Studies on Chemotherapeutic Agents.III. A Synthesis of 3-Phenylpurine Derivatives

Analogs of 8-azaguanosine

“…7-(Benzylthio)-3-(2,3-0-isopropylidene-j8-D-ribofuranosyl)-3H-l,2,3-triazolo [4,5-d]pyrimidin-5-amine (18) and 7-(Benzylthio)-3-|8-D-ribofuranosyl-3/f-l,2,3-triazolo[4,5-d]pyrimidin-5-amine (19). A solution of 3-20 (500 mg, 1.06 mmol) in EtOH (20 ml) and 0.5 N H2S04 (5 ml) was stirred in an oil bath at 44°for 41 h, cooled to 25°, neutralized with 4 N NaOH to pH 7, filtered, and evaporated to dryness in vacuo.…”

“…group of 19 with various nucleophilic reagents gave 8-aza-6-thioguanosine 17 and analogues 8c, 15, and 16. The thione 17 rearranges in aqueous solution to the thiadiazolopyrimidine 21. The parent [l,2,3]thiadiazolo [5,4d]pyrimidine-5,7-diamine (24a) was prepared by nitrosation of the triaminopyrimidine (23a).…”

“…The use of Raney nickel in this reduction gave a lower (43%) yield of 14. Addition of NaN02 to a cold solution of 14 in dilute AcOH gave a 4:1 mixture of iV-acetyl-7-(benzylthio)-3-(2,3-0-isopropylidene-/3-D-ribofuranosyl)-3H-l,2,3-triazolo[4,5-d]pyrimidin-5-amine [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and the corresponding a-anomer (a-20). Although jS-20 was found to be stable in AcOH, the amine 14 racemized at an appreciable rate under these conditions.…”

“…Attempts to improve the yield of 19 by increasing or decreasing the reaction time gave higher yields of 7c and 18, respectively, with a resultant decrease in the yield of The benzythio group of 19 could be easily displaced with a variety of nucleophiles at room temperature. Treatment of 19 with NaOMe in MeOH gave a 72% yield of 7methoxy-3-d-D-ribofuranosyl-3i/-l,2,3-triazolo [4,5-d]pyrimidin-5-amine (8c). In a similar reaction with MeSH in MeOH containing NaOMe, 19 gave a 75% yield of 7-(methylthio)-3-d-D-ribofuranosyl-3H-l,2,3-triazolo [4,5d]pyrimidin-5-amine (15).…”

“…In contrast to 8c, the positional isomers 8a and 8b show a very low order of toxicity. The low toxicity of the remaining 8-azaguanosine analogues in Table II is also contrasted with the high toxicity of the corresponding 8-azainosine analogues.1 The lack of L1210 activity and low toxicity of the thio and alkylthio analogues 15,17, and 19 indicate that simple hydrolysis to 7c or 25a does not occur in cell culture or in vivo and that the presence of the amino group in 15 prevents it from functioning as a substrate for adenosine kinase, the enzyme that activates 8-aza-6-(methylthio)purine ribonucleoside.1 In contrast, the presence of the amino group of 8c does not interfere with its ability to function as a substrate for adenosine deaminase (see above).…”