4-Aminopyrazolo -pyrimidin

Formycin Nocardia interforma 7-Aminopyrazolo- pyrimidine Ribose Adenosine... 

Aminopyrazolo[4,3-d]pyrimidine moiety (47) is present in several nucleosides of both biological and synthetic origins. Among them, formycin (47, R = 3/3-D-ribofuranozyl) is of particular interest as a C-nucleoside analog of adenosine. 

Aminopyrazolo[3,4-6]pyridine was reacted with EMME in acetic acid to give pyrido[2, 3 3,4]pyrazolo[ 1,5-a ]pyrimidine-3,9-dicarboxylate... 

The enzymatic conversion of many analogues of the naturally occurring purines directly to their biologically active form, the ribonucleotides, in vivo [5, 8, 10, 13, 39] underlines the importance of these enzymes to the drug action of this class of compounds. 2-Aminoadenine (2, 6-diaminopurine, I) [107], 2-fluoroadenine (II) [108], 4-aminopyrazolo [3, 4-d] pyrimidine (VIll) [109]. and 2- and 8-aza-adenine (IX and X) [ 110, 111] have all been shown to be substrates for the adenine phosphoribosyltransferase [J12, 113]. Extensive studies on the metabolism of 2-aminoadenine (I) in E. coli [114, 115], L cells [116], and mice [117] have also shown its conversion by this enzyme to the ribonucleotide. 

Conversion of 4-aminopyrazolo [3,4-d] pyrimidine (VIII) to its ribonucleotide by mouse tumours and host tissues has been observed [118,119]. Although no evidence of the anabolism of A -methyladenine (111) [120] to the ribonucleotide was obtained in mice with Ehrlich ascites carcinoma [121, 122], it is anabolized by bacteria [123. 124] and the enzyme responsible was partially purified from Salmonella typhimurium [125]. Human epidermoid carcinoma No. 2 cells resistant to 2-fluoroadenine (H.Ep.-2/FA) have lost adenine phosphoribosyl-... 

Although demethylation, which occurs in the liver, is normally considered to be a catabolic process, it may result in conversion of an inactive form of a drug to the active form. Thus 6-(methylthio)purine (XXXIX) is demethylated by the rat to 6-mercaptopurine [205]. This demethylation occurs in the liver micro-somes and is an oxidative process which converts the methyl group to formaldehyde [204, 207]. The 1-methyl derivative of 4-aminopyrazolo[3,4-d] pyrimidine (XLI) is demethylated slowly, but 6-mercapto-9-methylpurine (XLII) not at all [208]. The A -demethylation of puromycin (XLlIl) [209, 210], its aminonucleoside (XLIV) [211], and a number of related compounds, including V-methyladenine and V,V-dimethyladenine, occurs in the liver microsomes of rodents [212]. In the guinea-pig the rate-limiting step in the metabolism of the aminonucleoside appears to be the demethylation of the monomethyl compound, which is the major urinary metabolite [213]. The relationship of lipid solubility to microsomal metabolism [214], and the induction of these demethylases in rats by pre-treatment with various drugs have been studied [215]. 

Although adenylic acid deaminase is a well-known enzyme that has been isolated in crystalline form, little work has been reported on its substrate specificity evidence for the deamination of 4-aminopyrazolo[3,4-d]pyrimidine ribonucleotide has been presented [118], but it is not known if it catabolizes any of the other intracellularly formed adenylic acid analogues. 

Several analogues of adenine or adenosine are reported to be incorporated into nucleic acids 2-fluoroadenosine [342], tubercidin [190, 192, 342a], toyacamycin [193,342a], sangivatnycin [342a, b], cordycepin [168,343,344], 4-aminopyrazolo[3, 4-d] pyrimidine [119], formycin [344a], and 9- -D-arabinofuranosyladenine [152, 154], The evidence for the incorporation of 9-(3-D-arabinofuranosyladenine has been questioned [345]. 

Amino-3-phenylazo-4,5,6-7-tetrahydropyrazolo[l,5-a]pyrimidines add acrylonitrile to yield the tricyclo derivatives 238. Condensation of 239 and -keto esters has been reported. The behavior of the 2-aminopyrazolo-[1,5-a] pyrimidines toward the same reagents was also reported (76HCA155I). 

C-NMR studies on l-isopropyl-4-aminopyrazolo[3,4-4]pyrimidine(240, R = i-Pr) and the isomeric 2-isopropyl derivative 241 (R = i-Pr) indicate that N-5 and N-7 are the respective protonation sites (77JA7257). 

Aminopyrazolo[3,4-d]pyrimidines 257 were converted into the corresponding 4-aryl substituted derivatives 259 via treatment with alkyl nitrites and boiling in aromatic solvent. The isomer distribution of 259 prepared by these route was that predicted for a radical intermediate (ortho, meta, and para). The structure of isomers was established by H-NMR. Unusual fragmentation products were isolated these probably result from collapse of the radical intermediate 258 (83JOC4605). Methylation of 257 takes place at either N-1 or N-2. Further methylation affords methylamino derivatives structures of the products were established by C-NMR as well as by chemical methods (75JOC1822). 

Aminopyrazolopyrimidines exist in the amino form. The only exception is 7-aminopyrazolo[l,5-a]pyrimidine, which exists in the solid state as an amino-imine mixture. The evidence is not conclusive (70BCJ849). Previous work on the same series has assigned an amino structure (62CPB620). Other aminopyrazolo[l,5-a]pyrimidines investigated were shown to exist in the amino form (74JHC423). 

Neutral 4-aminopyrazolo[3,4-d]pyrimidines exists in water in two tautomeric forms 1//-4-amino (1H4APP) and 2//-4-amino (2H4APP) isomers (X = 2H4APP/1H4APP = O.I at lOO C and OH tautomerization = 9.0kcal mol ). Interconversion of the two forms is catalyzed by and OH through either an intermediate cation common to both tautomers or through an intermediate anion. 

Table I. Biological Activity of Substituted 7-Aminopyrazolo[4,3-d]pyrimidines (79)...

The tautomerism of 4-aminopyrazolo[3,4-J]pyrimidines as well as aminopyrazolo[4,3-d]py-rimidines has been investigated. 4-Aminopyrazolo[3,4-J]pyrimidines exist in water in two tautomeric forms l//-4-amino (85) and 2//-4-amino (86) [K (86/85) = 0.1 at 100°C AH = 9.0 kcal, mol ]. Interconversion of these two forms is catalyzed by acid or base <77JA7257, 80ZN(C)878, 82MI 712-02). Together with these two predominant species there are smaller proportions of the 7//-4-amino (87) (1 x 10-3) and the 5//-4-amino isomer (2 x 10-4). The species (87) exists only as an amino tautomer whereas the 5//-4-amino species in water has a partial imino structure (amino/imine =10) <77JA7257>. 

The reaction of isocyanates and isothiocyanates with 3(5)-aminopyrazole-4-carbonitrile affords aminopyrazolo[3,4-d]pyrimidines <90CCC728,91TL6787). Intermediate pyrazolyl thioureas were isolated in several cases and cyclized into aminopyrazolo[3,4-. The reaction of the amines (315) with formamide gives aminopyrazolo[3,4-t/]pyrimidines <8lOPP379>. 

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