POTEKTIAL AKTICANCER AGENTS. I1
September 196s
1015
TABLE I
s0. 1 2 3 4 3
0 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 2 F, 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 4s 49 .0i 31 .2i 53 54 5.5 56 .3 7
s 3-C1 3-C1 3-CI 3-C1 3-C1 3-CI 3-CI 4-C1 4-C1 4-C1 4-CI 3,5-C12 3,5-C12 3,5-C12 3,5-C12 3,5-C12 3,5-C12
3-Br 3-Br 3-Br 3-Br 3-Br 3-Br 3-Br 3-F 3-F 3-F 3-F 3-F 3-F 3-F 3-CF3 2-COOH 2-COOH 2-COOH 2-COOH 2-COOH 2-COOH 2-COOH 3-COOH 3-COOH 3-COOH 3-COOH 3-COOH 3-COOH 3-COOH 4-COOH 4-COOH 4-COO11 4-COOH 4-COOH 4-(2-Pyridyl) 4-(2-Pyridyl) 4-(2-Pyridyl) 4-(2-Pyridyl) 4- 12-(4-31ethyl pyrid yl )] 4- [2-(4->Tethylpyridyl)]
RI
H
H H OCH3 OCHs OC2Hj H
OCHa €1 OCH3 OCzHs
H H OCH3 H OC2Hs H
H H
R2
H CH3 OCHI H
H H H
H
H
oc&
H C1
H H
H
H H OCHI H H
OCH3
H H H CH3 H OCHI
H C1 H CHI
OCH3
H
H
OCHi
OCH3 OCzHj H
H H
H H
H CHI H
OCH3 H OCH3 OC2H5 H OCH3 H H
K8
C1
OCHa
H H
c1
H H H H H H H H H OCH3 H H H H H H OCHi
H
H
H OCH3 H H €I
H OCH3
OCH3
H
H
OCH3
OC2Hj
H
H H
CI H
H H
H
CH3
H
OCHi H OCH3 OCzFTj H OCH, H OCH, OCPHL H H
H
H
OCHa
H OCH,
0c1-1~
H H H H H
H
H CH3
H H C1 I3 OCH3 H €1 CI H CH3
OCHI
e1
H OCH,
H
1-1 T I r3 H OCH3
H H I3 H H H H H
Mp, o c a
190-192 229-230 156-157 182-184 201-202 118-120 169-171 191-192 192-194 208-210 168-1 70 220-22 1 225-226 141-142 195-197 165-160 202-203 210-211 202-203 185-186 195-196 205-200 11.3-116 204-205 128-130 220-221 197-198 172-173 198-199 200-202 198-200 198-200 166-167 194-igez 147-148 113-115 182-183 159-160 182-184 245-246 2.54-2.55 217-218 215-216 219-220 222-224 243-244 222-223 198-199 228-229 220-223 248-250 130-131 Oil Oil Oil Oil 150-152
Formula
CiiITiiCl;jN2.HCIC Ci8HigC13N,>.HClc CirHigC1,~N20.HClc Ci8€Ti&I3N20
HCI‘
CigII2iCI3N202. IICIc CiqlT,iClaru’rO~IICle Ci?I IrsCIjS2. IICI‘ CI8IIigCI3N,O.IIClc Ci81€i!iClrNr0.HClc
jt nalysesb
C, C, C, C,
€1, N IT, N 11, x 11, N c, 11, r\‘ C, €1, N C, 11, N C, H, 9 N N N C, TI, N N N N N N C, H ru’
.I1ClG Ci !,I Inr Clr N& €ICIC Ci j T IrsCI4S2. TIClC Ci8Hr8CliS2.T€ClC Cr8Hr~C14N20.1ICIC CisHi~Clr?jiO~ITClc CigH~oC14X20~ llClc Ci7HijCliN2. I€Clc C17HijBrC12S2~ HClC Cl8Hl9BrC12S2.IIClc 3 C18HIIBrC1~N20.1€CIc N C181119BrCl~S20~ HClC N C1g1121BrC12?;202 HCIc N C1gH21BrC12N20~ITCle S C I 7 H ~ ~ B r C l 3 X 2 ~ H C l C5 Ci7Hi7C12FIY2.HClC C, H, S C I ~ H I ~ C I ~.HClC FN~ N C I ~ H ~ ~ C I ~ HCI‘ FN~O. N C18HinC12FS20 .HClc N CigH2iC12FN202. HClc N CigH2jC12FNaO. HClo N CiiITisCIsFS? .TTCIc ?1‘ C ~ ~ I I ~ i C 1 ~ F ~ N ~ O ~ .N HClc Ci8HlsCl,S202d C, 13, N clsFr20ci2?rT20,d x, CigH2oCl2ru’j,O3d N C I ~ H ~ ~ C I ~ N ~ O ~ N~ C2oF122C12N20rd N C:20H&lsX203d N Ci8HijCl,31\j202d N Cj8Hi8C12N20P.HClC C, H, N CigH~oC12N202.HClc N Cjq€I~oClaN~O,~ .HClc N CiaIT?oCI2S2Os.I1ClC ?: C~oH22C1.”204~HClc N C2o€I,,C12?;203. HCIc ?; Ci8Hi,C13N,02.HClc 5 CigTT2oC12S2Os .TTClc C, €1, r\‘ CinHyoC12N2Os .ITClc 5 C2OH22ClyX204.IIClc 5 C~oH22C12N208.HClc N C I ~ H ~ C I ~ NHCI‘ ~O?. N C22H2iC12N3d C, H , N C23H2jC12N3d N C23TT2aC12N3od N C~~H~OCI~N~~ N C23H&12N3d N C2JI,5C1,NaOd C, H, N C~!,112lcl3~202
a Melting points were taken in open capillary tubes in a sulfuric acid bath and are uncorrected. * Where analyses are indicated only by the symbols of the elements, snalyt-ical results obtained for those elements were within &0.4% of the t,heoretical values. c Prepared by method A ; pure compounds were obtained without recrystallization. d Prepared by method B and characterized as free Schiff bases; recrystallized from EtOFI.
\
0
1
2'4'1lJ
,
:;4 'I
iiii )
I!: I4
I1
\
4-('I
POTENTIAL ANTICANCER AGEKTS. I1
September 1968
1017
TABLE I1 (Continued)
8
Y
X
N0.C
4-C1
3'-OCH
14
Teat systemd
15.0 15.0 15.0
-7 5 -7
AA
100.0 33.0 10.0 3.0 50.0 400.0 200.0 100.0 50.0 150.0 100.0 66.0 42.0 50.0 30.0 18.0 10.0 40.0 40.0 40.0 40.0 40.0 40.0
11 0 14 16 - 48 -3.3 -4.8 -4.7 -3.1 -6.2 -5.9 -5.5 -6.3 -5.9 -3.7 -3.4 -2.7 - 20 - 15 - 18 - 24 - 20 - 20
100.0 33.0 10.0 3.0 4.0 400.0 200.0 100.0 50.0 75.0 50.0 33.0 22.0 25.0 15.0 9.0 5.0 25.0 25.0 25.0 25.0 25.0 25.0
24
WM
3-Br
3'-OCH3
AA
WA LE
WM
33
2-COOH
H
Cures
WM
WA LE
20
Dose, mdkg
Animal wt dif, g (T - CY
A.4
WA DL
WM
100.0 33.0 10.0 3.0 50.0 200.0 100.0 100.0 100.0 100.0 100.0 100.0 100,o
Tumor wt (g)' or survival days0
T/C
0.8/6.8 1.1;s.0 0.917.1
2.2/13.8 14.3/10.0 12.3/10 . O 15.7/10.0 12.3/10.0 10.8/9.3 12.5i9.3 13.0/9.3 12.8/9.3 11.8/9.6 12.5/9.6 11.3/9.6 11.2/9.6 0.9/6.9 1.0/7.5 0.517.4 0.2/5.9 0.215.2 0.1/6.0
T/C,
%
Specificity test
Confidence, 7a
11 13 12' o
99.7
o
99,7
o
99.7
o
99 7
15
143 123 157 123 116 134 139 137 112 130 117 116 15 13 6
a
3 1'
-8 11 -2 -1.6 -0.8 -1.9 -4.4 -3.6 -3.5 -4.3 -0.8 -4.7 -3.9 -3.4 -2.6 - 19 - 10 -21 - 11 - 15 - 16
0.9/5.5 10.5/8.5 10.0/8.5 10.0/8.5 10.8/8.5 12.717.7 11.0/9.7 10.5/9.7 10.8/9.7 12.0/8.8 13.0/8.8 14.0/8.8 12.8/8.8 0.5/6.1 0.318.7 0,2/6.8 0.7/8.7 0.4/7.1 1.016.2
16 123 117 117 127 130 113 108 111 136 147 159 14j 8 3 2 8 J
16k
8 24 29 27
7 3
1 -20 -7 -4 0 3 0 -3 -1
9.6/10.7 30.0/16.0 29.0/16.0 11216.7 2.215.7 2.0/4,4 1.815.9 1.115.2 0.5/5.4
89 187 1811 17 38 45 30 21 9c
l0lX
x4
I 2-1 12:: 1 .?-I
12; I40 Iii2 l:il
121 !I7
110 1-11'
I22 loll 1 li-1 I .-I1 I II IO I ::
12 I :;
