N o,rES CHjOCH,C(CHz)LEHj
N
I
N CHd&COOCJL I1 CH,OCH,C( CH~)IOCHJ
I1
N I
N 11
CHjOCHX(CH2)jCHj V
discontinuance of Walker 236 testing system in the general screening.
T ~ B LI E --Antitumor Compounds
mg/k:!
I
230 100
acti\it> against \\ A-25b\Tt did, Sur1 I \ ors T-C
6 16 6 6 6 6
- 27 - 14 -9
T/C
(Yo)
9 8 63
Experimental Section
1,4-Dimethoxy-2-butanone Azine (I) and 1,4-Dimethoxy-Zbutanone Hydrazone (III).--I solution of 32 g (1 mol) of aiihydrous NIHa in 250 ml of anhydrous AIeOH vias stirred in an ire 6 6 -lh 18 I1 .0) bath while 33 g (0.25 mol) of l,ldirnethoxy-%-biitaiioiie (pre6 6 -7 72 103 pared by the method of Heiiriion and Kupiecki12 from 1 , P b u t y n diol dimethyl ether13) in 50 ml of hIeOH was added dropwise 6 6 - 16 41 I11 105 over a period of 30 min. The reaction mixt,ure was then stirred 6 6 -1i 25 70 a t room temperature for 16 hr. Removal of hIeOH and excess 6 '6 -7 42 45 NzHl followed by fractional distillation gave 22 g (60yc yield) 6 6 -3 89 30 ~ and 11.0 of t,he hydrazone (111),bp 91-92!' ( 5 . 3 mm), n Z 41.4671, g (17% yield) of the azine (I), bp 138-140" (2.6 mm), 7L2'D 1.4664. 1,4-1) imethoxyA n d . (CGHI~NZO~), C, H, X ; (CizHzJizO~),C, H, N. -2 60 4-butanone 400 6,6 Ethyl Pyruvate Azine with 1,4-Dimethoxy-2-butanone (II).A solution of 16.6 g (0.11 mol) of 1,4-dirnethoxy-2-butaiioiie -3 86 I IT 400 6 '6 hydrazone (111) in 50 m lof anhydrous MeOH was stirred at 0" while 13.2 g (0.11 mol) of ethyl pyruvate in 50 ml of VeOH was compounds were not reported. Wiley and coworkers4J added dropwise over a period of 30 min. The mixture w a d allowed to stir a t room temperature overnight, arid then distilled to prepared a series of substituted hydrazones of pyridoxal, give 19.0 g (70% yield) of the azine, bp 119-120' (0.4 mm), indole-3-carboxaldehyde and 2-methoxynaphthalden% 1.4708. Anal. (CnHzo3204),C, H, N. hyde, but only t w o of 35 compounds prepared were Ethyl acetoacetate azine with ethyl pyruvate (IV) was prefound t o have significant activity against sarcoma pared by a procedure analogous t,o the foregoing. The product, 183 in mice. mp 88-89", was purified by sublimation at 65' (0.1 mm). ilnal. (CIIHIINPOI), C, H, 3. A survey in the general area of biological activity 1-Methoxy-2-hexanone azine with 1,4-dimethoxy-2-butanone of azines again revealed little. Some synthetic azine ( V ) was prepared in an analogous fashion, bp 123-126" (2.3 mm), dyes, such as methyl violet and heliotrope, mere n Z 5 D 1.4628. d n U l . (CI~H&~O,), C, IT, 5 . chimed t o have good tuberculostatic effect against Ethyl acetoacetate azine with 1,4-dimethoxy-2-butanone ( V I ) human type tubercle bact'eria.6 The molluscacidal had bp 135-138' (0.35 mm), 12% 1.4938. Anal. (ClrHv&&a), activity displayed by azines of certain p-ben~oquinones~ C, H, N. 45
W M li~rgely att,ributed t,o the parent q u i n ~ n e s , ~ - ~ Acknowledgment.-The authors wish to thank 11r. :iud the d l known biological activity of nitrofuran John Gravatt' for his assist'ance in performing analytical derivatives could possibly be t'he reason for the antimeasurements. microbial activity exhibited by a number of J-nit,ro(12) G. F. Hennion and F. 1.' Iiapiecki, .I. Org. Chem., 18, 1601 (1953). ?-furfural aziries.loill (13) W.Reppe, J u ~ t u . Liebig, ; ArLri. Ctiem., 696, 38 (1Y35). The activity exhibited by compounds 1-111 is in a wag rather unique in that similar activit'y was not observed by et8hylacetoacetate azine with ethyl pyr/%Alanyl Thio Esters' uvate (117) nor by l,4-dimethoxy-2-butanoneJthe parerit compound of 1-111. Logically, other azine deI N D CHARLLS G . SICIIINLR GIL CLIFTOS~ rivatives of 1,4-dimethoxy-2-butanoiie, such as compounds V and VI, were prepared for a preliminary Department of Chemzstr?j,*Yorth Texas State Ytr.ucture-activit'y study. However, the study could L'niuerszty, Denton, Texas 76203 not be cont'inued in our laboratory because of the
Recezved October 10, 1969
G. Irick, J . Jfed. Phnrm. Chem., 5, 49 (1962). ( 5 ) R . H. W l e y a n d R. L. Clevenger, &id., 6, 1367 (1962). (6) 11.G. Good, Zantr. Bukteriol., Prrrasitenk. B b t . I. O r i g . . , 169, 99 (1957); (4) R . H. Wiley and
O r g . Chem., 26, 1614 (1960). (8) A . Halawani and N . Latif, J . E g y p t . M e d . Assoc., 37,957 (1954). (9) T. von Brand. 13. Mehlman, and hl. 0. Nolan, J . Pnrasitol., 36, 475 (1949). (10) J. D. Jolinston, U. S. P a t e n t , 3,099,663 (1963); Chem. Abstr., 60, 28U.l~ (1964). (11) J. 13. .Juiinrton, U. S.P a t e n t , 3,206,257 (l'Jti7); Ckem. d b a t r . , 67, 310011 (I'JHT,.
The introduction of chemically active centers in organic molecules which may serve as alkylating agents has been an area of recent interest in thesyntheses of (1) This invedtigation was supported in Vart lis Kational Institutes of IIealtlr Research Grant N u . C.\-08102. Sational Cancer Institute, and b y tlie Nortli Texas State University Vacnlty Researcli Fund. (2) Sational Defense Education .\et B'dlow, Title 11'.
