KOTES
May, 1963 Hydroxypyrimidine-5-carboxaldehyde Derivatives in Cancer Chemotherapy
Department
oj
C h e m i s t r y , College o j A r t s and Sciences, Cnizmrsitp o f Louisuille, L o u i s d l e 8 , K e n t u c k y Received December 18, 1962
Interest in the tumor growth retardation characteristics of aldehyde hydrazone derivatives' and pyrinijdines in general has prompted an extension of previous investigations2 concerning derivatives of pyrimidine-5carboxaldehy des. Substituted hydrazone derivatives of the j-carboxaldehydes of 2,4,6-trihydroxy-, 2,4-dihydroxp-, B-methyl-2,4-dihydroxy- and 4,6-dihydroxypyrimidine have been prepared and characterized along with a variety of ani1 derivatives of 2,4,6-trihydroxypyrimidine-3-carboxaldehyde (Tables I and 11).
in preparing derivatives: I. The aldehyde was prepared by the Reirner-Tiernann reaction.2 The reaction mixture was cooled and filtered to remove precipitated salts, including the potassium salt of the aldehyde. This salt mixture was suspended in enough 6 A' sulfuric acid to form a thick slurry which was heated for a few min. a t 60". The suspension was cooled, filtered and the preripitate washed with cold 0.1 iV sulfuric acid and with cold water until free of potassium. The dried aldehyde was suspended in boiling dirnethylformamide. To this solution was added a slight excess of the amine or hydrazine in dilute acetic acid. The resulting mixture was boiled for a few min., cooled and water added to assure complete precipitation of the product. The product was collected on a filter and recrystallized. 11. The aldehyde was prepared by refluxing barbituric acid with diniethylformaniide 3 The reartion mixture was cooled overnight and filtered to yield a solid intermediate. To this solid in hot n-ater was added the hydrazine in dilute acetic acid. The reaction mixture was heated for a few min., cooled and the product rollected on a filter, dried and recrystallized. A, not recrystallized; DhIF, dimethylformamide; TI'> water; DAIS, dimethylsulfoxide; DMh, dimethylacetamide. Calcd. for CllH&aOs: C, 47.83; H, 2.92. Found: C, 47.63; H, 286. "Calcd. for CloHiX70a:C, 43.40; H, 2.58. Found: C, 43.17; H , 2.88.
TABLE I
TABLE I1 HYI)RAZOXE DERIVATIVES~ OF HYDROXY SUBSTITUTED PYRIMIDISE-*s-CARBOXALDEHYDES
L) ERIVATIVES OF
2,4,6-TRIHYDROXYPYRIMIDINE-5-CARBOXALDEHYDE Reagent usedQ
Procedure*
31.p., OC.
Recryst.' from
N Analyses, 70 Calcd.
Found
333
Aldehyde ofb
Derivativec
RI.p., OC.
Recryst. frornd
N Analyses, 70 Calcd. Found
Isonicotinic acid 330 x 25.45 2 5 . 5 6 I hydrazide p-Yitrophenyl305 DMF 24.05 23.91 hydrazine I p-Hydrazino339 DMF/W 19.30 19.01 benzoic acid [ 2-Hydrazino276-276 DMS/W 23.56 23.42 quinoline I1 DMF 20.29 20.47 >360 I p-Sitroanilined 3,4-Dichloroani14.00 14.01 DMF >360 I line D h I F / W 16.86 16.96 343 I p-Fluoroaniline 2,5-Difluoroani325 DhIF/W 15.73 15.77 I line p-Hydroxy>360 D M F / W 16.96 17.06 I aniline DhIF/W 16 09 16 35 >360 p-Anisidine I 324 D;\IF/JT 16 09 16 01 m-8nisidine I Dirnethyl3,5i/dec D M F / W 20 42 20 43 aminoaniline I p-lliethyl200/der D M F / W 18 53 18 76 I aniinoaniline p-.4minobenzoir DMF/W 15 27 15 30 >360 I arid DhfS/W 24 13 23.99 >360 I 3-A4minopyridine DMF/\V 18 29 18.05 307 Pyridoxamine I D M F / W 35 89 35,65 330 I Adeninee 35l/dec DPIIA/W 17 80 17,92 I Sulfathiazole 320/dec DRIF/W 20 89 20.83 I Sulfamerazine 326/dec D M F / R 18 08 17.99 I Sulfapyridine 323/dec D M F / W 23 85 23.70 I Sulfaguanidine 276/dec DMF/JT 20 18 20.14 I Sulfamethazine 341/dec DMS/W 21 64 21 59 I Sulfadiazine * The first four reagents yield hydrazone derivatives. The remainder yield ani1 derivatives. * Procedures I and I1 were used
Screening data3 for these compounds have shown borderline response (+) in Sarc0m.a 180 tests in two or three determinations for the sulfamerazine, sulfapyridine, and sulfaguanidine aiiils and the p-carboxy phenylhydrazone (Table I) and for the isonicotinoylhydrazone derivative of the 2,4-dihydroxypj rimidinc. structure (Table 11). The p-hydroxy and p-carboxy anils (Table I) have shown single + Sarcoma 180 tests.
(1) (a) R. H. IViley, H. K. K h i t e , and G . Irick, J . Org. Chem.. 24, 1784 (19.59); (b) R. H. FViley and G. Irick, ibid., 24, 1925 (1959); 26, 593 (1961); (e) R. H.Wiley, G. Irick, and H. K. White, ibid., 26, 589 (1961); (d) R. H. T i i e y and G . Irick, J . M e d . P h a r m . Chem., 6 , 49 (1962); (e) R. H.Wiley and R. L. Clevenger, ibid., S, 1367 (1962). (2) R . H. Wiley and Y, Yamamoto, J . Orp. Chenz., as, 1906 (1960).
(3) The authors are indebted to Drs. C. C . Stock, R. K. Barclay, Chiistine Reilly, Elvira Falco, and Sophronia Myron, Gloan Kettering Institute for Cancer Research, for conducting these tests. The rating scales and procedures for the Sarcoma 180 test are given in Cancer Res., Suppl. No. 1, 91 (1953),Suppl. No. 2, 179 (1955),and Cancer Res., 18,X o . 8 , 49 (1958). (4) .\I.Ridi and P. Papini, Gorr. chim. ital,, 76, 369, 376 (1946).
I I I1 I1 I1 I1 I11 I11 I11
A IS 334-335 27.02 26.86 332 DMF 25.45 25.65 TP DNF 336 dec. DP 25.15 25.17 347 SP DMF 24.21 24.14 DMF 25.63 25.36 323 IN 316 DMF 22.94 23.06 P DMF >360 25.45 25.66 NPe DMF/W 26.25 26.38 DP 285 dec. 265-266 18.36 18.21 DMF BP a All derivatives were prepared from solutions of the unisolated aldehyde prepared by the Reimer-Tiemann reaction.2 The reaction mjxture was cooled and filtered to remove any precipitated potassium chloride. The filtrate mas acidified with acetic acid and refiltered if necessary. To the hot acidified filtrate was added an excess of the hydrazine in dilute acetic acid. The reaction mixture n a s boiled for a fern- min. and then cooled in an ice bath. The product was collected on a filter and recrystallized. * I, 2,4-Dihydroxypyrimidine; 11, 2,4-dihydroxy-6-methylpyrimidine; 111, 4,6-dihydrox~.pyrimidine. IS,Isonicotinoylhydrazone, XP, p-nitrophenylhydrazone; P, phenylhydrazone; DP, 2,4-dinitrophenylhydrazone; BP, 1,l-diphenylhydrazone. A, not rerrystallized, DMF, dimethylformarnide; J$-, TT ater. e Calcd. for CI,HsX501: C, 38.00; H, 3.30. Found: C, 48.13; H, 3 33.
OH
yq
