Synthesis and antitumor activity of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine.
The synthesis of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine (BW301U, 7) by a route that has general applicability to the preparation of many 6-(substituted benzyl)-5-methylpyrido[2,3-d]pyrimidines is described. The key intermediate, 2,4-diamino-7,8-dihydro-6-(2,5-dimethoxybenzyl)-5-methyl-7-oxopyrido[2,3-d]pyrimidine (4), is converted to the 7-chloro compound 5 by treatment with a 1:1 complex of N,N-dimethylformamide--thionyl chloride, and 5 is hydrogenolyzed with palladium on charcoal in the presence of potassium hydroxide to yield 7. BW301U is a potent lipid-soluble inhibitor of mammalian dihydrofolate reductase and has significant activity against the Walker 256 carcinosarcoma in rats.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002279:Carcinoma 256, Walker / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D005493:Folic Acid Antagonists; D006801:Humans; D066298:In Vitro Techniques; D007951:Leukemia, Myeloid / Q000201:enzymology; D008297:Male; D008727:Methotrexate / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; C024530:piritrexim; D008727:Methotrexate