Kovember, 1962
PYRIMIDINES. IX.
1085
and the product was redissolved in methanol and reduced to dryness. This process was repeated 2 or 3 times until a completely crystalline mass was obtained. The crystals were triturated in 50 ml. of warm petroleum ether (30-60°),filtered, and dried a t 60' to give the desired product (see Table I). Method C.-This method is identical to method A except that the crude reaction mixture was cooled and filtered and the precipitate washed with water and dried. The crude product was finely pulverized and triturated with 100 ml. of petroleum ether, filtered, and dried a t 60' to give the desired product. Method D.-Method D is identical to method C except that no dioxane was employed. 2-Amino-6-[(6-methyl-2-pyridyl)methylthio]purine.-To 10.0 g. of 2-amino6-purinethi01,~dissolved in 150 ml. of concd. ammonium hydroxide, was added with stirring and heating a t 40" 11.0 g. of 6-methyl-2-picolyl chloride hydrochloride. The reaction temperature was maintained for one additional hr., then the product was filtered, washed with water, and recrystallized twice from ethanol. The yield was 11.2 g., m.p. 236-237". Anal. Calcd. for CI2Hl2N6S:C, 53.1; H, 4.4; N, 30.9. Found: C, 53.6; H, 4.5; N, 30.6.
Pyrimidines. IX. 4- and 5 4 Substituted -anilino)pyrimidines1p2 DARRELL E. O'BRIEK,FREDBAIOCCHI, ROLAKD K. ROBINS, AND C. C. CHENG Midwest Research Institute, Kansas City 10, Missouri Received March 26. 1962
A number of 4- and 5-( substituted-ani1ino)pyrimidines have been synthesized as potential riboflavin antagonists. These compounds represent four general types of the uncyclized isoalloxazine ring. A new general synthetic method for the synthesis of 5-anilinopyrimidines has been devised.
Interference of the biosynthesis of important enzymes and cofactors, such as DP?;, TPK, FAD (flavin-adenine-dinucleotide) and coenzyme A, has generally been accepted as one of the best methods to block cellular g r ~ w t ' h . This ~ interference has also been postulated4 ( 1 ) This investigation was supported by research contract SA-43-ph-3025 from the Cancer Cheiuotherapy National Service Center, National Cancer Institute of the National Institutes of Health, Public Health Service. (2) Presented in part before the Div. of Med. Chem., 139th Meeting of the American Cheiiiical Society, St. Louis, Missouri, March, 1961. (3) F. Bergel, "Chemistry of Enzymes in Cancer," Charles C Thomas, Sgringfield, Ill., lYG1, pp. 47-80. (4) M. R . Atkinsun, .J. F. Jackson and R. K. Morton, .Vatwe, 19B,046 (IHGI), and references listed therein.
as the basis of antitumor activity exhibited by the purine antagonists. Accordingly, the inhibition of tumor growth might be expected from compounds that are riboflavin antagonists since riboflavin is directly concerned with the biosynthesis of the oxidation-reduction enzyme FAD. Compounds exerting anti-riboflavin activity should then act synergistically with the purine and pyrimidine antagonists. A number of compounds related to riboflavin have been shown already to possess certain carcinostatic p r ~ p e r t i e s . ~ - l ~ An examination of the structure of riboflavin (I) indicates that a ribit) I
0
I
pyrimidine might well be its biological precursor. Satural puriiies such as xanthine, adenine. guanine. and uric acid stimulate the biosynthesis of riboflavin in Eremothecium ashbyiz.l* The possibility of a “purine pathway” has been further supported by various tracer >t~dies.l3-’~These studies demonstrated that the tiiosynthesi5 of riboflavin from naturally occurring purines must involve a biochemical intermediate or precursor closely related t o :L ~,3-diaminopSrimidiiic. The literature also reveals that the naturally ocwrring pyrimidiiw do not stimulate the growth of riboflavin.19 This could be due to t h c a fact that none of the pyrimidines of the natural nucleic acids posses\ a nitrogenous substituent at the 5-position. ( 5 ) ti. P. JIorrisand JV. B. Robertson, J . .Tall. CariccrInat., 3, 170 (l!ll:j). (6) H. C. Stoerk a n d G. A. Emerson, I’roc. Soc. Ezgtl. B i d . ?bled., 70,703 (l!j.i!l). (7) V‘. W.Ackerinann a n d V. R.Potter, i b i d . , 73, 1 (IW9). :8) (a) F. IT’. Holly, E. \V.Peel, R.Moaingo, J . J. Caliill, I:. R,liuniitaay, C . 11, SIir111h i i i i i i IC. Folkers, .I. Am. Chern. Soc.. 72, 5416 (1950); (bj C . 11. Shunk and I
