Schönenberger, Helmut and Adam, Adelheid (1965) Chemistry and mode of action of aminomethylating carcinostatics. II. Cytostatics. Arzneimittel-Forschung = Drug research 15 (1), pp. 30-36.
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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[184.108.40.206,9]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.
|Additional information (public):||CAN 64:93484 38 Heterocyclic Compounds (More Than One Hetero Atom) 203209-59-0P; 1081773-77-4P; 1081773-86-5P Role: SPN (Synthetic preparation), PRP (Properties), PREP (Preparation) (Chemistry and mode of action of aminomethylating carcinostatics. II. Cytostatics); 51-46-7P (1,3,6,8-Tetraazatricyclo[220.127.116.11,8]dodecane); 51-69-4P (Imidazolidine, 1,3-bis[(ethylthio)methyl]-); 51-76-3P (Ethylenediamine, N,N'-bis[(ethylthio)methyl]-N,N'-dimethyl-); 51-76-3P (3,10-Dithia-5,8-diazadodecane, 5,8-dimethyl-); 51-80-9P (Methanediamine, N,N,N',N'-tetramethyl-); 51-82-1P (Carbamic acid, dimethyldithio-, (dimethylamino)methyl ester); 110-81-6P (Ethyl disulfide); 1017-56-7P (Methanol, (s-triazine-2,4,6-triyltriimino)tri-); 1952-37-0P (Ethanol, 2-[(p-hydroxybenzylidene)amino]-); 2037-00-5P (Methanol, (diethylamino)-, acetate (ester); 3089-11-0P (Melamine, hexakis(methoxymethyl)-); 3275-13-6P (Piperidine, 1-(ethoxymethyl)-); 4135-86-8P (Ethylenediamine, N,N'-bis[(ethylthio)methyl]-N,N'-dimethyl-, dihydrochloride); 4396-19-4P (Methane, bis(ethylthio)-); 5752-37-4P (Melamine, hexakis[(ethylthio)methyl]-); 5752-40-9P (Ethylenediamine, N,N'-dimethyl-, dihydrochloride); 5752-42-1P (Imidazolidine, 1,3-bis[(ethylthio)methyl]-, hydrochloride); 5752-43-2P (Ethylenediamine, N,N,N',N'-tetrakis[(ethylthio)methyl]-); 5766-67-6P (Acetonitrile, (ethylenedinitrilo)tetra-); 5766-68-7P (Glycinonitrile, N,N'-ethylenebis[N-methyl-); 5766-69-8P (Glycinonitrile, N,N'-(6-chloro-s-triazine-2,4-diyl)di-); 5766-70-1P (Acetonitrile, [(6-amino-s-triazine-2,4-diyl)diimino]di-); 5766-71-2P (Glycinonitrile, N,N',N''-s-triazine-2,4,6-triyltri-); 5766-74-5P (Phenol, p-(N-methylformimidoyl)-); 5766-75-6P (Pyrocatechol, 4-(N-methylformimidoyl)-); 5766-76-7P (Anthranilic acid, N-benzylidene-); 5766-79-0P (1-Piperidineacetonitrile, alpha -phenyl-); 860394-79-2P (3,10-Dithia-5,8-diazadodecane, 5,8-dimethyl-, dihydrochloride) Role: PREP (Preparation) (prepn. of)|
|Institutions:||Chemistry and Pharmacy > Institute of Pharmacy > Retired Professors > Prof. Schönenberger|
|Keywords:||Aminomethylation (by cancer-inhibiting substances) Cancer (inhibitors of, aminomethylating substances as)|
|Subjects:||500 Science > 540 Chemistry & allied sciences|
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Unknown|
|Deposited On:||19 Nov 2010 10:55|
|Last Modified:||19 Nov 2010 10:55|
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