80360-08-3Relevant academic research and scientific papers
5-methyl-5-deaza analogues of methotrexate and N10 -ethylaminopterin
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, (2008/06/13)
It is disclosed that 5-methyl-5-deazamethotrexate and 5-methyl-5-deaza-10-ethylaminopterin are more than 10 times as potent as 5-deazamethotrexate in the L1210 cell growth inhibition test.
Synthesis and Biological Activities of 5-Deaza Analogues of Aminopterin and Folic Acid
Su, Tsann-Long,Huang, Jai-Tung,Burchenal, Joseph H.,Watanabe, Kyoichi A.,Fox, Jack J.
, p. 709 - 715 (2007/10/02)
N-pyrimidin-6-yl)methyl>amino>benzoyl>-L-glutamic acid (1a, 5-deazaaminopterin) and the 5-methyl analogue (1b) were synthesized in 14 steps from 5-cyanouracil (4a) and 5-cyano-6-methyluracil (4b), respectively, by exploitation of the novel pyrimidine to pyridopyrimidine ring transformation reaction.The 5-cyanouracils 4 were treated with chloromethyl methyl ether to the 1,3-bis(methoxymethyl)uracils (5, which were treated with malononitrile in NaOEt/EtOH to give the pyridopyrimidines 6.Diazotization of 6 in concentrated HCl afforded the 7-chloro derivatives 8 in high yield.After reduction of 8, the 7-unsubstituted products 9 were reduced in the presence of Ac2O and the products, 6-(acetamidomethyl)pyridopyrimidines 10, were converted into the 6-acetoxymethyl derivatives 12 via nitrosation.After removal of the N-methoxymethyl groups from 12, the 6-(acetoxymethyl)pyridopyrimidine 2,4(1H,3H)-diones 14 were converted into 2,4-diamino-6-(hydroxymethyl)pyridopyrimidine (15a) and its 5-methyl analogue 15b by the silylation-amination procedure.Compounds 15 were brominated to the 6-bromomethyl derivatives 16, which were treated with diethyl (p-aminobenzoyl)-L-glutamate, and the products 17 were saponified to afford 5-deazaaminopterin (1a) and its 5-methyl analogue 1b.Compopund 1b was also prepared by an alternative procedure in 10 steps from cyanothioacetamide and ethyl β-(ethoxymethylene)acetoacetate via 2,4-diamino-6-(hydroxymethyl)-5-methylpyridopyrimidine (15b). 5-Deaza-5-methylfolic acid (2) was also prepared in four steps from 15b.The aminopterine analogues 1 showed significant anticancer activity in vitro and in vivo, whereas thefolic acid analogue 2 did not exhibit any significant toxicity.
Syntheses and Antifolate Activity of 5-Methyl-5-deaza Analogues of Aminopterin, Methotrexate, Folic Acid, and N10-Methylfolic Acid
Piper, J. R.,McCaleb, G. S.,Montgomery, J. A.,Kisliuk, R. L.,Gaumont, Y.,Sirotnak, F. M.
, p. 1080 - 1087 (2007/10/02)
Evidence indicating that modifications at the 5- and 10-positions of classical folic acid antimetabolites lead to compounds with favorable differential membrane transport in tumor vs. normal proliferative tissue prompted an investigation of 5-alkyl-5-deaz
Pyridopyrimidines. Synthesis of the 5-Deaza Analogues of Aminopterin, Methotrexate, Folic Acid, and N10-Methylfolic Acid
Temple, Carroll,Elliott, Robert D.,Montgomery, John A.
, p. 761 - 764 (2007/10/02)
Reaction of bromoacetic acid with N,N-dimethylformamide and phosphorus oxychloride gave a triformylmethane derivative, which was condensed with 2,4-diaminopyrimidin-6(1H)-one (2) in water at reflux to give 2-amino-4(3H)-oxopyridopyrimidine-6-carboxaldehyde (4).The structure of 4 was confirmed by conversion to the 2,4-dinitrophenylhydrazone and oxidation to the known 6-carboxylic acid (6).Similarly, condensation of 1 with 2,4,6-triaminopyrimidine gave 2,4-diaminopyridopyrimidine-6-carboxaldehyde (5).Reductive alkylation of diethyl (p-aminobenzoyl)-L-glutamate (9) with 5 in 70percent acetic acid over Raney nickel gave diethyl N-pyrimidin-6-yl)methyl>amino>benzoyl>-L-glutamate (10), which was saponified with base to give the corresponding glutamic acid 11 (5-deazaaminopterin).The latter was methylated with formaldehyde and sodium cyanoborohydride to give 5-deazamethotrexate (12).Reductive alkylation of 9 with 4 gave diethyl N-pyrimidin-6-yl>methyl>amino>benzoyl>-L-glutamate (13), which was converted to the corresponding glutamic acid 14 (5-deazafolic acid).The preferred route for the preparation of 14 involved the hydrolysis of 10 with base at reflux, which resulted in replacement of the 4-amino group and saponification of the ester groups.Methylation of 14 with formaldehyde and sodium cyanoborohydride gave 5-deaza-10-methylfolic acid (15), which was also prepared by alkaline hydrolysis of the 4-amino group of 12.
