A. Rosowsky, M. Chaykovsky, M. Lin
Aug 1, 1973
Citations
0
Influential Citations
6
Citations
Journal
Journal of medicinal chemistry
Abstract
A number of new 6,7-disubstituted 2,4-diaminopteridines (1) and 2-amino-4-hydroxypteridines (2) were synthesized for biological evaluation via the Isay reaction of symmetrical a-diketones with 2,4,5,6-tetraaminopyrimidine and 2,4,5-triamino-6-hydroxypyrimidine, respectively. For the synthesis of 6,7-bis(arylmethyl)pteridines, it was found that 1,4-diaryl-2,3-butanediones can be replaced by 2,5-diaryl-2,3-dihydrothiophen-4-01-3-one 1,l-dioxides (3), which are known to be converted into a-diketones on Zn metal reduction to 2,5-diaryl-2,3,4,5-tetrahydrothiophen-4-01-3-one 1 ,I-dioxides (4) followed by SO2 elimination. A useful preparative method was developed whereby conversion of 3 into 1 (R = ArCH2) or 2 (R = ArCH2) was effected in a single continuous operation without isolation of either 4 or the a-diketone. Condensation of 3 with 2,4,5-triaminod-hydroxypyrimidine led to 2-amino-6,8-diaryl-6,8-dihydrothieno[ 3,4-g] pteridine 7,7-dioxides (5), the first examples of a new heterocyclic ring system. 2-Amino-6-benzyl4-hydroxypteridine (6) and 2-amino-7-benzyl-4-hydroxypteridine (7) were prepared from 1,l -dimethoxy3-phenyl-2-propanone (8), and their identity was established on the basis of nmr spectra in 4: 1 CF3C02HFS03H solution. Reduction of 6 with Zn in NaOH yielded the 7,8dihydro derivative 9, whereas catalytic hydrogenation in CF3C02H led to the 5,6,7,8-tetrahydro compound 10. The 2,4-diaminopteridines were potent inhibitors of the folate-requiring organism Streptococcus fuecium (ATCC No. 8043), but no significant antimalarial or antitumor activity was observed with any of the compounds tested. A number of symmetrically 6,7-disubstituted 2,4-diaminopteridinesp4 have been reported to possess antibacterial5-" and antimalarial"-" properties, although significant antitumor activity has not been found." Recent enzyme studies with purified dihydrofolate reductase of mammalian and nonmammalian rigi in'^,^' tend to support earlier indications that large hydrophobic substituents at positions 6 and 7 exert a favorable effect on the activity as well as the species selectivity of these compounds.21 In this paper, as part of a broader survey of new folate antagonists as candidate antimalarial and experimental antitumor agents,'* we wish to report the synthesis of some 2,4-diamino-6,7-bis(aralkyl)pteridines (1, Table I) from a-diketones and 2,4,5,6-tetraaminopyrimidine via the Isay reaction.23924 Also prepared from the same a-diketones and 2,4,5-triamino-6-hydroxypyrimidine were the corresponding 2-amino-6,7-bis(aralkyl)4-hydroxypteridines (2, Table I). Application of the Isay reaction for the synthesis of a variety of symmetrical 6,7disubstituted pteridines, including some 2,4-diamino and 2-amino-4-hydroxy derivatives, was reported by us some time ago.25 2-Amino-4-hydroxy-6,7-bis(aralkyl)pteridines were of particular interest because of the possibility that,