154
SOTES
Potential Anticancer Agents. I. S?iithesia of Some _Nitrogen Jlustard Containing
Heiiz?-lideneh?;drazi~~es
\Il'
.ltiaI,vse-
C(
heb
C, H, ?j c, 11, N e, I I , K ,'j
N
c1, s S S
against Duriiiirig leukeniia JValker 266 (subcutaneous), L1210 lymphoid leukemia, a n d Walker 266 (intramuscular). Thc compounds are, in general, of low toxicity arid sonie coriipouiicls are nontoxic even at high closes. Benzylidenehydrazides obtained from S-(Z-thiazoly1)maloiianiic acid hydrazides and substituted beri-
NOTES
January 196s
155
TABLE I11 p - [ N,N-BIS (2-CHLOROETHYL)AMINO]BENZYLIDENEHYDRAZIDES
RZR, I
x
NO
I
Ri
4-Nitrophenylb H 4-Nitrophenyl H 4-Nitrophenyl H 4-Xitrophenyl H 4-Xitrophenyl OCzHs H 3-Chlorophenyl 3-Chlorophenyl H H 3-Chlorophenyl 3-Chlorophenylb OCH, H 3-Chlorophenyl 3-Chlorophenyl OGHL I% 3,4,5-Trimethoxypheiiylb 3,4,.i-Trimethoxyphenyl €I H 3,4,3-Trimethoxyphenyl 3,4,,5-Triniethoxyphenyl OCzHj H 3,4,5-Trimethoxyphenyl 3-Pyridylb H H 3-Pyridylb 3-Pyridylb H 3-Pyridyl OCzHs 3-Pyridylb H H 3-Pyridylb 4-Pyridylb H H 4-Pyridyl H 4-Pyrid yl H 4-Pyridyl H 2-Pyridylb H 2-Pyridyl H 2-Pyridyl 2-Pyridyl OCH3 2-Pyridyl H 2-Pyridyl OCzHs H 2-Pyridyl 3-(2-Hydroxy-4,6-dimethyl)H pyridylb 35 3-(2-Hydroxy-4,6-dimethyl)H pyridyl a Pure compound was: obtained without recrystallization. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
Mp, o c a
Analyses
228-229 203-204 213-214 204-206 132-133 164-165 192-193 198-200 1.39-160 2 18-2 19 145-146 192-193 205-206 197-198 17,3-176 208-209 152-153 164-165 179-180 122-124 175-176 2 lS3-2 17 207-208 218-220 221-222 265-266 147-148 140-141 154-155 128-128 129-130 124-125 191-192
c, H, N
N
N N N
c, H, N
N
N N N N
c, H, N
N N N
N C, H, N N
N N N N
c, H, N N N N C, H, N N N N N N N
218-219
C, H, N
210-212
c, H, N
* Screened for antitumor activity.
TABLE IV SUMMARY OF THE SCREENING RESULTSAGAINST DUNNING LEUKEMIA A N D WALKER 256 (SUBCUTAXEOUS)~ R I
_ R
I%
_
~
-
Dunning leukemia (solid)--------
Dose, mg/kg/day
Survivors
Curesb
T/C,C %
400.0 400.0 200.0 200.0
6 /6 4 /6 6/6 7/7
2 2 4 0
150' 187" 187" 106e
Dose,
mg/kg/day
Walker 256 (subcutaneous)--------Tumor wtd Survivors T/C, g
T/C, 70
50.0 6/6 0.2/7.3 2 2-c& 50.0 6/6 1.1/7.3 15 2-OCH3 50.0 6 /6 6.8/10.7 63 2-c1 50.0 6 /6 9.2/10.7 85 2-NO2 .so.0 6 /6 5.3l5.5 96 a For testing procedures 5ee Cancer Chemothempy Rept., 25, 1 (1962). Survivors at 30 days without meaburable tumors. c Ratio of mean survival time of test animals ( T ) to control animals (C). d T stands for test animals, C for controls. e Mean survival time of control is 16 days.
zoic acid hydrazides were inactive against all the tumor systems studied. Similarly, compounds from picolinic acid hydrazide and isonicotinic acid hydrazide did not show any appreciable activity. However, derivatives of nicotinic acid hydrazide demonstrated significant untitumor activity against Dunning leukemia and
Walker 256 (subcutaneous) and their screening results are included in Table IV. {p-[Bis(2-~hloroethyl) amino] benzylidenejnicotinic acid hydrazide (17, Table 111) gave two cures against Dunning leukemia at 400.0 mg/kg/day and also produced 9S% inhibition against Walker 256 (subcu-
