1. [51] Int. Cl.
C07D491/22 (2006. 01)
A61K 31/4745 (2006. 01)
A61P 35/00 (2006. 01 )
[21 J $ij!j~ 200810070276. 1
[43] 07f B 2009 if: 4 jj 1 B [11] 07f~ CN 101397301A
[22] $ij!j s 2008.9. 10 ~J~~ft~m~ m:l*~W~~•*m
[21] $ij!j~ 200810070276. 1 1-:~A. Jfj~~
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±m±.lt 4ooo16 m:l*rnnw q:r 13:6[ ~135GJI!-* 1 %
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rn ?f ~m.-'¥ f~ ~ 1~&~
[54] £~,ij~;fff,
1'1 1o - ~~ ~% :fJ'f ~ 1¥J 1K m: ·11: 1¥1 :t:t 1m Edjjtl ~ 1J
~*
[57] :100~
*~~0ffT-~~*~~1'!~1o-~~•w
~~~m:t:t1mi¥J•~•n. #~R~MI¥J*m:ttm
:t:t 1m~~ mu ~ :n ¥* 0 ~~ * m·11: ~r :t:t 4m J'i. ~ w:It
( I) , ~ 9=' A 7g {'pUO 1¥J ~ :lt 1-t if 4o/J; D ~bJ" 1'1 ~ jjt
~~I¥J~m~m: ~*~~~~m~m~MI¥1
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0
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~~n•£*M· ey~~ili1o-~~•w~~~m CI J
:t:t4m. J-J.. rm~Wmmi1tffl 0

2. 200810070276. 1 ~1/2:9!
D-A
~B y 0
0
;It~, m=O, 1, 2, 3: n=O, 1, 2, 3: m ~ n if§~:e)Z::f~: R1=H, Me, Et; R2=H,
Me, Et; R~R
1 2
if§~:e)Z::f~:
D *~13lfiit)]t-=fB"J::fftJL~~. D=NR3 4: ;It~ R R4;t{7J' H., Ct-6liJJ!EJZ15:3[~~
R
~. R3 ~ R4 ,f§~:e)Zi!r::f~:
/CH 2
D= N'-..... I ; n= 1,2,3,4,5
(CH 2)n
R 5 , R6 ,R 7 ,R 8 ~~H, C 1 _ 3 li:flt!!.X.*::10ii:J9Ht~nCH3, CH2CH3,
CH 2 CH 2CH 3, i-Pr, R 5 , R 6 ,R 7 ,R 8 PJ~~§IJ'lj, -!BPJ~/f'ffiiJ'l];
E=CH 2 , 0, S, NR9 ; R9 =H, CH 3, CH 2CH 3 ,
CHzCHzCH3, i-Pr, Ph, CHzPho
Hs~mey*~~mB"l~m•~~•,•• .. ••EJZ••; :eJGey*~~mB"l::ffm•~
Zft,~ft, ~aB .. T=B,~Mft,a~B .. ~*•EJZ•~•o
2. ;tx~u~* 1?JTJ£B"l13 1o-r~~:g:~~B"Jt{r::±Jm-g.mt7J¥!, Jt~tiE:tEr*1r¥!~=
iitt1o-r~~:;:~~:tE::fftJLm1fu~~*,j)j(~g;;B"Jm:Jt~B~tt*$ ~~ 1:1-s, :a:~ ~~*,J)l(
~~B"Jw;:j(~ft~~-{-g:*jjB"JP~(PJE:e)Z DMAP EJZ,j)j(~B"JfFfflr, tEJi@ti!JJt-20----50°Cr,
&.&% JVZ 13 ,J)l(~g;; s{] w~;
mmB"l::ffmm~~*~•B"l::ffmm~=Jt~~ .. JtWEJZC*: EJZ::f13~•B"l::ffmm~
*' ~*' C.;J;7'G:e)Z;EfC.~; EJZ13Jt1ffi*)]t-=fB"J::fftJLfitjfUP~(PJE., z:.nw . pgm, DMF., DMSO.,
2

3. 200810070276. 1
3. 1x~u~* 1 ?!fiii3" 1o-1£~W;f%t~I¥Jfrr:±.~~JJX;:1J¥!, ;ttt~tiE:tt-=f~:1Jrid!:
:iitt 10-1~~%;f%t~:ft:ffffLm1fU ~ 1=j ,IJ$1.:~ 1:1-3 I¥J~~f~=F~EJt=F¥lfJR~ CBZ E)(;,]lt
T¥lfJR~ BOC 1~1?1¥J~~!W:ft~)J$1¥J DCC, E)(; DCCIDMAP, EJ(;;lt{t!!~1);).-f" DCC #{'F
ms{]mt±~MI¥J1tJtrr, a&m¥li!ll:-2o,_,sooc-r &m%JJX;W~. M:tE:ffil'JLm1fu~Jm~~t?~
*
rn l0 -t§ m1¥1 ~PX; 1ik ;
Mffll¥l=frmm~~*~•l¥l=frmm~=•~m,•~~•*; ~~*~•l¥l=frmm~*'
~*' 3m~:tt3m: ~*;lt{tB~~-=fi¥J:ffil'JLm1fU~rtPA:, z.nf, pg~, DMF, DMSO, THF
BJZZ.~: :ffil'JLmtfUffl:;l: ~mM~l0 &ml¥1 10-1~~%;f%t~~~1L
4.il'X~U~* 1 Mii* 10-1~~W;f%t~I¥J1rr1:.~~JJX;1Jr!, ;tt~tiE:tE-f"i~:1J¥!t!:
3Mtt 10-1~~%;f%t~~tE:ffil'JLm1fU ~ 1=j ,IJ$1.:~ 1:1-3 l¥l*,]ltn~ I¥J~~Jl:ft~,IJ$1¥J DCC,
9JZ DCCIDMAP, ~;lt1t!!~1);).-f" DCC fffFffli¥Jm·ti4mMI¥J1'Ffflr, :tE&m¥li!Ji:-20,_,50°Cr,
% PX;* ,J)ltn~ s{] w~:
Mffll¥l=frmm~~*~•l¥l=frmm~=•~m,•~~•*; EJt~*~•l¥l=frmm~
*' ~*' 3m:eJZ:tt3m: ~i3";lt{tB~~-=fi¥J:fffJLm1fU~rt~, z.nf, pg~, DMF, DMSO,
THF BJZz.~: :fftJLmrr:um:;;:~mM~l0&mi¥J 1o-1~~:t-;f%t~~i1L
5. 1'tHJi5tx~U~* 1?!fii* 10-1~~%;f%t~I¥J1rr1:.~, ;ttt~t!E:tE-f", ?!fkti¥J1t~~ C I ) :tE
~~&A~~ey*M~~ilitt&mtt~~~~:t-MMo
3

4. 200810070276. 1
tt*®i~
*~~~R-~~*~~#~••~••~~*mttm~~R~~4~~0
lfjj{ft*
1966~~1l!~Wall~§{j(f}.~ ll!¥-f:f:f~fJl4m#~ (Camptotheca acuminata) ~%/ib1~~0
7%~~~ (Camptothecin, CPT) (JAm Chern Soc. 1966 88:3883-3890), 129~3!R~~-}t~~
;t1;J~o~~~m~rfljj¥tf'ti'JI®~ti=!J'f·tB*Affl~:l:~. {B~#~M$11J1'Fffl-A, ~~i!JIJT;ltll{ij
*J-"Zffl o [))H)§ X}}.%~~ 5t ~ I:B 71 0-1£~#~M CHCPT), ~2 Jlftit*iJffl *. ~ ;ttJtfifmmiitf
}, fiJj[~~. $iiJfl=ffl/J~~2, ¥-f§JIJ~xt@:~t±Jff'ti:Jff@, ~~@, JmHJ'G@, :9dflJ~
$&$, ~~m, g~m;~~ttMjj:f:fB~fi~o~~~HC~~*Mtta~, RnDM
r~u&mi!JIJJJJG*M·titt1fum~''fti'*=
HO
HO
II a lib
IIa~~~:1l&:,@1~lli---I*Jn~PF~2*fD~JJJG7vt§J-"Z~~-%A;IIbJ§, ~~PJM~7JC {895% ~_t
E8HCPT~~ 7m$¥t!'ti[Cancer Chemother. Rep. 1970,54,461- 470; Cancer Chemother.
Rep. 1972, 56(Part 1), 95 - 101; Cancer Chemother. Rep. 1972, 56, 515- 521]o ;tt.:£~@:129~
®~~~~~~~~~(HAS)~*' *~~W~~. W~~~~~*~~R%A;~llb
:tE1* r*J~titi*¥:JJJ(tB*, F~~J§$·t1o Jj{ij'*_t7v 7 :0:~Utt=IJ-"Z~fi~:1l, R ~~~:*ffl!i:, l!
tflli ~3& 7 HCPT~:IillJ 11:ffl ~ ): o 7v 7 ~ ~HCPT~ ~4m5fUffl $, if~ ~~it.~*x-1~~
!fm3zHr 7 ~;f1;J1~t'rll 0
1994~, ~ll!FDArtti1b.KM•t11Jt.:fL'M'* Cirinotecan, CPT-11) _trtL ffl~mfi~~mi.
1_t=!_~-kJJJGE8I~~~. ~FJJJG*~o 1996~ffl~N~~mimA~=~mfi~4m7.KM·t111l1~'M
J* CTopotecan) ;J..:gjtfl_trtJ, ~OOFDAX ~1999~1ttfl;tt1t7v/J~JW!HiP@ CSCLC) ~=
~fflff~!fm, ~129~m$m~. -~*fflj(, .:£~~*·~~. ~~T~~~fflo 129~,
x1HCPT:itt1r ffiJ $1~t1p, :(:£ {~ 00 1*J @~ :Ef E8 IRJ Bt, BJC~;tt l.KM·ti:A:f:f :m:~ g 3C
4

5. 200810070276. 1
Yu-Ling Leu CJ. Med. Chern. 2008,51, 1740-1746) t~mTtEHPCT7J1~~_tiJIAIF£Jit
1fl::J,~1~;tt?KriH'iiW!i.io ~IW!i.Jilitl~I~~~. 7.KtiH'i~j]Q~j(o W02005062985~~T
f~;(W:f~~,&;ttirr'±.ttml¥110, 20 CS) XJl.ltitB"Jn~JW~W~ .. :lJ~W~ . :lJEJZ:lJ~It~~W~.
rmr:f 00 8"J § 141~ Xirfflt 71 o, 20 CS) •~t1-tEJtXJl.w;;1tB"J~~n~ CCN 1673225) *ll~mlW~
CCN1673226)o B1i'J:frlfn.31( r:f1~7.KfD~~J]J(ili B"Jffitl:fflt?J-~1~~%~~. {B ~j!JJ:~{tirttm#
&ffflHtB"JfD~~HCPT7.KtiH'iB"J IQJ~io
7'17 fD~~HCPT?Km:tl: IQJ II, ~1i'J W:it 7 J!:r; CI) 1tirttm, ~!R1tif!jo/.)~1J.A:ff ~M­
B"J?Km:tt, W~:fr*A~~~~~~ili~~!i.JttmH~T, ~'±.!i.i~o
tt~~~
:;$:'jj:_~ ~M~B"Jti* fPJ JII~, ~1~:fr~ OOI¥Z 1tffl8"J1~~%;f%J~ft;tttn'±.!jo/.)B"J I o-~~
gwB"J~~~J-JmJ!i.J, ~~~~;ttffimB"J~~~~oi!~!i.J!jo/.JJJ-1f~~~*mtt,:fr*A
1*~~PJ 7tfD~~J1Jtte Io-1~~•~1WX2Z;tttn'±4m, ~'±m~f~=m 0
:<$: 'jj:_ E)j ~ ,& 8"J Jlj; 7'J :
<I)
;ttr:p, m=O, 1, 2, 3; n=O, I, 2, 3; m ~ n PJI::J,if~~. illPJ~~; R1=H, Me, Et;
R2=H, Me, Et; R1 ~ R 2
PJI::J,if~~. illPJ~~;
D ~~151f~~-TB"J1f~JL~IIJ, D=NR3R ;ttr:f R3 , R ~7J H-. C1-61[~9)(;~5(~~ 4
~. R3 , R4 PJI::J,~if~~~EJ(;i!f~~~~;
/CH2
D= N'-... l ; n= 1,2,3,4,5
(CH 2)n
5

6. 200810070276. 1
RS. R6,R7,R8*7f-H, C 1 • 3 1[f!!lX;1Jj)t'{!;I1G~,~OCH3, CH2CH3,
CH2CH2CH3, i-Pr, R 5 , R6,R7,R81lJ!?J,;j{JIEJ, -fE.IlJ!?J./f';f§IEJ;
E=CH2, 0, S, NR 9 ; R 9 =H, CH3, CH2CH3,
CH2CH2CH3, i-Pr, Ph, CHzPho
~~mey~~~m~~m•~~•,••,••~~•; ~ey~~~m~~m•~
z•,~•, ~aa,r=•,~••,•~•,~*•~•*•o
J::i!W:rt c I ) 1tir4m~tu~ 7Jrt-§t5:
A. }:1£*~~:ffn~tP;E r:f ~13-~Hg;:~Jc.. ~&ifk&J.SY, ~ey:ff~~JLfiHiUr:f~JJODMAP
~~Hg;;, :tE -20,__,50°C~1*1-501J"Bt, %J1X:tloii:rt C I) ~1tirlmo
HO
0
+
II
C I - C - A - D • HB
OH 0
D-A
~B y0
0
B. fl£*~~:t£~mm~r:p~-£-~£~~Z~BOC~~~-~-:ff:DIT, ~
DCC/DMAP, ~~{$;f§@m·ti4o/JJYt~1tJ=frr, :ff&J.SY~/1t-20,__,50°Cr &J.SY%fiXW~, W:ff
~mm~r=rm~~~£00#~ffiJ.SY~&fiXifk, %fiX~m:rtci)~~irtmo
6

7. 200810070276. 1
HO
0
+
II
HO-C-A-NH-P
DCC/DMAP
!lll.f~Jf'
HB
C. ±m.tt 10-1~~%;f*J~ C Ila) :fr:ff;J;JLt$}fU~~15-=~1~~~1¥J~~~:fr DCC, EJG
DCC/DMAP, BJt~11E.t§mi¥Jmti4mmii¥J1t!Wf%pj{;W~, &mllti'BJ l!Jat~J:, &m~ft-20""'
50°C o
HO
0
+
II
H O - C - A - D . HB
OH 0
7

8. 200810070276. 1
DCCIDMAP
HB D---AYO
0
mm~~mm~~*~·~~mm~=•~m,•~~•*; ~~*~•~~mmm
*' ~*' cm~PFC:.m: ~*:1t1ffi~l*-TI¥J~mmifUP~tPJE, 6m~, Wfmij, DMF, DMSO,
THF ~6ML
*litE)jJiffJ£~15"10-t~~:g~~~f{j:±_~ C I ) PJfflr$~~X1Alki;JJ~f'=:±.mmimt£1¥J
tJg4m 0
*1tEA1£~BJF~IO-f£~*~~!f!l~~ll!mtt~ru-m r, Jm.tttt~&m c~fZJf!itffl) m
~*•~•~m:±.~. #~ffim~-~~~~ru-~. Mw~~~*:1t*mtt.•&•~~
ffl~§~o
A1*~1f8!:1Jj_
~OO~~~~~PT~*~fttt#A~~~OO~~M*~~. ~~~ffW:1J~~~*~
EJL
;g;118!-wrll
n~%~~1o- c Y-N,N-=6•~) r•w~~-~~it~~
1±-T1*1¥J~~~1tr, r25ml-Tf*~-=~PHrnr:f:tJOA80mg10-t£~%~~. 4 ml:lGl.KP~t~,
1±~¥1ffi.rt9U-f~:¥E~mMo ~4f300mg c Y-N,N-=6-~) T~a~ml~m-Tsml-T-1*1¥1=
•~mr:f, ~tt¥~:to. ¥:¥1ffi.r&m2-3!JIt-L &ml$, :tE&m~r=F:toJ.k~¥~. ~Ws?t~rr.
:tOA15mlZML ;fJT lli !f!lf*, tl¥~, ffl ~M!9tf¥7t!f!li*o ~4f!f!l1*mr ~M, ~:to ~m!~¥¥¥!RIIt
1L fitll:;fJT~, 1ffi1m, ffl Z.ft{ltl¥Jt: ~I.J£1Ji!:~~ ~J§, .lli-Tf*, 1~¥tJ1~~-@.ml'f*60mg,
m.p221-223 DC, t&.$54% o IR CKBr,cm- 1) :3559,3435,2942,2646,1774,1743,1653,
13
1602,1587,1462,1437,1346,1234,1194,1161,1141,1107,1068o C-NMR (500Hz) , B :
7. 745(C-18),8.369(C-28), 18.267(C-25),30.311 (C-19),30.535(C-24),46.098(C-27),49.175(C-5),5
0.138(C-26),65.222(C-17),72.334(C-20),96.680(C-14),119.094(C-9),119.117(C-16),125.911 (C-1
1), 128.203(C-8), 130.289(C-12), 130.376(C-6), 131.133(C-7), 145.225(C-13), 145.837(C-3), 148.82
8

9. 200810070276. 1
7(C-1 0), 149.948(C-15), 152.485(C-2),156.709(C-22),171.055(C-23),172.376(C-21)o
0
5
7
28 27
~
__/N 0
28 27 OH
11 12 18
ESI-MS: 506(M+-HC1)
~bl!if?tl2
t~~:WfX>J1ifoX10- C Y -~~) T&i~~mf~~B"Jittl~
~~CBZ15iH?B"3280mg Y -~~T~;fll250mgDCC1$-T10mlCH2Ch~, :hllA40mgDMAP,
~¥1i! ~:f9Hf10min, {I}:JJUA0.5ml Prt~;f0150mg HCPT o _&@10/Jai ~_I:, J:1~, ~~fflpH3
B"JM*~~*~~-ttoWffl~~NiliC~~~*~~1ifoXtt,.§ffl~~-~*~~~tto
~~fftJ1~f§3G7}(Na2S04T-i~L ~T-fftJ11$37Uo fflTHFmfrl¥, :hUA0.5mlZ.ml, &if10%re-
1Jffi, ±IA~~~frl¥, &@1/Jaile:;fl, J:i~, :hnAZ~~~. {~¥U~jt~lfll1*100mg, 1&$
46%o IR (KBr,cm- 1 ) :3428, 2927, 1745, 1657, 1623, 1591, 1504, 1235, 1193, 1162,
1109, 1047 o ESI-MS: 450(M+-AcOH)
~bl!if1!J3
H~~y-~~T~D~~~B"J~~
~~230mgBoc1*J?B"J y -~~T~;f0250mgDCC1$-T10mlCH2Ch~, :h!lA40mgDMAP,
tff.ti'f10mino :hOA0.5mlPrtP;E;fll150mgHCPT,_&$10/Jai~J:, _&@%JJ.X§fflpH31¥J®7J<~~.
¥7t~)}(~7'J®'t'f., {I}JiH'@;fllNaHC03~~$3?)}(~7'J1ifoXtL .§fflt{Q.~-!bk¥7t~3~)j(~~
~-~, f3:tJ1~ffl7C7kNaS04T-i*o tff!i!:ff:tJLm1fU{~¥U200mg~jt~[EI'f*, L&$85% o ~~
Lf!l'f*m-T ZM~W~~=~ lf!J1GI¥J¥~-g.~, i7J<mit!Pr1001JUHCl~;foi¥J ZmlZWam~, _&@
%JJX:J§, tt¥m, ~~V!tJtm-TJk, :hoAJAJIPJ, tJT~, tt~{~3§UHCPT- Y -~~TmlWa~~~
20mgo 1&$11% o ESI-MS: 450(M+-AcOH)
9

10. 200810070276. 1
~M!i19JJ4
1~~WfXf~10- CY -N,N-= ftll(~) T~@~~~!ki¥J1ttl~
:tE-T~-*I¥Jw/=tmtr, -T25ml-T~-*1¥1-=~JjHfti:J:f/JoA100mg10-1~~WfXf~, 4.5m17GJJo~t~.
:tE~tffil.rtJ.t:f-'f~1G~m~!fo ~~300mg c Y -N,N-=ftlle~) TM~!k~M:m-Tsml-T~I¥1=
j(Ef3;11GJ:f, ~2Hf¥00.1JO, ~¥!!r&@2-31J,Bt, J1¥J!t, IBI1*~1li-T~, f{}~U130mg*£1.Jtro ~~*£1.
Jtr l¥J~;f)};;K:I!.g~7tl'ti:tE ftiM!=f, fJ.t#-2-Smin, J1~, ~lli -T~, f{}~tl~-~IBI1*90mg, t&
$64%, m.p247-2so·c. IR CKBr,cm- 1 ): 3582, 3435, 3035, 2964, 2676, 1757, 1663,
13
1634, 1606, 1554, 1503, 1467, 1230, 1190, 1158, 1143, 1130o C-NMR (500Hz) ,
o: 6.670 CC-1), 18.615 CC-2), 29.758 CC-3), 30.283 CC-4), 42.237 (C-5), 48.919 CC-6), 55.998
CC-7), 64.985 CC-8),
72.764 CC-9), 97.881 CC-10), 117.590 CC-11), 118.216 CC-12), 125.172 CC-13), 126.737 (C-14),
127.615 CC-15), 128.001 CC-16), 130.790 CC-17), 143.074 CC-18), 143.404 CC-19), 144.977
CC-20), 149.235 CC-21), 149.986 CC-22), 156.187 CC-23), 171.537 CC-24), 173.531 CC-25).
5 7 4
"--N~o
I 2 ~
5
3 OH 0
ESI-MS: 478(M+-HC1)
~M!i.Wtl5
j~~WfXf~10- CY -N,N-= ftl~~) T~W~~~!ki¥J1ttl~
:tE-T~-*l¥1-=3Jjt*K!=f/JOA90mg y -N,N-=ftlle~T~!k~~. 180mgDCC*Il60mgDMAP,
:tE 1Oml=it: fti :l9t*ll1mlP~tPJE 1¥J¥~ilm:1fU J:f fJ.tf¥ 15min, ¥} /JOA 1OOmg HCPT, :ff~~ r ,&@
2-3*, ttfzHJT~4:1t, f{}~Usomg~-~IJI!I'f*, m.p: 247-2so·c, t&$35% o
ESI-MS: 478(M+)
~Jlffi1~tl6
1~~W;J-xf~10- CY -~!W*) T~W~~~~l¥J1ttl~
10

11. 200810070276. 1
tE-T~ff.Jl'( '=t$tr, -f"25ml-T~ff.J-=:~mi:~:hllA80mg10-~~_:;:~·· 4 mlx7J<PI:t~,
tE~¥lffi.rtll.!ft~%1::mM. :m-3sOmg Y -Jl!h~TIUt!t:&!t:m-TIOml-Trlk~=-lfttt'fl, ~
·tt•:hu. 1t~r&~2-3 1Jf!1a &~%~.15, :tE&~~'P:hU7.l<fl?lii, m~sJt#, :hOA15ml
Z~, ~W~~. ttd, fflZM~~~~--~~-~~M, -~Z·~-~H~.a#
:ffffs, tm~. ffl ZM{lfl~. ~ffi-T•• ~JU~:lt-@.fiM1*25mg. t&*-20%. IR (K.Br,cm-1 ):
3425, 2929, 2614, 1747, 1658, 1602, 1503, 1463, 1366, 1233, 1193, 1158o 1046o
ESI-MS: 520(~-HCl).
11