Chemistry and mode of action of aminomethylating carcinostatics. II. Cytostatics

cf. CA 63, 5474c. The growth of Ehrlich ascites tumor in mice was inhibited by mono- and dialkylthiomethylamine derivs., which react with the higher H+ concn. in tumor cells to give carbonium-immoninm ions which alkylate the substrate. The low toxicity of these compds. is explained by the ease with which the alpha -aminoalkyl radical splits from the blocked substrate. Melamine and formalin at pH 8-9 (NaHCO3) was heated for a few min. at 70-80 Deg and cooled to yield 60% N,N',N''-tris(hydroxymethyl)melamine (I), m. 130-60 Deg. N,N,N',N',N'',N''-Hexa(hydroxymethyl)melamine (II) (prepd. analogously to I) was etherified to give 65.5% of the corresponding methoxy deriv., m. 47-9 Deg (petroleum ether). HOCH2SO3Na (III) was prepd. in 90% yield from equimolar amts. of NaHSO3 and formalin by heating for 45 min. at 75 Deg, cooling, adding EtOH, and stirring the mixt. for several hrs. until the product pptd. [CH2NCH2(SO3Na)2]2 (IV)and (CH2NMeCH2SO3Na)2 were made from the corresponding amine and III. I and NaHSO3 kept 2 hrs. at 70 Deg gave melamine-N,N',N''-tris(methane-sulfonic acid Na salt). II, EtSH, and concd. HCl gave a mixt. of CH2(SEt)2, b20 71-2 Deg, and 79% N,N,N',N',N'',N''-hexa-(ethylthiomethyl)melamine, m. 58-60 Deg (Me2CO). (CH2NHMe)2 (V), paraformaldehyde (VI), and excess EtSH gave 66% (CH2NMeCH2SEt)2, b18 170-1 Deg; hydrochloride (VII) m. 141-2 Deg (decompn.). Heating VII above the m.p. to 150 Deg caused partial soldification to crystals, m. >200 Deg. The products were identified as CH2(SEt)2 and V.2HCl, the latter a probable decompn. product of the postulated intermediate, N,N'-dimethylimidazolidine dihydrochloride. VII decomp. in aq. soln. to the starting materials. Recrystn. of VII from MeOH with traces of H2O yielded V.2HCl, m. 230-5 Deg. N,N'-Bis(ethylthiomethyl)imidazolidine (VIII) b14 167-70 Deg; hydrochloride m. 146-9 Deg. IV (0.05 mole) in 50 ml. H2O, 50 ml. EtSH, and 0.22 mole NaOH in 50 ml. H2O was stirred 6 hrs. on a water bath to give 41% VIII, b0.2 100-1 Deg, and 30% [CH2N(CH2SEt)2]2 (IX), b0.3 169-74 Deg, m. 8 Deg. (CH2NH2)2 (X), VI, and EtSH gave 27% VIII and (EtS)2 instead of the expected IX. A mixt. of the appropriate amine, formalin, and H2SO4 was treated with a soln. of NaCN to yield 86% [CH2N(CH2CN)2]2, m. 128.5-29 Deg (H2O), and 80% (CH2NMeCH2CN)2, m. 79 Deg (Et2O). To a soln. of 0.1 mole cyanuric chloride in 100 ml. dioxane at 0 Deg was added 0.3 mole H2NCH2CN (XI) followed by a slurry of 0.3 mole NaHCO3 in H2O. The mixt. was stirred 3 hrs. at 0 Deg, kept overnight, and dild. with H2O to give 97.5% 2-chloro-4,6-bis(cyanomethylamino)-1,3,5-triazine (XII), m. 285-90 Deg (decompn.). XII (0.1 mole) in 50 ml. EtOH was treated with 0.5 mole NH3 for 2.5 hrs. at 90-100 Deg to yield 77% N,N'-bis(cyanomethyl)melamine, m. 282-4 Deg (decompn.). XII (5 g.) and excess XI was heated to 40-50 Deg to give 44% N, N',N''-tris(cyanomethyl)melamine, m. 216-28 Deg, contaminated with decompn. products from XI. X (0.25 mole) and 0.5 mole formalin was stirred for 1 hr. to yield 92% 1,4,6,9-tetraazatricyclo[4.4.1.14,9]dodecane, m. 195-200 Deg. CH2(NMe2)2 and CS2 gave 77% Me2NCS2CH2NMe2, m. 36-40 Deg. The following Schiff bases 3,4-RR'C6H3CH:NR'' were prepd. (R, R', R'', and m.p. given): H, OH, CH2CH2OH, 171 Deg (dioxane); H, OH, Me, 160.5-64 Deg (tetrahydrofuran); OH, OH, Me, 170-80 Deg (decompn.); H, H, o-C6H4CO2H, 116-24 Deg.