J m m a l of Medicinal Chemistry, 1971, Vol. 14, No. 6 451
NOTES
As an extension of this work the preparation and study of some new Schiff bases from m-aminophenylthiazoles appeared worthwhile. The earlier work on Schiff bases with different substituted benzaldehyde nitrogen mustards having shown that compounds derived from 4-[N,N-bis(2-chloroethy1)amino 1-m-anisaldehyde are in general significantly more active against L-1210 lymphoid leukemia,3$4we first prepared and studied the corresponding Schiff base from 4- [ (3-amino-4-methoxy)phenyl1-2phenylthiazole. The compound was submitted for antitumor screening to the Cancer Chemotherapy National Service Center, and was found to display considerable activity against leukemia L-1210 even at a low dosage. It has passed the sequential screen as well as the confirmation tests5 It also produces a high degree of inhibition in Walker carcinosarcoma 256 (intramuscular). Furthermore, it had a lower order of toxicity compared to the other nitrogen mustard derivatives reported earlier. A few more Schiff bases from other substituted benealdehyde nitrogen mustards have also been synthesized. All the compounds could be obtained readily by heating 2-phenyl-4 - [ (3-amino-4-methoxy) phenyl ] thiazole * HC1 with the appropriate aldehyde in EtOH. The requisite aldehyde mustards were prepared by the hydroxyethylation of the anilines with ethylene oxideRand treating the resultant products with POCI, and DNF.' All the Schiff bases prepared are shown in Table I along TABLE I SCHIFFBASESFROM 2-PHENYL-4-[ (3-AMINO-4-METHOXY)PHXNYL]THIAZOLI.: c l c H z RJ c H z ~ 2 CH30 N & - c H = N ~ ~
Ph Yield,a No. RI 1 H 2 M e
3 4 5 6 7
F H OMe H OMe
Rz H H H OMe H OEt H
Ra H H H H H H OMe
% 68 72 65 71 68 70 65
Mp. "Cb 215-218 185-188 156-157 146-147 205-207 224-226 190-192
FormulaC CnHuCl~NaOS.HCl CzaHz7ClzNaOS.HCl CzrHaClzFNaOS. HCl CzaHzrClzNsOzS * HCld CzaHzrCIzNaOzS * HCl C~SHZPCIZN~OZS. HC1 CzaHzoClzNaOaS.HC1
a Recrystd from EtOH. Melting points are capillary melting points and are uncorr. All comps were analyzed for N, S. Analytical results obtd were within &0.4y0 of theoretical values. Anal. Calcd: C, 58.28; HI 4.69. Found: C, 58.01; H, 4.70.
with their analytical data while the antitumor screening results on 4 are given in Table 11. Experimental Section 2-Phenyl-4- [( 3-amino-4-methoxy)phenylIthiazole. HCI.-A mixt of 2.0 g (0.01 mole) of 2-chloro-3-amino-4-methoxyacetophenone,s 1.5 (0.011 mole) of thiobenzamide, and 8 ml of (4) M. G. Dhapalapur, 9. 9. Sabnis, and C. V . Deliwala, J . Med. C h e n . , 11, 014 (1968). (5) Cancer Chemother. R e p . , 26, 1 (1962). (6) M. Freifelder and G. R. Stone, J. 078. Chem., 26, 1477 (1961). (7) R. H. Wiley and G . Irick, ibid., 26, 593 (1961). (8) J. R. Catch, D. F. Elliot, D. H. Hey, and E. R. H. Jones, J. Chem. Soc., 552 (1949).
TABLE I1 ANTITUMORACTIVITY' OF SCHIFFBASE4 Tumor wt,O Test* system
Dose, mg/kg
Survivors
L1210
Animal wt diff (T C )
-
g, or survival daysd
T/C 6.5/9.3 9.5/9.3 15.5/9.3 14.4/9.3 12.5/9.3 11.8/9.1 11.8/9.1 9.0/8.7 9.3/8.7
T/C 7%
80.0 5/6 -5.7 40.0 6/6 -4.4 102 20.0 6/6 -3.5 166 10.0 6/6 -2.3 154 -1.2 134 6/6 5.0 129 -2.0 3.30 6/6 129 -1.4 2.20 6/6 103 -0.3 1.40 6/6 106 -1.4 0.96 6/6 AA 330 0/3 0 110 0/3 0 36.0 3/3 3 12.0 3/3 14 WM 45.0 5/6 -29 0.7/8.7 8 For test procedures see Cancer Chenwther. Rep., 25, 1 (1962). * L1210 = L1210 lymphoid leukemia, AA = toxicity WM = Walker 256 (intramuscular). Tumor wt for WM. Survival days for L1210.
abs EtOH was refluxed. The solid pptd from the mixt after about 0.5 hr was filtered, washed with EttO, and dried, 2.45 g (80%). It was of anal. purity, mp 248' dec. Anal. (CISHidN2S.HCl) N, S. 2-Phenyl-4- [3-({ 4-[N,N-bis( 2-chloroethyl)amino] -3-methoxya benzylidene ] amino)-4-methoxyphenyl]thiazole HCI (4).-To soln of 2-phenyl-4- [( 3-amino-4-methoxy)phenyll thiazole. HC1 (3.0 g, 0.01 mole) in 10 ml of EtOH was added a soln of 4-[N,Nbis(2-chloroethyl)amino]-m-anisaldehyde (2.76 g, 0.01 mole) in 5 ml of EtOH. The soln was heated on a steam bath for a short time and allowed to stand a t room temp for 1 hr. The solid that sepd was filtd, washed (EtOH, Et20), and crystd (EtOH). All the Schiff bases were prepared by this procedure.
Acknowledgments.-We are greatly indebted to Dr. H. B. Wood, Chief, Drug Development Branch, Cancer Chemotherapy National Service Center, for his cooperation and for making the screening data available and to Mr. M. T. Jaokar for microanalyses. We are grateful to Dr. N. I
