~ cona~.t~ t~d ~o dryne~ under redu~e~ pre~ure ~o af~ord (~) 5-amino-4 ~S~-~enzyloxymethyl-4~-~hydroxymethyl)cy~ p~n~-2-e~-lS l~-yl~a~ino-6~chloro~y~im~din~ (34~ mg, y~ 82%j ~ a color~e~ oil.
IR (~HCl3~ s 3370, 1580 ~m ; l~_N~ ~c~Cl~, 6l1 MU12)~
2.16 (lH, m, 4-H 0~ 5~, 2.77 (lH~ m, 4-H 0l~ S_H), 3.
to 4.0 (7~ m, ~C~2-~2, -~H~ and -0~)~ 4.54 ~2~
PhCH2-), 5.03 ~1~, m, 1-~), S.73 3H, m~ 2-~I, 3-~ and -NH )~ 7-29 t5H, ~ ~6~5-~, 7-9~ (lH, ~, ~yrJ.mL~ine ~-H) MS: Cal~d. ~o~ C~8H2lN402Cl ~ Z~ 360.1352. Found ~ 36~. 132; Cal~d. ~or Cl~M2lN602Cl* (M f)) M/Zt 362.
. 1322~ Found M~Z~ 362.~33:L.
~e f ~renc~ ~xampie 9 (+) g-~min~-4-t5~en~10xymethy7 ~-(hydrc-x~eth~l) c~alopent~ n_l~_yl~amino-6-chloro~yri~idln ~ S~-ben~loxym~t]lyl-4~-(h~droxymeth~
cyclopent-2~en~ amine (42~ mg, ~.81 m~lo.~.) ~a~
pro~e~ed in tn~ ~am~ manner a~ ~efer~nc~ E;x;~mple 8 ~o a~o~d (~)-5-~mln~-4~1~-h~n~yloxymethyl~
(h~droxymethyl)cyclopont~ en~ 13ami~o-6 chloropyrimi~ine (517 mg, yield 79~) aB a c:o;.orles~
oil.
IR (CHCl3) ~ i370, 15~0 a~ NM~ (C~19, ~l) MHz) 91~ 5~ 16B~36~jTA~.EDA PATENTS OSAKA Fether3t~n i 063osB6ol;#4l~72 - 38 - 2 ~

2.88(2H, m, 4-7~ and 5-~), 3.31 (3E~, broad 8~ -NH2 and -~ 3 ~ ~ ~ t 4H, 3~, ~CH70H and BnOCH2- ), 4 . ~1 (: !II, ~, PhCH2-), 5.3g (lH, m~ l-H), 5.~4 (3~, m, 2-1~1/ 3-H and N~ 7-2B (5H~ ~ C6~s-)~ 8.O~ (lH, ~, pyrlm:.~in~ 2-S ~)-MS: C~ d. for ~l~H2lN402Cl ~) N~s 360. 135:!. Found M~: 36~- 1335- S C~lcd. ior ClBH~lN402~1* (~+:~) M~Z:
~2. 1322. Fou~d M/~- 362. 1314, Re~Eerence ~amp1~ 10 1 û ( ~ ) -9- [ 5~-ben~loxym~h~1 -4,6- ~ h~droxyn~ethyl ) I :yclopent-2-enr 1~-yl]-6-chloropu~ine ( ~ ) -5-~nino~4- ~ 50~-bellzyloxym~thyl-4,~-hydro~ymeth~yl ) cyc ~ opent~ en ~ yl ] amlno~
~hloropyrrimidin~ (~03 mg, 0.56 mmol~ ) was di!;~ol~ed in 15 ethyl orthofoxmatè ( 3 . 1 ~ To -the ~olu~i.on wa~
added, while ~.ir:ring under cooli3n~ wi~h ic~water~ 12N
hydroc:}llor~c acid (0.04 mL) . ~he reac~io~ ~m: xture wa~
s~lrred for ~2 hour~ at room temper~tur~3 and wa~ th~3n conc~nt~a~d under xeduced pressure. The c!o:llcentr~te w~s d~ol~ed in te~rahydro~uran (~ m~), t~ 17hiah ~a~
~ed O.SN hydrochloric acid ~12 mL)~ and t:hl~ mixtur~
wa~ ~tirred f~ 2 hours. Tne reac~lon ~ixt:u'~a wa~
neutrali~ed ~i~h lN solut;Lo~ of ~odiu~ hy~ro:~ide and ~ concen~ate~ ~nder reduced pre~sure. l'o ~h~
concentrRte wa~ ~ded water. The resultant;l~ily pr~duc~ wa~s extra~ted ~ith ethyl acetato. Tl~ extract ~olu~lon was dri~ ~v~ al1hyd~ou~ ~diu~ ~ te~
~ollow~d ~ concentra~io~ under r~duG~ pres;sure. The ~ entrate was ~ubjected to a ~illca gel ~ ) colum~
chromatography~ eluting w.ith h~xane-ethyl ac,~tat~
~l~l). The ~ractlon thu~ elu~ed ~a~ concoJlt:~t~d d~yn~ to af~ord (~ .S~-ben2ylox~methy~
(~ydrox~m~thyl)~yclopent~ e~ 1]-6-chlo~purine (180 mg, yleld 86~) ~5 a colorle~s oil.
I~ (C~C13) 2 3450, 159~, 15~0 cm~~ ~NM~ (~'r,Cl3, ~0 MHz)~ : 2.6~ q~ 3-6 ~z~ 4-H or 5~ . 38 ~lH! m"

91~ 5~ 16~36~;TA~EDA PATENTS OSAKA Fethergt~n . 063006601;#~2Z72 ~ ~ r~

~-H o~ S-H~, 3~23 (lE~, ~road s, -C~H), 3.72 ~;~H, d, ~6 Hz, :BnOCH ~ 3, 3 . 8 0 ( 2H, m t -C~20HI ) r 4 . 51 ( 2H:, 8, PhC~-), 5.58 (lHI m, 1-~1), 5.77 (lH, ddd~ ~-5, lt l~l~, 3-~), 6 .0~ (l~, ddd, ;~-5, 2~ z, 2-~I) J 7 .2S (5H, s, C~H~
8.24 (1~, s, purir~e~ r 8.66 (lH, 5, pur~n~
MS > Calcti. ~or Cl9HlgM402~1 ~M ) M~; 370.11g~ Found M/Z 370.1158. ; Cal~d. for ClgHl9N402Cl* (Mt~2 M/Z:
372.1165. Found ~/Z~ 372.1138.
~eference Ex~ le ll ~0 (~ S~-B~nzyloxy~e~hyl-4~-(h~drox~neth~l)t;yc~opent-2-en- 1 0-yl ~ - 6 -chloropurin~!
( ~ ) -5-Amino-4- [ 5~-ben~:yloxymethyl-4,~-(hydrox~methyl ~c:yclo pen~2-en-l,B-~l jamino-~ .
chloropyrimi~ine (517 ms~, 1.43 mmol. ~ ~ag p~ ces~ed in 15 th~3 ~ame manner as R~3fex~nce Example 10 to a:l or~i ~+)-9-e5~ en~yloxym~hyl~4~-~h~roxyIoethyl)cyclc~pent-2-en-l~-yl~-6-chloropurina as t:olorle~ p~l~ms ~c:lystallized ~om di~hl~romethane - hexane).
Yield ; 37~ m~ (70~); m.pt~ 120C~ IR (CHCl3) s 3450, ~O 1590, 1560 am~~; ~H-N~R (~13~ 60 M~ t 3... 85 (3H~ m, 4-H, 5-~ and -OH)J 3.51 (2H, ~, -CH2-~/ 3.83 (~H, m~ -CH2-), 3.95 (2H, ~, PhC~), S.9~ (2H, mt l-~R and 3-H~, 6.36 ~l~, m~ 2-H), 6~92 to 7.23 (5H, s, C6N,~, 8.43 , purine~ 3 (lH, B, purine-~)-~5 ~lemen~Al ~naly~i~ fo~ C1gHlgN4O~
~lad~(~)s C,~1~53; ~I,$.16s N,15tlO; C1,9.56 Found ~%); C~61,~; H,5.18; N,15.10; C1,9.54, Re~exen~e ~am~l~ 12 ~ 2-am~no-4-~5~-benæy~oxylmethyl-4~-~hy~ox~!methyl)-cyclop~nt~2-en -1~-yl~amino-6-chloropyri~ldi.n~l~
~ o a ~olu~ion of ~+) r 5~-benzylox~nn~hy.:.-4~-(h~droxynn~hyl)cyclop~nt-~-en~l~~yl~a~in~ (3"3 mg, l.~O
nunol.) ~n eth~nol (40 mL) were ~ed 2-amino~ 4,6~-dichloropyri~ldine ~324 mc~, l.9~ nunol.) and t~ieth~lamine ~85 m~ 4..8~ nunol.), and th~ rlixture ~a~
he~ted at lOO~C ~or 40 ho~lr~ in a ~i~aled t~:bli~. The 91~ 5~ 16~36~;TAKEDA PATENTS OSAKA Fether~t~n ; 063006601;~43~72 J~
40 ~

~ol~rent wa~ ~lstill~sd off undex reduc:ed pre~!ux6~, ~nd the re~i~iue W~ uk ~0~ted to ~ ~ilica gel ( .~l: g) c:olumn chromatocJraph~, eluting wi.th hexane-ethyl ac~ tate (1~1) . ~h~ ~xac~ion thu~ e~lut~d w~s conc~llt3 ated to S dr~,rness uncler r~duced pre~;~ure to afford amino-4 - ~ 5,~-benzyloxy~n~thyl- 4 $~- ( hydr~ ; methyl ) ayclopent~-en~ yl]amino-6~c~10ropyr~idînl t526 mg~
yield 91~) a~ ~ colorle~s oil.
IR (CEICl;,) :3350, 34$0, 1610, 1580, 1570 cm ~ H~NMR

11~ (CDCls, ~0 MH~ 2 . 6 to 3 . 0 ~ 2H, m, 4-H ancl 5-H~, 3 . 1~ t 1~ road g, -OH ), 3 . 61 ~ 4~ C~ nd CH2~Bn), 4.39 (~H, ~, PhC~2-), 4.g2 (1~, m, 1 :H), 5.27 (~H, ~road ~, -NH2), 5.74 (lH/ ~, ~y~imidin~ 5-H), 5.82 (~H, ~, 2-~I ~nd ~-~), 5.7 to ~.O ~lH, broad. ,~;, N~
~5 7-~5 (5H, 8, C6~
MS s Calcd. ~or Cl8H~N6O2Cl ~M ) M/Z: 3~0.1352. Found M~Zs 360.2384. ; Calcd- ~or Cl~H2l~4O2Cl* ~M ~ /Z
362. 1322. ~ou~d N/Z: 36;~.1337 Re~er~n~e ~xampl~ 13 ( ~ ) -2-}~nin~-4- [5~-~enzylo~cyqneth~ 4~ -(hydroxy~nethyl)cyclopent-~-en-l~yl]amino-5-l p-chlorophbn~l)azo-6-~hloro~y~imidine In ~ mixture o~ ~e~i~ a~, wa~r ~nd r,lçthanol (17:17:10, 44 ~iL) wer~ di~,~olved (~)-2-aminD ~4-t5~~
25 bengyloxg~nethyl 4~-(hydroxynnethyl)a~clopent-.!wen~
anlin4~6-chloropy~imidine ~1201 mg/ 3.33 nNnol 3 and sodium acetate (6.6 g~/ an~ ~he ~olu~lon W~ stlrre~
under ice-~oo~inSI~ To ~he ~olution wa~ ~de,l a cliazonium ~alt ~;olution cooled wi~h i~e ~prel)ared fxc~n 30 a 3N hydrochloric acid ( ~ mL) o:e p-chl~xoani .ine ~ 510 m~, 4 . O mmol . ) and ~ ~qu~30u~q solution t ~ mL, of ~odium nitrit~ ~303 mg, ~.~ numol,)~ d the ml~turl~ w~
~:irred ~or 6 houx~ oorn temp~ra~uxe~ q~hl! reac~ion mixtur~ was cencentrated under reduc:ed pxe~sllre. To 35 the collc~3n~r~a~e ~a~ added wate~ to gi~re (~ mi:no-4-[ 5,~-ben~yloxymath~ ( hydr~ thyl ) c~clc,pl snt- 2 ~en-91~ 6~ 16~36~jTA~EDA PATENTS OSAKA Fether~ton ; 063006601;#44/7~

~ V ,~

1~-yl~a~ino-5-(p~chloroph0nyl)~zo-6~
chloropyrimidine ~s ~ cry~talline p.roduct (:L;~36 m~, ~ield 80%, re~ry~alliz~d f~om diçhlorome~ha~e -hexan~).

Yellow amorphou~; m.p.: 208 ~ C; IR (Nu~oll ~ 3450y 1570 cm~; lH-N~ (D~SO-d~, 60 MH~)~ ; 2.6 ~o .~.0 (2Ht m, 4-H an~ 5-~), 3.t~ ~o 3.~ (4H, m, -C~OH ani -C~OBn~, 4.1B (lH, d, ~-12 Hz) and 4.41 (lH/ ~t J=l~
~ Ph~2-3, 4.77 (lH, ~ro~d ~, -OH)~ 5O4 tc~ 5.8 llH, m, 1-H), 5.~2 (~, m, 2-H ~nd ~-H~, ~.17 (5~ H3-)~ 7.3 ~o 7.~ (~H, m, Clt~6}I4- and -~H23/ 1~.0(, (l~{, broad ~ H-).
NS: ~lcd. ~or C24H24~6O~Cl2 (M ) ~Z~ 4~8. 13.3.l. Foun~
~ 9B. 1346.; C~la~. ~c)r ~4H~4N6O~ClCl* (]~l ~) M~-500. 1307. F~uncl M~Z: 500. 12~5~ ; Calcd. for C~4~24N6~2~12* ~ ~4~ M!~s 5~2- 1337. Found ~,~Z!g S0~.
1325~
;~e~er~nce Exampl~ 14 (I)-2~5-di~ino-4-~5~-bens:ylox~neth~l-4~-~hyelrox~-me~hyl)~yc~o~ant-~-en-l~-yl~amino-6-chloropyrimidine To a ~olution of ~ ^2-amino-4-[5~-b~nz1rloxy-methyl-4~-~h~droxyme~h~)cyalopen~:-2-en~ amino~5-~p-chloroph~nyl)~o-~-chloropyrimidine ~l3~6 m~, 2.03 m~ol.) in a mix~uxe of ~thanol ~nd watsr (l;:, 80 m~) ~5 wer~ added 7inc powder (1.74 g, 16.6 ~mol.) ,!lnd ~ce~ic acid (0.~5 mI.). The ~ ture wa~ heatad for :I h~u~s unde~ ~ef lUt~ . Insoluble~ were i~ ered o~, ~d the filtrak~ wa~ ~o~cen~rated under reduced pres;!~uxe. ~h~
concen~rate ~a~ su~iecte~ to ~ ~lica gel ~711 g) ~olumn a~romatograph~ eluting with hexane-ethyl ac~i~ta~e (l:2). ~he r~c~i~n thu3 eluted wa~ concent:1ated to drynes~ under r~!3duc;ed ~ ur~ o l:h~ C:o~llc:~ 9ntrfa t:e~ wa~
added ~ s~all ~olume o dichloromethane to g.:.ve 2,5-di~mino-4~[s~-b~n~ylo~methyl~4~-(hy~o~yme~hyl)~yclope~t~-en~ yl]amino-6-chloropyrimidine a~ aolori~ cal~s (76~ ~1g yield 91~ 6~3~;TA~EDA PATENTS OSA~A Feth~r~t~n ; 063006601;~45/7 ~ 4 76~3. m.p~: 107 to 10g~C;
I~ (CHC13) 5 35~0, 1610r 1560 cm ~ 7MR(Cl~C:1.3, ~0 ~z) ô~ 2.7 ~o 3.0 (2H, m, 4-~ and 5-H), 3.08 ~4~, bro~d 0, --~z x ~ 4 t4H, ~ C~OH ~nd --C~03311 1, 4.40 ~H, ~, PhCH2~ 4.75 ~1~, bruac~ a ~ -OEI), ~.~' 4 (1~ m l~I)r 5.82 ~2H, m~ 2~H ancl 3-~), 6.11 (1~ :b:load ~, 3-10 Hz, ~ ), 7 .24 ~5H, ~, C6Hg~) .
MS s Ca1ad. ~or Cl~H~2N5O2C1 (M+) M~Zs ~7S. 146.l. Found ~æ~ 375. 144~. ~ Ca1~d. ~r ~18HZZN~O~C1* (~+
377. 1~31. Found M/~; 377. 145~.
R~f ex~n~e EXA~P1e ~5 Amin~-9 c5~-ben~yloxyme~hyl-4~ hydrox!~ethyl) ~Y~1OPent-2-en~ 1]-6-Ch1OrOPUrine ( * ) - 2, s -Di~mLno- 4 - ~ 5,B-ber~ylQ~ th~l - 4 ,~
(hydro~ hyl )c~yclc:p~nt-2-en-1,B-srl]amlno-~-chloropyr~nidine ( ~06 mg, 0 . 55 mmol . ) was ~ul;pen~ed i~
ethyl or~ho~ormat~ ~ 3 m~ o thle susp~3n~;.0ll . was added, whil e ~irrln~ und~3r cooll;n~ with ic:o wi~ter, l~N
hydrochloric acid ~0~14 n~). ~rhe r~a~tion m:.x~ure was ~stirred ~or 14 hour~ a~ rt~om ~emp~Y~ature~ arld wa~ than c~nc~ntra~ed und~3r ~e~u~ed pre~sure, The c:ol~cen~rake was di~olve~, in tetrah~rorllr~n ( 3 m~) r ~0 ~Jnich was wh$1e ~tirriIIg under coolin~ with ice . ~ . 5~7 hycl~ochloric a~id ~ 3 ~ , followed 1~y ~$irri~ f hourg at rooTn ~;~mper~tllre. The r~ction mi.x :ure wa~
neutxali2~d with a ~N solution of ~odium hyd:~xide i~nd w~ then concentra~ed ulld~3r ra~duc~sd pr~u~ he aoncerltxato was sub jected to a ~ilica gel ( ~0 g ) column chromatogr~aphy, elutin~ w:L~h chloroform met;hiulol (50~ he fractlon thus elut~d w~ con~e~;xated to dxyne~s undsr rodu~ed pres~urQ to ~ord ( :t ) -2-am~no-~~ t S~-benzylos~ ~h~ ,B-(h~droxyme~hyl)c~clop~nt-~-en~ yl~6-chlc~repuxine (1~3 mg, ~ie1d 53%) a~ ~ CO1Or1eS5 Oi1.
I~ (CHC~ 3450, 1610, 1570 C~ N~ C[X'13, 6~ krH~) ~; 2 . 8 to 4 . 3. ~ 7H ~ 4 -H, 5-H ~ 2~ t -C~12C~ 3n ~nd 91~ 5E lBli~3~;TAKEDA PATENTS OSAKA Féither~t~n ; 06300~601;#46~72 - ~3 -OH), ~.0~ (2H, s, Ph~H2-), 5.2~ t2H, bxoad ~3, -N~
5.54 to 5.~0 (2~, m, 1-~ an~ 3-H), 6.22 (1~, ml 2-H), ~.85 to 7.36 ~SH, m, C6H5~), 8.0~ (lH~ ~, pu.r;l.ne 8 H).
M~ ~ Calad. ~or cl9~20~5o~Cl M/Z : 385. 1305. ~ound X~'Z
t 385. 1289, ; C~lad. for Cl9~20~502Cl* (M~2) ]'t/~ : 387.
1275, ~oun~ ~/Z3 387. lX42.
Re~e~anc~ ~x~mple 16 2~N-(3-methox~-2-n~ethylacrylo~ arba~oyl]~ n-b~n~y1~xymeth~ azab~cyc,lo[~,~.l]hept-~-en-3-one To a ~olutlon o~ 3-methoxy-~-m~thylacry:l.oyl chlo~i~e tl7~ mg, 1.3~ mmc~1.) in anhyd~oux benz~ne (10 mL) wa~ ~d~d ~llver cyanAte ~ 293 mg~ 1 . 95 m;n~ol~)r and ~he mi~ture w~ ~tir~ed ~ 3 hou~ at 50~.
In~oluble~ were ~iltex~d o~. To the ~lt~ e wa6 add~ 7-~yn~en~yloxymeth~1-2-az~bi~clo~2.2.13hep~-5-en-3-on~ (~00 m~, 0.87 ~mol~) obtaine~ in Re;l:erenc~
Example 1~ The mlx ure w~ tlrr~d ~or fu~ e~ 5 h~r~
at 50bC. rhe reactLon mixture was ¢once~tral;ed undex reduaed pres~uro~ and ~h~ co~aen~ate was ~u!l-~c~e~ ~o a ~ a gel (10 g) colu~ ch~omato~raphy, e:.utin~ wi~h hex~ne~e~h~l ac~ate (2~1~. A~ the prec~delnl, ~ra~lon~
2-lN-(3-m~hox~-2-m~thylao~yloyl)-o~r~amoyl. ] 7 - ~yn-~ehz~lox~me~hyl~2-azabicy~lo~2.2~l] hept-5-en 3~ono (113 mg, ~ield 41~ was eluted, ~hen, a~ th~ 3ucceedin~
~ractlon, unreact~d 7-syn~enzylo~methyl~
azabicy~lo[2~ hep~ e~l-3~on~ (54 m~, re:c~:~v~r~
r~te:31~) W~$ ~lU~
2-fN-t3-m0~hoxy-~-lneth~lacryloyl)carbamoyl~ syn~
~en~y~oxyme~hy~ za~icyclol2.~l]hep~-5-en 3-one:
3~ colorlex~
IR (C~Cl3) o3300t 1755, 1730r 163~ C~l "
60 M~lz)~: 1.82 (3H, ~, -CH3~, 3.17 ~lH~ m~ , 3.4S
(3H~ m~ BnOC~Iz- a~ld ~ H3, 3.8S (3H, s, ~OCH~,3, 4.56 PhCH2-), 5.24 (lH, m, l~-H), 6.52 (lH" m, 5-~31 6.~3 (lHr m~ J-5, 2Hz~ 6-H), 7.27 (lH, ~, ~cryloyl 3~ 7.32 (~H~ ~, C61i5-), 10.50 ~ b~s~at ~ H-)~

9~ 5~ 1D~3a~;TAKEDA PAT~NTS OSAKA Feth~r~t~n ; 06300~601;~47/7 _ 44 ~ G V g MS Ca1~ Or C20H22~25 (M ) Mt~: 370.1529. F~
D~Z: ~70 . ~497 .
R~ere~ce Exan~ple 17 5ac~ yL~xym~thyl 4)~- hydr~ymeth~ ' ( 3 S m~thOXY_2_~thOXYaCr~1OY1)UreidO]CYa1~Pent-~ ene TO ~ ~O1UtiOn O~ 2~N-(3-methOXY-2~meth~,1aCr~1OY1) CarbamOY1~-7-~Yn-b~nZY1OXYm~hY~
aZabiCYC1O[~,2.1~heP~_5_en_3_One (118 m~ 0.:'.1 ~mOl.) in ~hYdrOUS me~hanO1 13 n~ W~ ~dded ~Odi~ll ~OrOh~Qri~e (60 mg, 1.$8 n~O1.) Under COO1~n!;- With iCe-Wat~r, and ~h~ mi~tUre Wa; ~tirred fOr on~ :h~ r at ~oom ~empe~ature. lrhe reac~ion ~nix~ure wa~ n0u~r.!.1iz~d with aaetic a.cld-methanol (lsl~ ar~d ~a~ then conlc~!!ntrated ~nd~r xeduced pres~u~e. ~he ~ncen ra~e ~a.s subjeated ~ ~ æilic~ gel ~10 g) ~olumn ~hromato~raphy, elutln~
with hex~n~-ethyl aaetat~ 1). The raction th~s ~lu ed w~a~ concent~tec~ under xe~du~ed prC:o~;ul.e. ~o th6 concen~rate wa3 add~d dichlorom~than~-hexane to afford (+)-5a-be~z~lox~me~hyl~ h~droxymeth~ 11 ' ( 3-metho~-2-mathoxy~cr~loyl)ureido]c~clopent-2-ene ~s colorl~ n~edle~ (97 mg, yleld 81~). ~.p.: 113 ~
114 C ~ C~C! 13 ) : 3 4 5 0 ~ 3 3 0 () ~ l l; 5~ O r 11i 21:1 cn~ H-NMR
~CDC~13~ ~iO ~q~z~ 1. 7~ St -CH3) ~ ~ 12 ( LH~ m~ ~-H), 2.76 ~1~, m, 4-~), 3.3 tO 3.8 ~5H~ m, -C,!I~OH and ~5 ~nOC~2-), 3.~1 ~3H~ S~ ~OCH3), 4OS7 t~H, ~ P;1CH2_), 4.77 (1H, m, 1-H)~ 5~7~ H, ~t 2-~ and 3-~). 7.31 (6~l, ~, C6H5- and ~Cr~1OY1 3-H)~ 8.~7 (1H, brOad ~. -N~
8.90 (1H, b~Oad dl J~10 HZ, -NH-).
MS ~a~d- fOX ~ZOHZ6~2O5 (M ) N/Z : 374.184X. POUnd M/Z S 374,1825, R~erenCe E~amP1e 18 ( + ) ~ nino-4- 1 5~benz~ o~{yrne~hyl-4~5- ( hydrc~ rm~thyl ) . c~clopen~_2_en-1~-yl]amino~-chloropyrlmi~i.n ~ [Sa~Benzyloxymeth~l 4 (hydroxymethyl)c~yclopent~ n l~-yl~mine c~;alned i~
Re~erencl3 Example S t49~ y~ 1.3f~ mlnol) w~ ub~eot~d 91~ 5~ 16~36~;TAKEDA PATENTS OSAKA Fether~t~n ; 063006601;~8/72 2 ~ ~J ~ ~ ~ ~

su~tantially the same p~ocedure a~ ~efex~erl~
~ample 1~ ~v give ( ~ amino g ~ 5u-b~anzyl~ nethyl-4,~- ( hydros~me~hyl ~ c~c lopent - 2 -en~
yllamin4 ~-~hloropyrimidine (552 In~, yi~ld l3~ %~ a~ a 5 colorle~ oily produc~
IR(CHC13~ : 355()~ ~450r 1610~ 1580, :1.570 ~m I; H-NMR
~CD~13, 60 ~E~æ) s 2.11 (I.H, m, S-H), 2.~4 ~:IH, m, 4-X~, 3.35 (1}~, hroad ~, -OEI~, 3.4 ~o 3.7 ~4H, m, -CH~OH
and -~20Bn), 4.54 (2H, ~, PhCH2-), 4~65 (l~:I, m, l-H), 1~ 5.21 (2H, ~roa~ NH;2) ~ S.41 (1~, broad ~, JalO H~ -), 5 . 7 0 ( 2H, 8 ~ 2 -~1 ~nfl 3 -H ~, ~ . 7 9 ( l}I, ;3 pyriln1d1ne ~ ), 7 . 28 ( 5H, ~, C6H5- ) ~S ~ Calcd. M/Z ~or C~ 21N4~ (M ~: ~601; 52-F~unà ~/2 o. 360 .1; ;23,;
1$ ~alcd. M/Z ~or CL8~21N4O~Cl* (~ ~ 2~ 362-1 Found M/2 362.1306.
Re~enc~ ~x~unpl~ lg A~Lno-4~ ~5~-benzylox~eth~l 4~-(hyd~ox!~ethyl) . a~clopent~2-en 1~-yl]amino-S-(p-chl~xophenyl;azo-6-chlo.ropy~lmidine ~+)-2-Amin~4-cs~-b~I~zyloxym~hyl-4~-(h!~r m~thyl)cyclop~nt-~-en-l~ yl)a~ino-6-~hl~roE~ .imidi~
(498 mg, 1.38 m~ol) wa~ subjected to sub~t~nl:ially ~he ~ame p~oc~dure as ~ef~r~nce ~xample 1~ to ~i~re (~)~2-amino-4-~5~-~en~loxymethyl-~-thydro~m~thy~
cyclopent-2-en-l0-yl]~ino-5-(p-chlo~ophen~ ~æo- 6~
chloro~yrimidine a~ cry~ 55~ mg, yleld ~
~llow ~morphou~ c~stals ~recryæ~ ed ~rl~m dichloromethane-hexane) ; ~.p.: 202 to 205~C
IR(Nu~ol) s 3450, 1570 cm 1; 1~_N~R ~V~o-cl6 60 ~H2)~
~ 2.~ , m, 5-H), ~.67 (l~, m~ 4-~, 3.4 ~o 4.1 (5~, m, -CH20H, -C~20~n and -OH), ~51 (2H, ~, Phl~ , 5.20 ~ m, 1-~), 5.82 ~HI m, ~-H ~nd 3~H), 7.26 (5H, s, C6H5-), 7.3 to 8.0 ~6~, ~, ClC6H5- ~nd -NH,)), 10.33 ~lH, bxoad ~ 8 ~z, ~

~S ~ Calcd. M/Z o~ C24H~4M62~12 (M ) ~ l98.1~7.
.

91~Fll,q 5~ 313~;TAXE~A PATENTS O~AI~A F~ther3t~n ; 063008601;#4g/72 ~ ~ ~J

~ound M~Z ., 4~8.13~0.;
Calc~ 2 ~or ~4~24N6O2~1Cl (~ 2) ^
Found ~JZ ~ 500~1~10;
C~4~4N~02~ (M+~4~ ~ S02 1337 Found ~J~ ; S02.1324.
Re~er~nc~ Exampl~ 20 ~+)~,5-Diamlno-4-[5a-benzylOx~meth~1-4~-(hydr~xymeth~l~cy~lo~ent-~-en~ yl]~mino-6 ahloro~yrimidine (~2-Amino-4-~5~-b~n~yloxyme~ 4 ~h~droxymethyl)cyclop~nt-2-en-l~-yl]a~ino-5-lp-chlorophe~yl)azo-~chlorolE~yrlmldin~3 ~520 mg~ 1.04 mm~l) was.~u~; ct~d to sub~tanti.all~ th~ s~me proc/ldure as Re~eren~e Example 14 to gi.~e (~ ,5-~iamin.o 4-~ga-~nzyloxyme~yl-4~-~h~droxymethyl)~y~lopent~ en-l~-yl]ami~o-6-chloropyrim$dille as cry~talæ ~231 mg, yield 53~).
Colorle~ n~edle~ (cxyhtalllzed from dL~hlorome~hane -hexane) ; IR (CHC13) : ~520, 1~10, lS60 cm 1; H~NMR
(CD~13, ~0 MH~)6 : 2.1~ (:LH, m, S-H), 2.7~ , m~ 4-H), 3.~ (3H, broad ~ and O~), 3.1 tv .l.9 (4~ m, -CH20E~ and -C~OE~n), 4.5~ ~EI, 8, PhCE12 3, 4 68 (2H, broad ~ -NH2), 4-74 (1~, m, 1 H), 5.70 (2~, ~, 2~ and 3-~), 5.74 tlH, b~o~d d, ~=9 H~, -NH-), 7.~7 (5 ~5 )-MS: C~llc:~. Mf3 ~ox C18H2~ 5 2 ~ ) s 3'l5.1461.
Poun~ ~Z : 3't5.1474;
Cal~. M/Z ~or Cl~H~N502Cl* (M +2) ~ 3'17-1431^
Foun~ M/Z : ~l7.1468 Reference ~xampla 21 ( l )-2-Am~o 9~[5~-b4n~10~ymethyl ~4~-~hydr~e~hyl~
c~clopent~ n~ 13~-ahloro~urine (i)-2,5-~a~ino-4-~5(x-benz~loxymethyl-4,3-thy~xo~
methyl)~yclopent-2-en~ ]amino~6-chloropy.^lmidine ~150 mg, 0.40 mmol) was ~ubjec~ad to ~uh~t~ iall~r the ~ame procedure a~ Re~erenae Example 15 to gi7e (~

91~ 5~ 16~36~;TAK~DA PATENTS OSAKA F~ther~t~n , 0~3~o66ol;#5Qi~2 - 47 ~ ~ v!"

a~ino-9~5a-ben2~10~methyl-4~-(h~droxymeth~
cyclopen~ en-l~-yl]-6-ch.loropurine (142 ~a, yleld 92~) as a c~lorl~s ~il.
IR(CHCl~) ; 345~ 1610, 1570 cm 1 1H-NM~ ICl3, 60 ~Hz)S ~ 2.5 to 3.1 (~, ml 4-H and 5-H), ~7C (2~, d~
6 Hzt CH20H~, 3.B to 4.1 (3H, m, -CH~ORn ~ OH), 4~55 ~HI ~, PhCH~-), 5.27 (2~ br~ ~, NH;), 5~38 (lH, ~, 1-H)~ 6.0~ (lH, ~, 2-H), 7~32 (5H, IS,, ~H5-~
7.86 (1~, ~, purine ~H) Reference E~ample 22 ~lS, 5R, 6S, 7R)-6-t-~utyldimethylsi~loxym~31:hyl-7-hydroxim~thyl-2-oxQ~i~yclo~.3,03Ootan-3-~n~
~1~, 5R~ 6S~ 7~)-7~B~!nzoyloxy~nethyl-6-h~;dro~2-oxabicy~o~3.3~o]o~tan-3-one ~.76 C~i, lO ~m~:l..) wa~
gradually added to a 2N NaOH-~eOH solutlon ~'.0 ml) while ~tirring . The mix~urq w~ stirred ~.r lS minut~
at r~o~ t~p~ratur~ ~d the~e wa.~ then a~de~

hy~xo~hlor~c a~id unde~ ic,e-cooli~g to mak& I.he ~lution acid. The ~i~ture wa~ ~ub~eated ~o ~0 ~istilla~i.on to dr~nes~ utlder redllce~ pr~su:l~e. The ~esidue was d~o~v~d in athyl ~ t~t~ - MeOLE ~Ssl~
and the 801ution was ~u~e3ct~d ~o a silica g~l column ~hromato~raphy. ~lution ~as per~o~med u~n~ th~ ~ame solven~ sys~em t~ give 1.72 g ~uant~tati~e~ ) of (lS~
2~ SR, 6S, 7~)-7-hydroxy-6-hy~ro~y~eth~ ox~ .a~clo-r 3-3 7 03oat~n-~-ons.
(1$~ 5R~ 6S1 7R~-7-hy~rox~-6-hydroxym~tl,lyl-2-o~a~icyclo~3.3,0~oc~an~ one (1.72 g~ 1~ mm~ .) was ~ olved in D~F (30 ~1), To ~he ~oluk~on wl~e ~dded~
under i~e-~:ooling, t-butyl dimethylsilyl ch.lorlc~
(~BDSCl) ~1.80 ~ mmol~), th~n ~m~da~ole: l1.63 g~ 24 mmol~). Th~ rnlxt-lre wa~3 lef-t ~tandin~ ~03: 5 hour~ at ~oom tempex~tur~ and wa~ p~ured in~o ice-~.t~
~ollow~d by ~xtraction with e~har. The ethel~ layer ~a~
3~ dri;ed 4~r anh~rous ~odium ~ulfa~e, then ~tller wa~
~i#tilled off. The r~sidue was ~ub~ected t~ a silica 91~ 6~ 36~;TAKEDA PATE~TS OSA~A F~h~r~on ; 0~3006601;~51f~2 ,,3, ~J
_ 48 ~

gel column chromatography, elutin~ wL~h ethy], ~cetate-hexane (lsl), ~o giv~ 2.55 g ~89~ of (lS, S~i, 6S~ 7~)~
6-t-Butyldime~hyl~ilylo~y~l~thy~-7-h~droxym~yl 2 ox~bic~cl~t3,3,0~o~tan-~-one~ m.p. 58-59C.
~a]25~ 12.~9 (c-1.8, CHCl3) Re~e~enc~ ~xample 23 ~lS, SR, 6S) ~-t Butyldimethyl~lyloxymethy.L
o~abLcyclo~3~3.o]oct-7-en--3-ona (1~/ 5R,. 6S, 7R~6-t~Butyldi~ethyl~ lc~x~me~hyl-7~hydroxy-~ox~ yclo[~.~l.O]o~an-3-one (l.l~ g, 4 mmol.) ~nd O-n~tro~en~ne~i~le~o cy~nide (l.l. y, S
mmol.) we~e dl~solved ln ~nhydrvu~ THF (~0 m~ o the ~olutio~ war; addecl ~ropwis;e, in nitrogen 9t r~i~a~
tri~u~ylpho~phine ~l g, 5 mmol.) while ~tir~;l.n~ ~nder ic~-cooling. The mi~ture w~s ~tirrod for 15 hour~ ~t room temp~ratuxe and there w8~ ~hen add~3d 30'i: E~202 (3 ollo~red by ~irr~ng ~or ~urther o~e h.ou~ a~ room ~emperature, The reaction mixtur~ wa~ ~a~ ireakly alkaline wi~h a ~atura~ed aq~eous ~olution o:l. NaHC03, to which was then adde~ h~r (50 ml), ~oll.o~i~ed ~y washin~ wi~h water. T~e organic layer wa~ d~ then ~h~ ~oiv~nt was d~ led of~ und~r reduaed l~r~suxe, ~nd t~e residu~ wa~ ~ubje~ed to a ~i1iaa ~e:. ~oluunn chromat~graphy~ ~luti~g wl~h hexane - ethy1. ,l~a~tate (3;1) to o~t~in 0.7 g t69~) O~ (lS~ SR~ 65~ t~
~u~y~i~o~hy1silyl~xynn~th~rl-2~ox~bi~y~lo~3.3 0lo~t-7-en-3-one a~ a colorless o~l.
[~]u + 15g,4 ~c=l.O, ~HCl3) Ref~rance Example 24 (lS, ~S, 6S)~ tyl~im~hyls~lyloxym~th~l 4-~y~r 2--ox~J~ a 1~ [ 3 . 3 . O ~ oct--7 -i~n - ~ - ono (lS, ~ s)-~-lt-Bu~ imethyls~lyl~x~ml3~hyl-2-~
oxabiay~lo~3~3.o]oct-7 -~n--3-one ( 1. OD ~, 3 . 7 I mmol.) was dissolvod in anhyd~ou~ ~HF ~40 ml). ~c) :he ~olutio~ wa~ ~dd~d ~ 7~C ~Ho~Ds ~ 0 . 5M he~a~
solut~on~ (15.9 m1, 7.94 mnol.). The mix~lrl~ w~s 91~ 16~36~;TAKEDA PAT~NTS OSAKA Fether3t~n ; 0~300B601;#52~72 $
4g -~tirr~d for 15 ~inu~es ~ the same kempe~a~u~:e~ to which wa~ ~dded~ a~ one ~roke, MoO5.~D~PA.P y (Z.58 ~
5.60 nunol~ ollow~d by ~tirring for 3 hourSI. To the r~sultant ~ix~ure were added at -78C 10% HC]. (2 ml) S and a sat~rated ~q~eous ~lution of Na~03 ('l~9 ml)~
which was ~h~n war~ed gradually to ~oom t~mp~rature.
To th~ reaction m~tur~ was ad~ed wa~err wh:Lch w~
~ub~c~d to ~x~xaation with ethyl ace~ate. ~he e~t~ct wa~ driod and the ~olvent was diætiL:Ied ~f, Th~ resld~e was ~ub~ec~ed ~o a sili~ gel co:l~mn chromatography~ eluting wi.~h he~arle - ethyl ~! ce~ate .
t4;1) to r~ove~ ~15r 5RI c~
Butyldim~thyl~ilylo~ymethyl-~-oxabicy~1O[3.3,~oct-7-en 3~one (42S my, 42~5~). Elution wa~ ~ur~hlxr con~inu~d ~o obtaln 468 m~ (44~) o ~S, 5S, 6S)-6-t-~ut~ldimethy~ lo~me~hyl-4-hyd:roxy-2-o~ea~icyQlol3.3.0]oot-.7~ 3-on~.
(M~13Si~2NK
~,~, *
0xo~iperoxymoly~denum(p~ri.dine)~hexamethylp~h/l~phori~
tri~mid~
E. Vede~, D.~. En~ler, and ~. ~. T~l~chow J. Org. Ch~., 43l 188(197~) Re~erence Example 25 2S (15, SS, 6S~6-~ Butyl~im~thy~ yl~K~methyl~,4-dihyd~o~y-2_~xabioyclo~3.3.0]oc~_7 ~ene (lS, ~S, ~S)~ utyldimethylsily~ox~ hyl 4-hydro~y~2-ox~bi~clo[3.3.0~oct-7-en-3-on~ (4l;8 mg~ 5 m~ol.~ wa~ di~ol~ed in anhyd~u~ ether (lO rll). To the soluti~ was added ~du~lly ~iAl~4 ~6~ m~/ 1.66 mmol.) in ar~on ~r~am~ w~lile stirri~ und~r i~~
cooling, The mlx~-ur~ was s~ ed for 1. 5 hour and th~re w~ ~hen added saturated NH4Cl (lO ml.) an~ lO~
HCl ~.5 ml)~ Th~ mixture ~as diluted with !~hyl 3 5 aceta~e, then washed wlth water. ~he or~ er wa~
d~ie~, then the ~olvent wa~ di~tilled o~ un~:ler reduced 91~ 5~ 16~36~;TA~EDA PATENTS OSAeA F~thergton ; 063006601;#53f7 - ~0 - . ' pres~ure to lea~e 447 mg o~ (lS, 5S, ~S1-6~
Butyld~me~hyl~ilyloxymethyl-3,4-dihydro~y-2-ox~icyclo[3.3.0~oct=7~ens~, which wa~ u~ad ~:r the ~uccQ~ing rea~t~on with~.t re$inin~.
$ Reference Example ~fi (lS, ~ 6-t-Butyl~ime~hyl~ilyiox~.m~lthyl-3,4-dihy~ro~y-2-o~bicyclo~3~.3~o]oct-7-ene (321 mg, 1..l2 mmol.) ~nd K2C03 (~7~ ~, 2.01 m~ol.) w~re ~ pended in anhydrou~ benzene (10 ml), ~o ~h~ ~uspensior. ~a~ adde~
P~0~)4 (51~ mg, 1.15 mmol.) in li~ d amol;nts, an~
th~ mi~ture was ~irred ~o~ one hour at room t~mperature. T~ the: ~e~c~:iorl ml~ture~ wa~ ads:.ed ~atu~ated NaHOC3 to make render the pH 7, ~o:llowed by extrActio~ with ~hyl ac~t~te. Th~ extrac~ as dried o~er anhydrou~ Na~SO4, follow~d by distillin~; of~ the solvent under reduced pr~sure to ob~ain 27B mg (87%) o~ (lS, 4sl sRj-4-~-Butylcli~th~ yl~x~m~t~
form~loxy-5-~mylcycloperlt-2-ene.
Refer~nce ~ple ~7 ~lS, 4~, SS)~4~ Butyldlm~hyl~ yloxyme~h~l l-hy~roxy-5-~hy~xox~methyl3 çy~lopen1;-~-en~
(lS, ~S~ SR~-~-t-Butyldimethyl~ilyloxymethYl~
form~loxy-5_fo~ylc~c~operlt-~-en~ ~271 ~, 0.95 mmol.3 w~ di~solved ~n anhydrou~ eth~r (5 ml), ~'~ th~
~olution was adde~ LiAlH4 ~50.5 mg, 1~33 m~o.:.. 3 in ted ~molln~3 wh~ ;ti~n~f undsi,r ic~-cclca~ g in argon strea~3~ The mixtuxe wa~ ~tirred ~or ~:\ne houx at oac, ~o which were added a ~atura~sd a~ueou~ ~olution o~ N~14Cl ( 5 ml ) and 10~6 Ht~l ( 0 . 2 ml ) to make the resul~arat ~olu~lon weaX~y ~cid, ~oll~wed ~ ~l~xk~ ion wi~h ~Lh~l ~ae~te. Th~ ~3xtrac:~ wa~; dried, I:hen the solv63nt- was di~illed of~ under red~lced p~ ure. ~he re~idu~ ~a~ ~ub~ec:~eci to ~l ~illca ~el ~olumn ~hromatograph~, ~lu~ing with hRx~ne ~ ~thyl ,!~cetate ~ / to obka~n 155 mg ~63~) o~ (lS, 4S, SSI-4~t-Butyldime~hyl~ loxymethyl-l-hydroxy~5-91~ 5~ 36~;TAKEDA PATENTS OSAKA Fether3torl ; 06300B601;~64/~2 ~hyd~ m~thyl)cyclop~nt-2-ene.
Re~r~nce ~xample 28 (lS, 4S, 5~)-4-t-Butyldim~hy~ yloxymethyl-5-t-butyldiph~n~ yl~ime~hyl-l-hyd~oxycy~lop~l:t-2-ene ~1~, 4S, 5$)-~ ut~l~imethyl~ilylo~in~ yl-1-hydro~y-5~(hydrox~methyl)~clopent_2-ene (1:3l m~, 0.507 m~ol.) and imida~ole (75 mg, 1.~0 mmol.) wer6. dl~olved i~ ~MF (1 ml)~ Tv ~he ~ol,~ion was ~dd~d T~IP~Cl (148 m~, 0.542 ~ol~) dropwi~e gradu~lly while s~ ring at 0~ he mix~r~ wa~ then s~lrred for one hcur at 0C~
~ollowed by ex~action wlt;h ether~ The ethe~: layer was dri~ nd ~h~ ~olvent wa~; dis~ e~ ~ff. ~rl.o re~idue was ~ub~ected to a ~iliça gel column ch~omatc~raphy, elu~ln~ wlth h~xane - ethyl a~eta~e ~10.1) tcl o~ain 14~ mg ~59~) of.(lS, 4S, 3S)~4-t-Butyldi~eth~l~ilylo~ymeth~1-5~t-bu~yl~iphenyl~ilyloxymethyl-l-hydxo~cyayalope~ ene.
Referen~e E~mple 29 g ~(lR, 4S, s~)-4~ utylcllmethy~ oxym~t~:~yl-5-(t butyldiphenyl~ilyloxyme~hyl~cyclopent-2-en-1 yl]-6-chloropurine 45! 5s)-4-t.-~utyldimeth~ ox~rm~ ;hs>l-S-t;~
btl~yld~p}~n~l~ilyloxymeth~l-l-hy~:rox~rcyclope;~ 2-~ne ( 138 mg, O . ~B mmol . ), 6-chloropurill~ t44 mg~, O . 2B
mmol~) and tripheny~pho~phine ~147 mg, 0.2~ ~ol~) ~er@
di~ol~r~cl in ~nhycl~ou~ ~HF ~5 ml'~ rO th~ OE~ ut~i~n ~a~
added 90~ diethYl azs:dicnrboxyla~e ~EAD) (;.0~.6 m~
O.S3 mmol~ dropwise at -30~C while ~ ring ~h0 mlxtur~ wa~ le~t ~t~nding ~vernigh~ at room ~e~pera~ure an~ was ~hen ~ubjec~ed to a slli~a g~l cul~mll ahro~a~og~aph~, ~luting with hexane. - ethy;. acetate (4al) ~c~ o~tain 64 mg (36!~) ~ ~-r (lR~ 4S, 51~ 4-t-Buthyldimethyl~ilyloxyme~]l~l S-(t-b~t~ldiphenylsil~loY~ymethyl)c~clopent-2-en-1 yl]~6-ahloxopur~n~.R~forence E~mple 30 g~ 5~ 1D~3~;TAKE~A PhTENTS OSAKA Feth~r~ton ; 06300a601;~55~7~
6~ 3 J~ ~

9 [ ( lR ~ 5R ~ 4, s-Di l hy~ro~ thyl ~ ay~lo]E~! n~ n yl~adenin~
~-~(lR, 4S, SR)-4-t~utyldimeth~ls~lyl~ yme~hyl-5-(t-~ut~ldiphenylsilylox~m~thyl)~yclopan 2-erl-1-yl~
c~loropurln~ (63 m~, 0.1 ~mol.) w~8 ~i solvecl in methano~ (20 ml). ~o the ~olutlon wa introclu~d ammonia ga~ ~or 5 mlnute~ under csoling with brine.
The resul~n~ ~olution wa~ hea~ed ~ ~O~C foI 11 hour~
in ~ sealed tube. FrQm ~he r~ac~ion ~ixtur~a, exces3 ammonia and the 801~ent we~e dist~lled of ullde~
r~duced pressure to obtain ~ t~ S, 5~ t-sutyldimethy~ ylox~methyl-5-(t-~uty~iph~n~yl~ilyloxymeth~l)cyclopent-2~n-:L-yl]adenine. T~i~ wa~ ~is~4lvb~ in THP ~1 ~1'l. To he lS solukion wa~ added 1 M BU4~F-THF ~olution (1)"3~ ml), and the mix~ure was left standlng for 2 hour~ o the r~s~ltant mix~r~ wa~ addq,d waterr whi~h wa~3 washed with ~thyl a~e~a~e ~d ~uk~ec~d t~o evapora~i:on ~o dryne~s und~r redu~ed p~e~ure. ~he reæi~ue wa~
~u~ected to a silica ~el ~olumn c,hro~atogri~hy, elu~ing with CHC13~0~ to o~in ~ g (3~) o~
9-~lR, 4S~ 5~)-4~ 5-Di(hydroxyme~hyl~c~clo]?~.nt~ n-l-~l]adenine.
m.p. 2n4-206OC ~eOH) ~D - 24.30 ~0.6, Me~H) ~orre:~ponding rclGemlG modi~lc~iorl eepara~ed b~r m~an6 of liquid ~hro~atography (~xample lS~:
m.p. 206-207C (MsOH~
~ D~ ~ 24~71 (~1.4, ~leo~I) E~ampl~ 1 5~-Benz~loxyme hyl-4~~(hydroxyme~hyl)~:yclopent-~-en-l~-yl]adenin~ and (~)-g-[5~-b~zyloxym-3lhyl-4~-h~droxymethyl~cyolop~nt-2-0n~ yl]-6~methox!!pu~i~e In~o A ~0 1 utlon o~ ( ~ ) -9 ~ 5~-ben~syLoxym~i ~hyl-4,~-th~o~ hyl )cyclc~p~nt-2-er~ -y~ hlo~ purine .

91~ 5~ lB~36~;TAKEDA PATENTS OSAKA F~the~ton ; OB300~601;$6B,~2 ' (lg~ m~, 0.53 mmi~1. ) o~t~ine~i in Re~er~3nce E~iampl0 10 in anhydrou~ me~hanol (20 mI ) wa~ int~oduced, while cooling with ~odium ch~ori.de-ice, ga~3eou~ ~mrloniA for one hour. Thiæ ~olutioll wa~ heatecl at 50C ~ a ~ealed tubei for 20 hours. Thç xea~tion mi~tur~ wa~
concentxated ~n~le~ reduced p~essure, ~nd ~hl concentr~t~ W~5 sub~ect~ o a ~llLca gel ~ ;I! g) colu~on chroma~ograpll~y, elu~i~g with ~thyl ac~ate-m~ thanol o ~epara~e ( i ) -~ - [ 5ct,-b~3nz~rloxymethyl- 4 ,3-~h~roxymethyl)c~alopen~-2 en~ yl3 adenin~ and ( + ) 9- [ 5a-ben%~loxym~i~hyl-4B-~hydroxymet~yl )cyclapent~2-en~ yl]-6-m~tho:i;ypurin63., ( ~ ) - g - [ 5a-~Bexl~yloxyme~hyl- 4 ~- ( hydro~ne'chyl ) c yclopen~-2-en~ yl)adenin~ rield 144 my (77%); colclrles~
needle~ (c~tallized fr~on~ dichloxome~hane); In.p,: 171 t~ 173~;
IR (Nujol~ so~ N~R (DMSO~-d6, 500 ~2)~ ~ 2.4 (lH, ddd, ,J ~5, 5, S, 5 HZr 5-EI), 2.72 (lH, m, 4-H), 3.S2 (lH, ddd, J-ll, 5,5H~:) ar~d. 3.~1 (lH, d.d~.l, J=llr 5,5 Hz) t-CHZOH), 3.66 (2~i, m, ~nOC'}~ta-), 4.46 ~lH, d, J~12 Hz) and 4,~ (lH, d, J~.2 Hz) ~PhCII~-), 4.77 (lE~, t~ JY5 Hz~ -~)t 5.S2 (l~r ddd, ~-~, 2, ~ H), 5.7~ cld, J-6, 2, 2 Hz, ~-H), 6.66 ~1~', dcld, J~
, 2 -~ ), 7 . 17 ( 2H, l~oad s, `-~H2 ~ r ~ ~ ;' 8 ~ 5~
C6~5-), 8.05 tl~I, s, purine~H), ~.13 (lH, ~, I?~rine-HI), Elemental ~nal~is ~or Cl9~2lN5C)2:
~alcd. t%) : C, 64 .94; ~, ~;;02; N, 19~3.
Founcl (~ C, ~S.13t H, 6.07; N, 19.~3.
506-B~3nzylo~ylneth~1 4,B- (hyd~oxymethyl. ) ~::ycl~pent-2-on~ yl3-~--m~hoxypurin~ ~i Yield 18 ~g (9i;);
aolorless c>11;
IR (C~Cl3)s 3450, 1600, l~8~ am~~ NMR (CllC'l~, 64 M~

~: ~.5-3.1 ~2~, m/ 4-H and 5-H), 3.71 (2H, d ~=~ }Iz, ~inOC~2-), 3.~iO (~H, mr -CH20H3, 4,17 (3~ CH3)l 4 ~2H, ~, Ph~'-H2-~, 5.51 (l~ H), 5.75 ~lEI, ddd, J=6, 2~ ~ Hzr 3-Ht), ~6.07 (lH, ddd, ;~=6, 2,2 HZ, 2 -H), 7.27 91~ 5~ 16~36~;TAI~EDA PAT~NTS OSAKA Petherst~n ; 06300~601j~67~

2 ~
-- 54 _ (5H, s, C6H~-3, 7.94 (lH, ~ urine-H), ~.46 1lHt 8r purine-H ~ .
MSs C~alc~. Ior C20H2~N403(M ~ M/Z: 3~ olind ~Jæ, 366~ 17~7.
S $x~m~1e 2 t. 5 ,B-B~n~yloxymethyl 4 ~- ( hydroxy~nethyl ) ~: yc 1 opent-2~en-1~6-yl ~ adenine and ~ ~ ) 9- ~ 5,~-~enzylox~rmel: hyl-4,B-(hy~ro~ymeth~rl)cy~:lopent-2-er~l,B-yl]-~ ?th~: ypurine g- [ 5,~-~3er~zyloxYmethyl-4~B ~ (hyd~oxym~l: hyl ) -cy~lopent 2~en~ 5-yl]-S~hloropurihe (244 m~, û.66 .
mmol. ) obtainec~ in Reference Example 11 was l,roces~eâ
in the~ ~am~a ma~nn~r as E~cample 1 to a~ord ( ~ ~ -9-lS,~-ben zyloxymethyl .. ~,B- ( hydroxyme~hyl j ~yc lopent - .; -en~
~l]ad~anina t20~ mg, yi~d ~9~ n~ (~)-9-t5 15 benzyloxymethyl-4,~- ( hyd~o~ thyl ) ~yclopent-2-en~ yl ~ -6 -me~hoxypu~lne ~ 2 6 m~g t yieid l l ~
n~yloxyln~thyl-~4~ (hyd~xy~nethyl)~ lop~t-2-e~n~ yl]adelline~s colorle~ noe~ cry~t~..llized from mqthanol); m.p.~ to 121~C; ~X~ (Nu~o;;.): 3450, 1710 c~ H-~MR (D~IS0-:16, 60MHz)~ 6 (1~, m, 4-H3, 3.06 (1~1, d~dd, J~g,9,9,9 Hz, 5-H), 3.27 (2:H, In, BnOCH2-3~ 3~59 ~ ddd~ J~ll, 5~5~z) and 3.~;9 (lH, ddd ~ ~-11, 5, 5 ~ CH70H ), ~ H, . d, .:r~ 12 Hz ) an~
4.09 (l~H, d, J~12 Hz) ~Ph(:H2-), 4~75 (1~ r ~=5 Hq~r -2S OE~),.5.l3 (1~11 broad d, J ~Hz" 5.~3 (lH, ddcl, J~6, 2, 2 Hz~ 3~ 6.26 (1~1" dc~dlr Ja6~ ~r 2 H2:~ 2-~1 t 6-9B
~ 2H~ m~ and 7 . 22 t 3~,m) t~6H5- ), 7 .14 ~ 2H, NH2), 8.07 (lH, ~, purine~I), ~.ll (1~, s, purlne~
Elemen~al An~l~8is ~Qr Cl9112lN5O2 30 C~lcd. (9¢): C, 6~.g4; }~ 0~; ~, 19.93.
~ound ~9~) s C, 65.12, ~II 6.11; N, 19.~4.
~ [ S~ Benzyloxynnethyl -4~ (hydrox~n~thyl.)l:~clop~nt-2~en~ yl ] -6-metho~ypuril-e ~ oolorle~s oil.: I~ ( CHCl~ ) : 3450, 1~0~, 1580 c:m l; IH-NMR ~CDCl3, 6~ P~.lz~ 3.36 3 5 ( 3H, m ~ ~ -H ~ $ -H and -OH ) ~ 3 . 41 ( 2H, m, ~C~[2~ 7 ~

9~ 5~ 16~3~;TAKE~A PATENTS OSAKA Fetherston ; 063006801;#58/

~ 55 - 2 (~H, m, ~C~X~-~, 4.00 ~H, s~ PhC~2~ .21 (.3~
CH3), 5 . 89 ( 2H~ m, l-H and ~~H), 6.23 ~lH, ~t~ 2-H), 7~03 (2H~ m) a~d 7,23 (3H, ~) ~6~s~ 12 (!~ s~
purin~ . 51 ( 1~, ~, puxln~
MS~ Calcd~ .~or C2~H~N4O3(M~ M/Z: 36b.1~ 2. Fouc~d 3~. 1708.
~xampl~ 3 ~ S~-D~(hydroxy~n~t:hyl~cyclop~nt-2-en~
yl]~d~ni~ .
A ~o1u~1on oï ~ 9-~Sc~-b~3nzylox~Tne~hyl 4,e-~h~drox~nethyl)cyclopen~-2Qen~ yl3aderlLne I 10$ m 0.30 rnmol. ) in anhy~rou~ cli~hlnrorQ~ch~ne (24 mL) wa~
cooles~ to -78~C, To the elolutiorl wa~s add~d .xopwi~e ~l~wly, in argon ~re3am~, a ~olu~ion ( 1 M so;l.ution, 9 1 S mL ) of k oron ~richloride i.n d1chlorome~hane . The reaction mi~tu:~ wa~ s~irxe~ for 3 hou~s at ll.he 6ama temper~ture ~nd ~here was then ad~ed dropwl~ lowly mixtllr~ a~lhyc~rou~ metharlc)l and anhydrou~
di~hlorome~-helne (1~ n~l,). 'rh~a cs~c~ling :bi~.th w~3 ~elno~ed and the :~eaation mi~ture lwas ~ re~ until the rea~tion tempe~ture w~nt up to room tempera l.ure . ~he r~aac~on m~x~cure wa~; c~n~nt;~ und~:: r~d.u~ ed p~e~ure and ~hex~e W2~# adcied anhy~rou~ metha~llol (5 mL), and the mix~ure wa~ l~sf~ ~tarading fo~ lO mi.nn~es, ~5 followed ~y ~oncen~ra~io~ Imder redu::ed pre~;,;ure onae more~ This proceduLe w~ repea~ed fC)ux ~me;l;~ th~qn ~h~
re~ult~nt ~onc~3n~rate wa~ dls~c:lv~ad i~ met~a:l~ol ~S mL
~o which was added Amberli~e I~ 5 ( OEI' typ~
then the mi~ture wa~ stirxed f or on~a hou~ ~t room ~en~p~:ratu~e, The ion-exchans~e x~e2~in wa~ ered off, and the ~ rate was conc~antrA~ed und~ ul:ed p~o~u~ h~ ~o~entrat~ was su~jected to !1 siliaa gal (10 ~) col~m chromato~raphy, eluting wil:h chloro~c)rm-methanol ( 10 ~ he ~xactlon t:hlls eluted 3S ~as corlc~ntral:~d unde:~ reduced pxe~ure, tc~ ilhl~h wa~
~dded a ~mall v~lum~ o m~thanol t~ a~o~d (~

91~ 5~ lB~36~;TAK~DA P.~TENTS OSAKA Fether~t~n ; 063006601;~59./7~

u~
- 5~ ~

9-t4~B,5c~di(hyd~o~ hyl)cyclopent-2-en-l~B-yl3ad~nine as cry~ (6~ m~, yie~d ~39~).
Colorle~s amorphou~ product; :n.p. ~ 179 to 18(: C; W
(CH,O~ nrn (e)~ 260.9 (14200)~ D~!SO-d6~ 50O
NHz)~ ~ 2.23 ~lH, dcldd, J-5, ~, 5, 5 Hz, 5~1~1, 2.70 (1}~, m, 4-H), 3,51 (lH~ ddd, J-10, 5, 5Hz~ d 3,S7 (lH, .ddd, J=10, 5, 5 H~ 2OH)I 3.61 (2EIJ ~d, J=5, 5 H~, -CH70H)~ 4.78 ~, J=5 H~, -OH3, 4.8:~. (lH, t, ~=5 ~,-o~), 5,43 (lH, m, l-H), 5.79 (lH, In, 3-H), 6.V6 tlH, m, 2-H), 7.18 (~H, broad ~, -N~12), 8.05 (lH, ~, pllrine-H), ~.13 (lH, s. purille-H~.
MS ~ Calc~ . f~r Cl2H15NgO~ (M ~ M~Z i 2~ 25 . Found NfZ: . 261. 1212 ~sample 4 15 ( ~ ) -9~ , 5,1~-D~ (hydro~net;hyl ) ~clopenl~-2-~n l,~- .
~11ad~nln~ ~
~ t~s~-Ben~yloxym~thyl-4~-(hyd~Qx~lel:h~
cy~lopent-2-en~ yl~adenln~ (1S4 m~, 0~4 ~ol.) was pro~ ecl ln th~ same manner as Example 3 t.o af~rd ~0 ~ [4~,5~-di(hyd~oxy m~hyl)c~clopent-~-e yl~ad~nlnR ~105 mg, yleld ~2~).
Colorle~ amorphou~ p~oduc~ ry~tal~ized ~ m metha~ol), m.p.: 177 ~ 17~~; U~ (CH3~H) i~,xnm (~:
2~ 14700)~ NMR (D~SO-~6, 500 ~z)~ : 2.85 (lH, ~, 5-H)~ Z.g4 ~lH, m, 4-H~, 3.10 (1~, ddd, J~Sll~ 9, S
HZ) and 3.21 ~lH~ ddd, Ja:Ll, 6, 5 ~2~ ~-C~OE), ~,.57 ~lHf d~d, J-~10, S, 5 ~z) and 3.65 ~1~, dddl J=lU, 5, S
~z) (~C~kOH), 4.4~ (lH, t, J~S ~ O~, 4.'7'i (1~
J-5 Hz, -O~, S.62 ~lH, d, ~ 9 Hæ, l-H), 5.g~ (lH, m, 3~ 6.31 ~1~, m, 2-H)~ 7.19 (2H/ bro~d g, N~2), 7.98 (lH, 8, purin~H), ~24 (lH, ~, purine-H).
~- Calcd~ 2~5N502 (~ M~z: Z61. 1225., Found M/Z; 2~1. 1214.
Ex~ S
35 (~)~g-~5~-B~nzyloxym~hyl 4~-(hydroxy~ethyJ.~cy~lo~ent-2 en-l~ gu~nin~

91~ 5~ 16~36~;TAREDA PATENTS OSA~A Feth~r~t~n ; 06300~B01;~B0/72 l~o a ~oluti~n o~ 2-amin~-9 [ 5~benæ~'lox~
n~ethyl-4 ~- ( hydro~3nne~hyl ) c~clopen t- 2 -~n~ y]. ~ ~ 6 -chloro~ rin~ ( 123 mg, 0 . 32 mmol . ) in dioxanle ( 3 n~) was add~ A O . S N ~;olu~ion of pota3~ium h~droxi~ 4ml ), 5 and ~he ~nixtur~3 wa~ ~e~luxed ~or 5 hours . ~'~he reac:t~ on mixture wa~ concentrat~d undel~ reduce~ ~r~ xe. The concen~r~te wa~3 ~ub jec:t~d ~ cs ~ilia~ ~el ~ l;i . g) ~olumn ch~oma~og:raphy/ elu~ wi~h chloro~c~rm-metllclIl4l (20-1), Thç~ frac~lon thus aluted was concent;rated 10 under reduced pre~ re . TO the con~en~rate ~i, a~ added a ~mall voluln~ o~ wa~er t~ ve t * ) ~9- C 51~-r b~n~loxyln~hyl-4~-~hyd~ yqne~hyl)cyclop~nt~ en~

~rl]gu~nine ~ cry6tal~ (75 mgt yield 81~).

Colorles s amorphous pro~uat l S ~-NMR ( DMSO-d~, j S 0 0 MHz ) ~ : 2 . 9 5 ~ aH, m ,. 4 - H and 5 -11 ~, 3.24 to 3v37 (~X, m, -CH2OH), 3.55 ~lH, dd, J=~l, 5 Hz) a~d 3.~ dd~ ) (BnOCH2-3, 4.n~ (lH, dr J=13 Hz) and 4.15 (lH, d/ ~=13 Hz) (I~h~:H~), 4.76 (lH, t~ Ja5 HZ~ -OH~ 5~4~ t~ H~ 5,~7 (lH, m, 3-H~

20 6.~1 (lH~ m, 2-H)~ 6.~4 (2H~ broad s~ -N}12~ ~ 7.07 ~o 7.29 (5H, m, C6Hg~)/ 7.65 ~lH, ~, purlne 8-~:[) 10.50 ~1~, Ç~, -NH--l ~
~xan:pl~ 6 ( t ~ - r 5cx-B~l~zyloxym~9thy~ - ( h~srd~rmet;hy~ clop~int-2S 2~en~ yl]-5-me~ 2,4~3.E,3E~-pyrimidinedic,ne T:> a solu~ioll o~ en~yloxy:rnethyl~4~-h~rox~
methyl-lJ~ 3-metho~ -methoxyacr~loyl)u:l~eido3c!yclo pen~ ne t6~ tng, 0.19 mn~ol. ) obt~ined in :RI.,fexence E~ample 17 in ~ne~hanol (3 ~) was ~dded 25~ queou~
30 ~n~nonia ( 2 ~ . Th~3 mixture wa6 heated a~ 8:'i for ~0 hours in a ~e~led tube. ~h~ ~c~io~ ~ ~t~.r~l~ wa~

concentrat~d under xeclucecl ~ressu~e. The concentrate wa~ ~ub~ ed to a ~ilica S~el ( ~ g ) colulnn chromato~rE~phy, elu~ing with he~{ane-~hyl a.c,i 1tatia 35 ( 1:1 ) . Th~ :er~ctiOn ~hu~ eluted was ~nce~t.~ to d~yne~ under red~lcad p~e~ure to afforcl ( ~ 5~
.

gl~ 5~ l6s~36~;TAKEDA PATENTS OSAKA Fetherston ; o63op6aol;#Bl/72 _ 5~ _ .
bç~næylox~ne~yl ~ (hycl~oxyme~h~l jcyc:lopen~ en~
yl ~ ~5-me~hyl-~, 4 [ 11~, 3H ~ -pyrimidin~dion~ ~ 6 Z n y, ylelc~
~8~ ~ a~ a colorles~ oil .
~E% (CH~ . 3430, 16~0 ~m l; lH-N~ ((:DCl3~ 6(l MH~
1.~0 (3~ s~ -C~3), 2.23 (lH, m, S-H~ 2.g~ (~H, n~
~nd -O~ ) ~ 3 4 tc~ d~ . O ( 4E, ~ CH~O~I and BnO~'H ~ ) ~ 4 . 5 6 ( 2H, ~ ~ PhC~2~ . 56 ~ m, l~H and 3-H) ~ 5 . ~7 ( lH, m, 2-H), 7.09 (lH~ m~ py~lmidine~H)~ 7.31 (i;F., s~ C6H5-)t g-1;2 (lH~ broc:d ~ -N~
10MS 2 C~lcd ~ ~o:~ C,4H22~2~,s (M*) ~Z s .34~ . 15~0 ~ ~ound M~Z: 342. 15~5.
E:~ampl0 7 4,B~Sa~ hydrox~neth~ yc!lopent~ 3n ~ yl]-5-meth~l-2 ~ 4 C lE~ 3H~ _pyrl~nldi.ncid~ on~
A ~olution of ( ~ 5aL-ben~ylox~nnethy ( hydro~ymeth~l ) cyclopen~ -en~ yl ] -5-me~hy.l ~
2,4(lH,3H)-p3~imidinediorle (80 m~,t 0~2~ n~no,l, ) in anhydrous dichlorome~hane ( 10 ~) wa~ ~oolecl to -78C
and there wa~3 ~;lowly ad~ecl dro~wi~e, whil~ ;sl..irri~ in 20 argon ~reams, a ~olutic)n of ~oro~ t~i~hlor.ic.e in dichl~ro~ hane ~ lM ~c)lution, 7 mI. ) . The re~. .ction mixture wa~ stirred for 3 hour~ at ~h~ same ~l~emp~rat~ e and t:here w~ ~dded slowl~ ~ropw~e 2nh~rdrol.ls methanol-~nhy~rous clichlo~omethane (1:1, lO l~). q~her~, 25 the coollng bath wa~ xemo~red, and the react.ion mixt~lxe wa6 ~tirrecl un~11 th~ t~mper~ture went up t3 roo3n ~em~era~ure ~ The :reac~ TI mixtuxe w~ a~nae~ ~ated und~ redu~ed ~pressllre. ~ro the col aentr~t~ ~ira~ added anhy~lrou~ meth~nol (5 tnL) ~ whi~h ~;~8 le~t ~anding f~r 30 1~ minute~ at xoom temperæ~ture, ~ollowed by c~na~ntra~ion u~der reducf3d pre~;ur~ once ~nor~ Thl3 proa~3du~ wa~ xopG~at~d f~ur t~me~. ~he conla~!ntrat~ was ~ub~cted ~o a ~iliaa gel ( ~ ~) c~lurn~ chromatogxaphy, elutin~a with ahlo:coi~orm-methanol (30~1). q~hl3 fractivn 3S thu~ elut~d wa~i concentra1:ed under redu~ec~ p.e~ure.
~ ~h~ aons :~nt~a~e wa~; add~d a ~mall VO~ mel:hanol , 914!11,~ 6~ 16~36h';TAKEDA PATENTS OSAKA F~sh~r~ton ; 063006601;#6~27 ~ ~ r to a$ford ~ 4~B/5c~ ~i(hydro~ethyl)c~c.lclpent-2-en-l,B~yl J -S-me~hyl-~, 4 [ lH, 3~ -pyrimidinedione ia~l ~ol~rl2s 6 pri~lnæ (44 m~ ~ield 74~) . m.p. s ~2~ to ~:3''C, I~ tCl~ 16~0 cm~~ l-NMR (~MSO~da, 500 M:E~ 1. 95 S (1~, ddd, J--5, 5, 5 Hz, 5-EI), ~.61 ~lH, m, 4~H)r 3~46 (lH, ~dd, J~10/ 5, 5 Hz), 3.51 (lH, ~dd, J=:Lt', S~ 5 H~)r 3.56 (lH! ddd~ J-10~ 5r 5 Hz) and 3.57 I;lH, dcld, J--10~ 5~ 5 H2~ (-C~20H ~c 2~, 4.~;8 (lII~ t~ J:55 H2~ -OH), 4.76 (lH~ ~S Hæ~ -OH~, S. ~6 (l~lt m, l-M~,, 5.58 (lH, m, 3~.01 (lH, m, 2-H) r 7 ~37 ~ 8~ pyximidine-H), 11020 (lH, ~, -N~
MS C~ o~ 16~2b ~ g~) M/Z: Zs~ .1110 . Found ~/Z s 252, 11 27 .
~xample 8 ~ [5~-~snæylox~neth~1~4~-(hydroxymethyl)cyclop~nt-~-en-l~-ylJguanine 2 Amlno-~- r s~-benzyloxymethyl~4~-~hydrox~methyl)cyclo~nt-2~en-l~-yl]~-chlo:r~:p~rine (105 mg, ~.~7 mmoll wa~ sub~ect~d ~o ~u~tanl;.iall~ ~he ~0 ~e pr~cedure a~ Ex~mpLe 5 to give (~-9~[Sc~
benæyl~x~m~thyl-4~-(hydroxymoth~l)cycl~pont-2~e~ yl]~uanln~ ;!.~ o~y~tal~
(7~ ~, yi~ld 78%), Colorle~ amorphou cry~tals ; 1H-NMR (DM80~ 00 MHz)~ s 2.30 ~lH, dddd, J=~, 6, 6, 6 ~z, 5-.H', 2.68 ~lH, m, 4-~, 3.4~ (lH, d~d, J-10, 5~ S H2) ;!.~d ~.59 ( lH ~ ddd , ,J~1 0 ~ 5 ~ 5 }~ CH ~O~ ), 3 . 6 1 ~ d , J- l O, 5 H~) and 3.64 (lH, dd, J~10, 4 H~3 ~BnOC~ , 4.48 ~H, s, Ph~H~-), 4.76 tlH, tl J=5 ~z, -o~ 8 (lH, m, l-H)t 5-72 (lH, m~ i.01 ~lH, m, 2-H , 6.39 (2H~ broad ~, -NM2), 7.22-7.33 (513:~ ml C~ 5- r 7-~
(lH, ~, pur~ne 8-H).

t+)-9-~4~5~-Di(hyd~oxym~thyl)cyclop~n~-2~!n 1~-3 5 ~:L ] ~uanln~3 5!o a solut~on oi~ t~)~g-~s~ enzyloxyJne)t~l~yl-4 91~ 5~ 16e~3~h`;TAKEDA PATENTS OSAKA Fether~t~n ; 083006601;#83~72 roxylne~hy~cyclope~k-2-~3n~1s -yl~gllanine i n anhydrou~ dichloromethane W~15 ~ded dropwi~E~ ~lowly, while cooling ~ 8~C in argon stre~m6, a 1 mol boron triahlorid~ - anhyd;ra~s dichlorometh~ne ~o] ution.
5 The mix~ure wzl~ ~tirred ~o~ 3 hou~ he ~ me tempe~ature, . To ~che re?ction mixture wa~ a~cled dropwise sl~wl~r anhyd~ou~ methanol - anhy~ o~s dichloromethalle, then the cool~n~ bath was r~!moved, followed by ~tirrin~ the ~nixture! un~il the r~.action 10 ~emp~rature ~sached rooln tempexature. ~ 3c lvent wa~
dis~illed o~f under r~duced pr~ ure, To the ~e~idue was added m~athallol7 whLC~ w~ co~entrated a~ain urld~r r~d~c~d pre~sure. This procedu~e wa~ repe~d ~ur times, then ~h~ residue w~s di~olved in me~anol. To the solution was added ~mherlite ~G-S0 (OH typ~)/ an~
~he mi~ture w~ irre~ ~o~ one hour at ro~3n t~3mper~tur~ ~ Th~: ion-exc:h~n~a re~3in waE~ r~ of :~, and the ~ rat~ wa~ qon~en~rQted und~r redu~e~
p~e~sure. The xe~idue wa~l ~ub~ected ~o a ~i:l.ica gel column chromatogxaph~, ~lutlng with chloro~o:lm~
m~thanol. The fraction ~huæ elut~d wa~ conca~ntrated un~er reduoe~ ~x~ur~. ~o th~ concentrat~ a8 ~dded a small ~lum~ of wa~er to giv~ (+)-9-[4~,$~-di(hydroxymethyl)cyclop~nt-~-en l~-yl~guaninlil as ~5 crystale (coLorle~s ~morphou~ cr~s~ls)~
Example 1 0 [ ~,~, 5O~i (h~,rdroxymet:hyl) cyc;:lo~ent-2-e;n~
~yuanine ~ 9-lSa-~en~ylox~mQthyl~
~hydroxyme,thyl)cyclopent-2-~n~1~-yl~guanin~ ~76 mgr O.~ ol) ~a~ ~.u'l~je~ated to ~u~t~tanti~lly ~h~ sam~ pro~ed~re ~ E~a~pl~ o giv~
~ 4p,$a-di~h~dro~y~ethyl)cyclopen~-2-~)n~
yl]t3uan1ne a~ cry~tal~ S5:L mg, yield ~
35 Colorl~ei~s Am~rphou~ r~ttnl~tt 1H_~MR, (DMSO-dl;~ 50~ ~Ha:) : 2.16 (lH, d~ldd, J~5~ 5, 5, 5 Hz~ 5-H)~ 2.6'~ (111, m~

91~ 5~ 16~38~,TAI~EDA PATENTS OSAKA F~th~r~t~n ; 06300~601;#~4/72 $

4-H), 3.4~ ~o 3.62 (~H, m, ~20H-~ 2), k~7A. ~
Jc5 Hz, -0~), 4.7~ ~lH, ~, ~=5 Hz, -O~), 5.:Ltl (lH~, m, l-H)~ 5~71 ~r m, 3 - H), 6.00 (lH, m, 2-H)~ ~i.4~ t broad 6~ -N~2), 7 62 (lH, 5, ~urine 8-H)/ 10.,5~ (lH~
5 hroad 5, -NH- ) .
~aml?1~ 1 1 ,4R,5,5)-4-~ ( lS~ Camphanoylox~m~.thyl3-5-(b~rlz~rlox~nel;h~l)cyclo~en~ en~l-~ 6 -~hlo~ opurine an~i ( - ) - 9 - ~ t 1~, 4~, 5R ) ~ t lS ) - ( - ~ -C~mphanoy:Lc xyme~hyl ~ -10 5- ( benzyloxymethyl ) ~yclol?0nt- ~ ~en-l-yl } ~ 6 -ch:l oropurlne S~-B~nzylox~lethyl-4 (h~d:~oxymeth~rl )ayclopent~ n~ ]~ hlo:~c purin~
(~10 mg, 0~57 mmol~ ) wa~ dis~olved in anhy~rcus t~a~rahydro~uran ( 5 ml ) . ~o the ~o9Lution werl~ added lS (13)~(-)-~amphanic acid ~hloricl~ ~240 ~ng, 1.'; 2 ~nol.
ancl ~ri~thylamin~ t230 mg~ 2.28 mmol. ), ~he~ the mixture WA~5 ~tirred ~r 1~ houxs ~t rs~om t~ atu~
The reat:tion mixtUx~ was poured irlto l~e-w~ir/ W~iCh wa~ ~ub~ec~ed to caxtraCtion wi~h CH~13. The e~tra~t ~O wa~ dried ove~ anhydrous ~o~ium sulfa~ h.er. the ~olvent was di~i~illed o~ rhe~ ~esidue wa~ ~i;ub~ted ~o ~ ~iLiaa ~el col~nn ah~ om~togr~phy, ~he~ lut$on w~s per~orm~ad wi~h ~ mlxture o:~ he~ane and e~hyl acetat~
( 1 s 1 ) ~o cb~in 244 mg (.78~6 ~ og a mi~ture of 1 and Z .
25 This mixture wa~ ~ub~e~ted to ~ high per~or.m,.lnce li~uid ch~smatography ~Natera, p~r~lcil ~ he~ne~ O~ 0 ~1 ) ]
'I:Q ~;epara'ee 9~ 3,4R,5S) 4-[ ~lS)-[-)-c~mE~h~no~rloxime~hyl ~ -5-benzyloxyn~ethylcyclop~!~nt-2-en yl~-6-chloropurin~ (~) ancl ~{ (1~,4S,5R~4~[, 1 30 camphanoylo~y~a~h~l ] ~5-ben~yloxym~thylcyclc~pi:nt-2 en 6 ~hl~opurin~ IB).
~A): 24~S min.

column ~ poracil 1/4" x 1'~B) t ~4 min.
~olv~ntj hexAne-~tOH
(25~1) .

91~Fll,~ 5~ 16~36h`;TA~EDA PATENTS OSA~IA Feth~rgton ; 06300e~01;#65~72 $ ~
. ~ 6~ -d~te~tor; UV 254 mm Example l~
~ 9~t ~ 4R~5s)-5-Benz~l oxymeth~l-4-s ~h~droxymet~l)cyclopent-2~en~1-yl3adenin~
9-{~lS,4R,5$)-4-C~lS~ 3~Camph~noylo~i methyl]-5-(benzyloxymethyl)~yclopent-2-~n~ l}-6^~hl~opurin~
(70 mg~ 0.127 mmol,) w~ dis~olv~d in ~eOH ~:lO m~), to which was in~rodu~ed ammo~la ga~ ~r S minu~ un~r so~lin~ with ~alt-ice. The re~ul ant was he~iteA at 70-80~ ~o~ 16 hours in a se~led tube. From ~h~ reac~l~n mixt~r~t ex~os~ ~mmoni~ a~d M~0~ w~x~ di~til:l~d o~, and ~he ~e~ldue wa~ ~ub~ected to a silica ~:l column chroma~ogra~h~, Elu~ion wa~ ~er~ormed wi~h ~! mixkur~
lS o~ eth~l ace~e ~nd me~hanol (8:1). The re~ul~-an~
cry~al3 WQre recry8talli2~d ~rom a ~ixture c~ ethyl a~t~t~ and mothan~ glve (~ (lS,4R,5~)-5~
b~nzyloxymeth~l-4-(hydr~xymeth~l~cyclopent-~ ~n-1-y~]adenin~ a~ ~olorle~ needle~ (:35mg, yield 78%~.
2~ m.p. 1~6 ~ 1~7~C
[~D ~ 50.50 ~c~O.~ OH) ~pl~ 13 ~ g-[~lR,4S~gR)-5-~ensyloxymeth~1-4-lh~ro~ymeth~l)cyclopent~ n-l-yl]~d~ine 9{~1R~4S~5R)-4-[~18)~ Camphanoyloxym~l~thyl~ 5 (benzyloxylne~h~l~cyclopent-2~e~-1 y~ hlo:lopurin~
~0 mg, 0.145 mmol.~ was processed in ~u~tarltially ~he ~me ~anner a~ above to obtain ~ 9-~(lR,~S,5R)-5-B0nzyloxym~hyl-~-(hyd~oxym~thyl)c~clopent~l en-1 yl]~d~nin~ (4~ m~, yi~ld ~%).
m.p. 186 to 137~C (colorles~ needle~) lal26- 45.00 ~c-~.8, MeO~) ~x~ple 14 ~)~9 r(lS~4~,5s) d~5-Di(.hydroxymethyl)cyc~o],~ent-2-en_ 91~ 53 1~36~;TAKEDA PAT~NTS OSAKA Fetherston ; 06300B601j#a6f7 1 -yl ~ aclanln~a 9-[~lS,~R,5g)-5~-~enzyloxylne~hyl-4 (hydroxy~neth~l)cyclopent-~-en-1-yl~a~enirle (.'8 m~, 0,0 nu~ol. ) w~ ditE30lv~d in anhyc~r~us meth~rlene s:hloride 5 ( lO ml ) . ~o ~he f~ol~tion ~a~ added d:ropwise,. while ~tirrin~ q B(::13-(~H2~12 ( 2 ml ) at 78C . Tll~ mixtux~
wa~ ~tirred for 3 hour~ at ~his telnp~ar~t.ure ~! nd there ~a8 add~d ~H2~12~MeOH ( 1; 1 j d~ ml ) I then the 1: elnperatu~e w~ reve~rted to room ~em~er~tur~. ~he? ~vlvel ~ was 10 di~tilled of under ~educed pre~sure. ~o tll~ re~idue wa~ a~ded ~et)H ~ 5 ml ), whi.ch w~ a.gain dried ko . Th~ ~ p~oce~ure wa~ condu~::ted fou~ t~ ~ l;hen the residue wa~t cli~olv~d ill Me~H ( 5 ml ) . Ts: ~he ~olu~ion w~s addecl Amberli.te-IR-45 (W~kl~ b 15 resin) ~ th~n ~he ~n~x~ure wa~ ~tirred, Atet:r one ~oux~
the re~in wa~ filtered off., then ~he ~ol~nt w~
di~tilled o~ ~nd~ rçdua~-d pr~6~ureO q~ho ;r-læidu~ was subjected t~ a silica ~el col~mn ~hro~atogral~hy, followed ~y elutl~n with L'HCl3~MQOH ~5:1) to obtain ~0 (~)-3-[(lS,4Rt~S3-4,$-d$(hydxoxyme~hyl)~clo])~nt 2-en-l~yl]aden~ne (l~ mg, yLelcl 7~
m.p. ~06~07C ~c~lorl~Y~ n~edle~ t MeOH) t~3D ~ ~ 7~62 ~ 6, M~OH) ~5 ~x~m~le 15 (-) 9-[(1}~4S,5El~-4,!i-Di~h~drox~n~3thyl)ayal~l~)e,nt-:~-~n-l~yl]ad~in~
subs~antially the xame pro~edur~ a~ bove, ~tar~in~ wi~h 24 mg of (-)-9~[(lR,4Sj~R~-5-~enzyloxymethyl-4-(hydrox~methyl)cyclop~nt~ n~
yl]~denin~ (-)-9-[(lR~4s~5R)-4~5-dl~hyd~x~le~h~l) c~alop~nt-2_en-l-yl~d~nine was ob~ained (1.~ mg, yield 78%3~ ~
m.p. 206 t~ 207C ~colo~l~s~ nee~le~, MeO~
3~ [a~JD -- ~4 . ~ C--1 . 4 / ~OH) Exampl~ 16 91~ 5~ 166~36~;TAKEDA PATENTS OSA~A Fetherston ; 06300a~01;~B7/72 - 64 - ~135 9-~4,B,51;L-cli(hy~xoxymethyl)cyclope~nt-2~e:r~ yl]
ad~n;i.ne (~00 mg), la~to3e ~50 mg~, ~ellulo~,~ (250 m~) and magn~silun ste~ra~e (~0 mg) w~re ~ufici~ntl~
b~ ded, whlch wE~3 c~lnpressed to mak~3 tablet,~!.
5 Exampl~ 17 9-C~,B~Sa-di~h~lro~ymet~hyl)cyclop~3nt;-2-e~ yl]
adenine ~20~ ms~) r ~4hite vaseline (40.O g), e1hanol ( 1~ . O g ), ~orbi~an ~esquiç,leat~3 ( S . 0 ç~ ), po:L~ oxylaury:l alaoho~ e~her ( ~ . 4 g ), met.h~l parah ~ roxybenZ!oate (0.1 g) and refln~ wa~e~ (36.3 g) w~r~3 ~lellded 1tc prepare a 0. 2% olntment.
Example 1 ~
(+ )-9-~4,~,5a-di(hydrox~mQkhyl)c~rclopent-~-en l~-srl]
adenine (25 mg), lactose ~100 m~) O ~karch ~.~' 0 mg) and 15 magne~ earat~3 (5 my) ~re su~E~icien~ly ]~ended, which wa~ ~hen filled intc~ a cap~ule.

Claims (7)

1. A compound of the formula wherein B is a purine base residue bonded at the 9-position thereof, or a pyrimidine base residue bonded at the 1-position thereof, to the cyclopentene ring; one of R1 and R? is a hydrogen atom, and the other is a methyl group having an optionally protected hydroxyl group; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein B is adenin-9-yl, guanin-9-yl or thymin-1-yl; one of R1 and R2 is a hydrogen atom, and the other is a methyl group having an optionally protected hydroxyl group; provided that, when B is guanin-9-yl, R1 is a methyl group having a protected hydroxyl group and R2 is a hydrogen atom, and, when B is thymin-1-yl, R1 is a hydrogen atom and R2 is a methyl group having an optionally protected hydroxyl group.

3. The compound according to claim 1, wherein B is a purine base residue bonded at the 9-position thereof, to the cyclopentene ring.

4. The compound according to claim 1, wherein B is adenin-9-yl.

5. The compound according to claim 1, wherein the conformation between the hydroxymethyl group at the 4-position of the cyclopentene ring and the methyl group having an optionally protected hydroxyl group represented by R1 or R2 at the 5-position of the cyclopentene ring is an E-conformation.

6. The compound according to claim 1, wherein the conformation between the group represented by B at the 1-position of the cyclopentene ring and the methyl group having an optionally protected hydroxyl group represented by R1 or R2 at the 5-position of the cyclopentene ring is an E?
conformation.

7. The compound according to claim 1, wherein one of R1 and R2 is a hydrogen atom and the other is a hydroxymethyl group.
] 9. The compound according to claim 1, wherein the salt is an acid addition salt.
10. The compound according to claim 1, wherein the compound is (?)-9-[4.beta., 5.alpha.-di(hydroxymethyl) cyclopent-2-en-1?-yl] adenine, or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1, wherein the compound is (?)-9-[5.alpha.-benzyloxymethyl-4.beta.-(hydroxymethyl) cyclopent-2-en-1.beta.-yl]adenine, or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1, wherein the compound is (?)-9-[4.beta.,5.alpha.-di(hydroxymethyl) cyclopent-2-en-1?-yl]guanine, or a pharmaceutically acceptable salt thereof.
13. An antiviral composition containing an effective amount of compound of the formula wherein B is a purine base residue bonded at the 9-position thereof, or a pyrimidine base residue bonded at the 1-position thereof, to the cyclopentene ring; one of R1 and R2 is a hydrogen atom, and the other is a methyl group having an optionally protected hydroxyl group; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.
14. The antiviral composition according to claim 13, wherein B is a purine base residue bonded at the 9-position thereof, to the cyclopentene ring.
15. The antiviral composition according to claim 13, wherein B is adenin-9-yl.
16. The antiviral composition according to claim 13, wherein the conformation between the hydroxymethyl group a? the 4-position of the cyclopentene ring and the methyl group having an optionally protected hydroxyl group represented by R1 or R2 at the 5-position of the cyclopentene ring is an E?
conformation.
17. The antiviral composition according to claim 13, wherein the conformation between the group repersented by ? at the 1-position of the cyclopentene ring and the methyl group having an optionally protected hydroxyl group represented by R1 or R2 at the 5-position of the cyclopentene ring is an E-conformation.
18. The antiviral composition according to claim 13, wherein one of R1 and R2 is a hydrogen atom and the other is a hydroxymethyl group.
19. The antiviral composition according to claim 13, wherein the salt is an acid addition salt.
20. The antiviral composition according to claim 13, wherein the compound is (?)-9-[4.beta., 5.alpha.-di(hydroxymethyl)cyclopent-2-en-1.beta.-yl]adenine, or a pharmaceutically acceptable salt thereof.
21. The antiviral composition according to claim 13, wherein the compound is (?)-9-[5.alpha.-benzyloxymethyl-4.beta.-(hydroxymethyl)cyclopent-2-en-1.beta.-yl]adenine, or a pharmaceutically acceptable salt thereof.
22. The antiviral composition according to claim 13, wherein the compound is (?)-9-[4.beta., 5.alpha.-di(hydroxymethyl) cyc?opent-2-en-1.beta.-yl]guanine, or a pharmaceutically acceptable salt thereof.
23. The antiviral composition according to claim 13, which inhibits the growth of retrovirus.
24. The antiviral composition according to claim 13, which inhibits the growth of AIDS virus.