SOTES
Sovcmber 1969 Experimental Section Melting points were determined on a Thomas-Hoover apparatus and are corrected. Ir spectra were recorded on a Beckman IR-9 recording spectrophotometer, nmr spectra were determined in CDCL on a Varian A-60 spectrophotometer (TLIS), and the mass spectra were run on a CEC 21-110 spectrometer with a direct-inlet system. All ether extracts were washed with water aiid dried over Sa280r. .halytical results for the elements indicated agreed within =!=0.3ycof the theoretical values. Z-(l-Propenyl)-m-dithianes (2a-d). Method I.-To a soliiiioii of 0.4 mole of the appropriate aldehyde (la-d) aiid 0.1 mole of 1,3-propanedithiol iii 200 nil of AcOH \vas added droplvise 5 ml of 20yCEtOH-HCl over 15 min a t 20" with external cooling. After stirring for 17 hr at room temperature, the reaction mixture \vas poured onto ice aiid extracted with EtyO. The extract was evaporated and the residiial oil distilled. Method 11.-Dry HC1 gas was pashed iiito a solution of 0.1 mole of 2a-d in 200 nil of AcOH a t 10" for 1 hr and then stored at room temperature for 3 hr. The soliitioii was then poured onto ice aiid extracted with Et20. The extracts were evaporated to give the crude product which wa5 purified either bjor distillation. Z-(Z-Chloropropyl)-m-dithianes (3a,b,e,f). Method 111.--A 30lutioii of 0.4 mole of the appropriate ddehyde and 0.4 mole of 1,3-propitiiedithiol in 200 nil of AcOII was p a t iirated with d1,y HC1 while iiiaiiitniriiiig the reactioii a t 25'. hfter stirring at room temperatiire. the reaction mixt iii'e wab poiiiwl oiitu ice aiid extracted n i t h Et,O. Removal of the solvelit afforded the crude tallization or distillation. pI'IJdlict \vhic.h \vas piirified by I-Methyl-4,8-dithiaspiro[2.5]octanes i4a,b,e,f). Method 1V.To a soliitioii of 0.05 mole of 3a,b,e,f in 100 ml of anhydrous THE' maiiitaiiied at -20 to -30" iiiider S?was added 20 ml of BiiLi (3 J/ i i i hexaiie). The wltitioti was stored at 0" for 17 hr aiid allowed t o warm to room temperature, aiid 100 ml of H 2 0 was added aiid extracted with E t 2 0 . The extract \vas evaporated aiid the residiial oil was distilled or crystallized.
Acknowledgment.-We are indebted t o the folloning members of our Physical Chemistry Department directed by Dr. 1'. Bommer: Dr. E'. Scheidl and his staff for the microanalysis, A h . S.Traiman for the ir spectra, Dr. T. Williams for the Iimr spect'ra, and Dr. \V. Benz for the mass spectra. We thank Dr. E. Grunberg of the Roche Chemotherapy Department for the biological result's.
Carcinogenic Activity of Analogs o f p-Dimethylaminoazobenzene. I>(. Activity of the Quinoxaline and Indazole Analogs
111s
I n this paper we wish to report the preparation and testing for rat hepatocarcinogenic action of the isomeric p-dimethylaminophenylazoindazoles and p-dimethylaminophenylazocluinoxalines. .All of theqe azo compou1id.i are new 5ubstances. I n the indazole case it is po54blc to attach the p-dimethylaminopheriylazo moiety :it the 3, 4, 5 , 6, and 7 poiitionb and we found we werc able to ma1;e :ill theye i5omer.i by the usual method of diazotizing the amine and coupling - - it with S,S-dirneth~lanilirIc. The 5-. ti-, and 'T-aminoindazoles were conimercially available. The 4-aminoindazole w i h prepared from 2,G-dinitrotoluene by the method of Iin-urtler and I,uca.i4 while the 5-amine was prepared from o-nitrobenzoic acid by the method of Aron arid Elvidne.5 The DAB analoes of indazole are listed in Table I n the case of the quinoxaline analogs of DAB, there are three isomers possible, i.e., the 2 , 5, and 6 compounds. The 5 and G isomers could be prepared by diazotization and coupling of the corresponding amines while it was found necess-ary to apply the procedure of Brown and lraessinger6 in order to prepare the 2 isomer. 2--Xminoqui1ioxaline was made by the method of Tishler and coi~orliers.~5-.~minoquirioxali1ie was prepared from ",3-dinitroacetwriilide by the method of Stevens and coworkers8 while 6-aminoquinoxalirie was synthesized from 4-nitro-1,2-diarninobenzene by the method of Platt and Sharp.Y The Quinoxaline analogs of DAB are listed in Table I.
f
I
Experimental Sectionlo
All of the dyes but the 2-quinoxaline compound were prepwed by diazotization of the amine followed by coupling with K,Ndimethylaniline. . 4 $pica1 procedure is given below and the dyes are listed in Table I. After applying the method below and several minor variatioiis t o the preparation of the 2-quinoxaline arialog, we applied successfully the sodium coupling with nitrosodiomethylaniline to the 2-aminoquinoxalirie.6 N,N-Dimethyl-p-(3-indazylazo)aniline.-3-.lmilloilldazole (4 g) was diazotized iii i . 5 ml of conceiitrated HCl and 60 ml of H20 at 0-5' \vith 2.1 g of S a S 0 2 . Excess iiitrite was destroyed after 1 hr by addition of siilfaniic acid, aiid coupliiig with 3.6 g of S,Sdiniethylaniliiie aiid 6.1 g of aiihydrous SaOAc in 50 ml of 505; EtOH-H,O was allowed to proceed for 2 hr. -kt the elid of this time the mistui.e wa:, treated with excesh SHdOH. The dye \vas filtered, lvashed well iHrO), aiid dried. Thih wah dissolved i i i I500 nil of C6H6aiid chi,omatographed o i l aliiniiiia. The oratige fixtion eluted by C6H6 \vas conceiitrated aiid re from EtOH.
Results and Discussion I n the biological evaluation3 DAB (Butter yellow) at the O.OG% level gave tumor incidences of 7/10 a t 4 month5 and 9/10 a t A months, while at the 0.37, level it gave ;/lo in ci months. Our most active compound, HPG, at the 0.03% level gave 10 110 tumors in 2 moiithh. BP5 gave 10/10 tumors a t 4 months a t this level and
\L7e have shown in earlier papers that replacement of the unsubstituted ring of p-dimethylaminoazobenzene
(DAB) with pyridinei and quinoline*gave analogs with a wide range of carcinugenic activity. 111later work this variation in activity among isomers has again been shown in the benzimidazole and benzthiazole seriesa3 ( I ) E. \'. H I I I S I I I .H . l;ws-iitgvr, 1'. > l n i l o y , .I. . I . T r a v r r a , P. >IvC'ar[Ity, and L . Cerecedu, Cicricer Ilea., 14, 22 (1954). ( 2 ) E. V. I3rown. R . AI. Nuvark, and .I. .\. Hamdan. .I. .Tutl. Caucer 1 r i . d . . 2 6 , 1461 ( 1 0 8 1 ) . (3) E . V. Brown and C. J . Sanchorawola. J. Met!. Chem., 11, 1074 (1868).
(41 C . I
