,January 1967
113
AT^^^^
Pyrimidines. V. Some Higher 5-Substituted 2,4,6-Trichloropyrimidines1 KERNANGERSHON, R l C L 0 PARRIEGIANI, A N D RICHARD Tl'Asc.or,~ Royce Thompson Instztute .for Plant Research, lnc., Yonkers, -\-ew York 10701
Received J u l y I ,1966
I n earlier work on ring-polychlorinated pyrimidines, we reported2 that a series of %substituted 2,4,6-trichloropyriniidines showed confirmed anticancer activity in the 1 3 cell culture test system. It should also be pointed out that none of these compounds demonstrated in vivo activity in the usual tumor systems; however. 5-propyl-2,4,6-trichloropyrimidinedid show a sufficient degree of cytotoxicity to warrant further evaluation in other i n vivo tumor systems.3 Since this compound was the last member of the series tested, it was considered worthwhile to make additional members for evaluation. The compounds were prepared by condensing the appropriate malonic wter with urea by means of sodium ethoxide to form barbituric acids (I) which, in turn, were treated with phosphorus oxychloride in the presence of dimethylaniline to yield the desired h u b s t i t u t e d 2,4,6-trichloropyrimidines (11). These methods are all found in the literature,2 and the specific compounds are listed in Tables I and TI. 4s5
Of the 22 compounds prepared, the following barbituric acids were previously described : Ib,5.6 I(*,' I c > If,' , ~ Ij,'" arid Ih." Conipouid IhI2 was mentioned but not characterized. Only IIb5 and IIk" of the trichloropyrimidiries were described; IIa12 and IIh'? were reportcd but riot fully characterized. The pertinent data on the 5-substituted 2,4,6-trirhloropyriniidines are summarized in Table I. ,111 of the barbituric acids and trichloropyriniidines were screened by the Cancer chemotherapy National Service Center'" against four animal tumors each, lymphoid leukemia L1210, lymphosarcoma P1789 or Sarcoma 180, Dunning ascites leukemia, Adenocarcinoma 7.7.5 or Lewis lung carcinoma, Walker 2.33 carcinosarcoma (intramuscular), and KB cell culture. These data are contained in Table TI and indicate that the conipoundq are inactive against the tumors studied. With regard to the effect of increasing the chain length of the substituent in the 5 position of the 2,4,6-trirhloropyrimidine., it can be seen that the cytotoxicity of the compounds in the KB cell culture system reached n maximum lyhen the side chain was propyl2 and diminished with increasing chain length. Furthermore, branching of the side chains of this family of compounds yields less toxic products than the corresponding, straight-chain, parent compounds. I t should also be noted that in our previous paper,2 compounds were considered active with greater EDso values than some of the compounds in our present re-
TABLE I Compd
I1
Yield, '%
B p , OC ( m m )
5-SUBSTITUTED 2,4,6-TRICHLOR0PYRI\IIDIR.ES --Calcd, %n n ("0 Formula C H C1
54 83(0.3)b 1.5368(23.5) 60 95(0.25) 1.5271 (23) d 99 81 ( 0 . 2 ) 1.5346 (23) e 16 89 ( 0 . 3 ) 1.5293 ( 2 4 . 5 ) f 32 107(0.3) 1.5237(23) g 45 lZO(0.35) 1.5219(22.5) ha 52 127 (0.2)" 1.5176 (24) i 26 141 (0.25) 1.5156(23) J 62 96-98 (3.O l d * Lit.12 a Mentioned in ref 12. not characterized. 1.5t50-1.5178. 31~38-39'. aa
C
OH
c1
I
I1
CsHsC13K2 40.11 C9HllC13X? 42.63 CgHiiCl,?U'? 42.63 C9Hl1Cl3X2 42.63 C10H13C13S2 44.88 CLlHllC13N? 46.91 C12HliC13N2 48.75 C13H,sC13S2 50.42 CiHSC13N2 37.62 bD 84-89.5" (0.1 mm),
a, R ? = ~ C H ~ ( C H Z ) Z C H ~ b, R!=/'CHaCHCHzCHa C, R = C H ~ ( C H P ) ~ C H P d, R = CHa( CHz)&HCH3 e, R = (CH3)2CHCH&Hz f, R CH3(CHs)4CHz g, R CHa(CH2)LCHP h, R CH3(CH*)sCH? i, R = CH 3(CH2)7CH? 1, R = CHzzCHCH2 k, R = CeHlCH, (1) This investigation was supported, in p a r t , b y t h e Cancer Chemotherapy National Service Center, National Institutes of H e a l t h , under Cont r a c t No. P H 43-63-579. (2) H. Gershon, R . Braun, A. Scala, a n d R . Rodin, J . M e d . Chem., 7, 808 (1964). (3) M. M. Macdonald, Cancer Chemotherapy National Service Center, personal communication. (4) 0.Gerngross, Ber., 38, 3394 (1905). (5) 8 . W.Dox, J . Am. C h e m . Soc., 53, 1539 (1931).
3.79 44.40 4.37 41.94 4 . 3 7 41.94 4.37 41.94 4 . 9 0 39.75 5 . 3 7 37.77 5 . 8 0 35.98 6 . 1 8 34.35 2 . 2 5 46.59 n25~ 1.5375.
-
N
11.69 11.05 11.05 11.05 10.47 9.95 9.48 9.05 12.53 Lit'.12bp
%-
-Found,
C
H
C1
N
-
40.18 3 . 8 2 44.17 11.96 42.56 4 . 5 1 41.57 10.83 42.50 4 . 4 5 41.83 1 1 , 1 4 42.32 4 . 2 4 42.23 11.48 4 4 . i 5 5.00 39.75 10.44 46.76 5 . 2 9 38.09 9 . 7 5 48.45 5 . 9 4 36.07 9 . 2 3 5 0 . 0 7 6 . 3 8 34.09 9 . 0 0 3 7 . 4 5 2 . 2 1 47.28 12.98 139-143" (0.5-0.55 mm), ~ Z Z
D
port,. This is due to a recent change in prot'ocol in which the base line for activity has been 10wered.l~ It' was reported by Gershon and ParmegianiI5 that ring-polychlorinated pyrimidines possessed antifungal vapor effects, and in the 2,4,6-t'richloropyriniidine series, the vapors of 2,4,6-trichloropyrimidine and of the 5(6) E. H. Voliriler, J . A m . Chem. Soc., 47, 2236 (1925). (7) -4. 11.. Dox a n d E . G . Jones, ihid., 60, 2033 (1928). ( 8 ) K.K e n n e r , Jubilee Volume Dedicated t o E m i l Christoph Rare11 Frederick Reinhardt, L t d . Co., Basel, 1946, p 435. (9) A . V-.Dox, J . Am. C h e m . Soc., 46, 1707 (1924). (10) T. 13. Johnson a n d A. J. Hill, Am. Chem. J., 46, 3 3 i (1911). (11) H. K a s t , Ber., 46, 3 1 2 1 (1912). (12) G . F. Deebel a n d P. C. H a m m , U. S. P a t e n t 2,8i9,150 (1959). (13) (a) T h e details of t h e screening procedures can b e found in Cancer Chemotherapy R e p t . , 1, 42 (1959); (b) J. Leiter, €3. J. Abbott, a n d S. .4, Schepartz, Cancer Res., 1 5 , 1779 (1965). (14) N. H. Greenberg, Cancer Chemotherapy National Service Center, personal communication. Ti-hereas in ref 13b, a compound was considered K B active when EDsa 5 4 pg/ml, t h e revised standard is EDaa 5 1 pg/ml. On this basis, four compounds of ref 2 a r e still considered active: 5-methyl-, 5-bromomethyl-, 5-propyl-, a n d 5-phenyl-2,4,6-trichloropyrimidine. (15) (a) H. Gershon a n d R. Parmegiani, A p p l . Microbiol., 11, 78 (1963); (b) H. Gershon a n d R. Parmegiani, Trans. .V. Y . h a d . Sci., 25, 638 (1963); (c) H. Gershon, U. S.P a t e n t 3,227,612 (1966).
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