*\lay 1966
421
XOI'ES
4 PHYSICAL PROPERTIES OF THIOSEYICARBAZONES SYNTHESIZED TABLE I : AX.\LYTICSLD . 4 ~ ~.\XD hlp, O C
Compda
Formula
------Calcd, C H
---
70---N
S
C
Found, %H N
AQjXEtoH,
S
2-Keto-3-methoxybutyraldehyde bis( thiosemicarbazone) (111)
208-212 C~HUXOOSZ32.1 5 , 4 32.1 24.4 32,8 5.5 31.4 24.1
2-Keto-3-~nethoxyethoxybutyraldehyde bis( thiosemicarbazone)
213-216
C~HI~?YI~O& 35.3 5.9 27.4 20.9 35.4 6.1 26.9 20.9
(IT) 2-Keto-3-acetoxybutyraldehyde bis( thiosemicarbazone)* (V) Pyruvaldehyde bis(N4-dimethylthiosemicarbazone) (VI)
210-212 C&4N60& 115 dec
33.1 4.9 29.0 22.1 33.3 4.9 28.2 22.2
COH~~N;BSZ 39.4 6.6 30.6 23.4 39.1 6.7 30.3 22.7
a Abbreviations in common use for these compounds are: 111, KMTS; IT', MKTS; prepared by B. D. Aspergren.
V,KATS;
and TI, PTSRIZ.
mw
233 271 348 237 267 347 247 346 232 328 410
t
9,100 7,350 47,450 9,250 7,500 48,200 14,200 28,500 15,400 24,300 3,320
Original sample
ACTIVITY'OF SEVERAL THIOSEMICIRBAZOXES COXPIREDTO KE.I~HOX.~L BIS(THIO~E.~~IC.~RB.\ZO~E) TABLE I1: THEANTITUMOR Dosing A body A tumor 70 Expt
Drug
Dose. mg/kg
period, days*
Survival
wt, g
size, mm
inhibC
...
Control . . . . (17) 9/10 70.0 33.9 ... I 25 oral 4-17 5/5 61.4 -1.8 > 100 v 25 oral 4-1 7 4/5 51.5 33.3 2 B ... Control . . . . (17) 9/10 45.2 32.5 ... I 25 ip 5-15 5/5 18.0 0.7 98 V 25 ip 5-15 5/5 8.2 7.0 79 C ... Control . . . . (18) 9/9 56.2 29.8 ... I 25 oral 6-17 10/10 47.2 5.3 82 I11 25 oral 6-17 10/10 41.5 0.6 98 D Control . . . . (20) 9/9 66.8 38.0 ... I 25 ip 6-19 5/5 29.2 2.2 94 I11 25 ip 6-19 4/4 22.8 -1.9 105 E ... Control . . . . (17) 4/4 88.8 42.3 ... I 25 oral 4-15 5/5 45.8 3.0 93 IV 25 oral 4-15 5/5 42.0 14.6 65 a Against a nitrogen mustard resistant variant of Walker 256 carcinosarcoma in Sprague-Dawley rats. * Days after tumor implaritation. Dosed daily except Sundays. Parentheses indicate the day on which final measurements were made. c % inhibition = [change in average diameter (control tumors - treated tumors) X 100]/[change in average diameter (control tumors)]. A
...
I t was found that this agent was equally active by either route of administration and that it was equal to or slightly more active than I, the parent compound, while the toxicities of the two drugs were similar. I n expt E we found that 2-keto-3-methoxyethoxybutyraldehyde bis(thiosemicarbazone) (IV) had less antitumor activity but that its toxicity to rats mas essentially the same as that of I. These data and those previously reported2 show that certain modifications of the ketoaldehyde portion of I can be made without great loss of activity but that such changes are limited. Substitution of a methoxy group for the ethoxy group of I seemed to cause an increase in antitumor activity (cf. 111) but the substitution of an acetoxy or methoxyethoxy group for the ethoxy radical caused a loss of biological activity (cf. IV and V). Previous work had indicated that pyruvaldehyde bis (thiosemicarbazone) and ethoxypyruvaldehyde bis(thiosemicarbazone) were considerably less active than I, which of course suggests that the nature of the ketoaldehyde is important in determining the antitumor activity of bis(thiosemicarbazones).
described earlier.2 Recrystallization was accomplished from hot ethanol (111-V) by adding an equal volume of water or directly from absolute methanol (VI). Testing of Drugs.-Drugs were prepared for testing and tested in the manner described earlier.2 All other experimental conditions were also the same as previously reported.
Experimental Section
As part of our program directed toward the synthesis of various nitrogen mustard derivatives as potential antineoplastic agents it was desirable to have the
Source of a-Ketoa1dehydes.-Pyruvaldehyde was obtained as a 30% solution from Aldrich Chemical Co. 2-Keto-3-methoxybutyraldehyde and 2-keto-3-methoxgethoxybutyraldehydewere obtained from B. D. Tiffany, and 2-keto-3-acetoxybutyraldehyde from B. D. Aspergren, both of The LTpjohn Co. laboratories. Preparation of Thiosemicarbaz0nes.-All bis(thiosemicarbazones) were prepared by small variations of the general method
Acknowledgment.--We wish to express our appreciation to E. E. Smith for his assistance with the animal studies.
Synthesis of Potential Antineoplastic Agents. XIII. 1- {p-[Bis(2-chloroethyl)amino]benzyl] pyridinium p-Toluenesulfonate and Related Compounds1P2
-
DRUR. ALWANI, ADRI.4
C.4T.4L.4 E O B L E , AiXD
FRANK D.
POPP
Department of Chemistry, Clarkson College of Technology, Potsdam, S e w York Received January 11, 1966
(1) P a r t X I I : (1964).
F. D. Popp and D. IT. Alnani, Can. J . Chcm., 43, 1506
( 2 ) This work n a s supported in part b y research grants from the American Cancer Society (T-17iD) and from tlie National Cancer Institute, U. S. Public Health Service (CA 06606-03).
a :tixat
Ilecr~stalliaetlfro111 diosatic. i, 1:ecrystallixetl from aretolie. aie. e Recrystallized froin beii~e~it~-dirneih~-lfr,l.niariii~e.
p-loluciiciulfonate of p - [bi5\2-cliloroethyl)aiiiino ]benzyl :d(~ohol(benzyl alcohol niust:ml) (I). 111 511 attempt l o Yynthesize this compound by the reaction of I with p-toluenesulfonyl chloride in the preqence of pyridiiic. it wai noted that instead l-{p-[bis(2-cliloroetliyl):~11iuio]bt~nzy1] pyridinium p-tolucnesulfonate (11) w\-a. o1)t:tiriecl Rcwtiori of I1 u itli imquinolnic~gave thti c.orre5,poiitling isoquinoliniuni ~ l 111 t M l w h 15 as alw obtained by reactioii of I TI I t h p-toluenesulfonyl cahloritlc 111 the. prcsence of iwquiriolinr\. I11 :I iiim1:ti niaiiri(~ t hc rcuctioii of I 11 it11 p-tolucne.ulfoii? 1 c~hloridc 111 til? ~ ~ l ' " C l l ( (' of othcr b a w gave thc rc1:Ltc'd ('0111-
?(Ch2CHICII 2
Q
i? ( CHICII-Cl) '
OTs3
CH20H
' 3
CH,-N
%I-
111
( I ) I< I 1 i w : l r l I < > L l , 1 \ I i L i l , l I I 0 l i U b b , \\ I, (Ioiidmhii J l l t d Chini 6,4 i ll'J6.31.
p - [Bis(2-chloroethyl)amino]benzyl Alcohol ( I j. -.'l'tic C~~llo\viiig procedure was more zuccePsEu1 in our hands tliati t1i:ti reported kJ)' Iwamoto, e1 Tit :isuspen&n of 12.3 g (0.05 mule) of p[ I ~ i s i 2 - c h l o r u e t l i ~ l ~ ~ i i 1 i i 1 i ~ ] b e i i z ~inl d 200 e l i ~ ~nil~ l rii' e ~ triel 1 i : i n ~ ~ l . c d e d in ntr ice bath, \vas added v-ith stirritig :irid iii simtll portions (over 25-30 min) 3.8 g (0.1 mole) of S:tHIT,. T h o mixtitre was stirred for 2 lir i i i tlie ice bath :tiid then f o r 2 lir :it ri)iim temperature. 11n-as then poured iiito ice v,*ith vigoruria S Iirritig id the white solid tiitit separated in S5-99(% yield was filtcrtxl, diied, and iised \r-itlitrrit further purifica(ii)n: ni1) 31--.i2°. l i \ . 3 rnp 52-53". 1-( p-jBis(2-ch1oroethyl)aminojbenzyl jpyridinium p-Toluenesulfonate (11): --To a mixture of 4.02 g (0.02 mole) CJFI atid 4.2 g (0.022 inole) of p-i iilueiiesu~fony~ cahloride,5-S nil of pyridiire \v;iadded with htiiriiig. The mixture was stirred overtlight rrl 1'1JO111 leinperaturc. poured i t i t i i iw, :iiiti estrac~ted(C'HCIi). C ' ~ ) i i ( ~ i i tration of the dried chloroforni estr:ic.t gave :I solid 1vtiii.ti \v:i. ized frorii dilisaiie t o give S.6 g (s
