Synthesis of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines and related heterocycles

The reaction between 5-amino-4-imino-1(2)-substituted-1(2)H-4,5-dihydropyrazolo[3,4-d]pyrimidines and several commercially available reactants afforded new heterocycles with a conserved pyrazolo[3,4-d]pyrimidine nucleus. The key intermediates employed proved to be suitable compounds by virtue of their two vicinal amino and imino groups that were used to obtain five, six and seven-membered rings.     

Iodocyclization of 6-allylamino-4,5-dihydropyrazolo[3,4-d]pyrimidines

6-Allylamino-1-R-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidines treated with iodine in the presence of potassium carbonate are converted into 6-allylamino-1-R-1H-pyrazolo[3,4-d]pyrimidines that at further reaction with iodine undergo the cyclization into 6-iodomethyl-1-R-1,6,7,8-tetrahydroimidazo [1,2-a]pyrazolo[3,4-d]-pyrimidin-5-ium iodide of a linear structure. In the absence of potassium carbonate alongside the mentioned linear products 8-iodo-methyl-1-R-1,4,5,6,7,8-hexahydroimidazo[1,2-a]pyrazolo[4,3-e] pyrimidin-9-ium iodides of an angular structure have been obtained.     

Electrophilic heterocyclization of 6-alken(yn)ylsulfanyl-pyrazolo[3,4-<Emphasis Type="Italic">d</Emphasis>]pyrimidin-4(5<Emphasis Type="Italic">H</Emphasis>)-ones

6-Allylsulfanyl-1-arylpyrazolo[3,4-d]pyrimidin-4(5H)-ones react with iodine and sulfuric acid to give angular pyrazolothiazolopyrimidine derivatives. The reaction of 6-(prop-2-yn-1-ylsulfanyl)-1-(4-tolyl)-pyrazolo[3,4-d]pyrimidin-4(5H)-one with sulfuric acid gives angularly fused pyrazolo[4,3-e][1,3]thiazolo-[3,2-a]pyrimidin-4-one, whereas in the reaction with sodium methoxide linearly fused pyrazolo[3,4-d][1,3]-thiazolo[3,2-a]pyrimidin-4-one was formed. Linearly fused pyrazolo[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazole derivatives were also obtained by reaction of 1-aryl-6-(3-phenylprop-2-en-1-ylsulfanyl)pyrazolo[3,4-d]pyrimidin-4(5H)-ones with sulfuric acid.     

4,5-Diamino-1-phenyl-1,7-dihydro-6<Emphasis Type="Italic">H</Emphasis>-pyrazolo[3,4-<Emphasis Type="Italic">b</Emphasis>]pyridin-6-one in the synthesis of fused tricyclic systems

Starting from the substituted 4,5-diaminopyrazolo[3,4-b]pyridine, derivatives of a number of tricyclic systems, viz., imidazo[4,5-d]pyrazolo[3,4-b]pyridine, pyrazolo[3,4-b][1,2,5]thiadiazolo[3,4-d]pyridine, pyrazolo[3,4-b][1,2,3]triazolo[4,5-d]pyridine, and [1,3]oxazolo[5,4-b]pyrazolo[4,3-e]pyridine, were synthesized and reaction schemes for the processes were proposed.     

Reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride leading to purine,thiazolo[4,5-d]pyrimidine,pyrimido[4,5-e][1,3,4]thiadiazine,pyrazolo[3,4-d]pyrimidine,and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivativese

The reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride in benzene afforded purine, thiazolo[4,5-d]pyrimidine, pyrimido[4,5-e][1,3,4]thiadiazine, pyrazolo[3,4-d]pyrimidine, and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivatives, while the treatment of 6-(benzylidene-1′-methylhydrazino)-1,3-dimethyluracil with thionyl chloride in benzene gave 4-methylpyrimido[4,5-e][1,3,4]thiadiazine and 1-methylpyrazolo-[3,4-d]pyrimidine derivatives. Plausible mechanisms for the formation of these fused pyrimidines are also described.     

7-(2-fluorobenzyl)-4-(substituted)-7-H-imidazo[4,5-d −1,2,3-triazines and −7H-pyrazolo[3,4-d]-1,2,3-triazines. Synthesis and anticonvulsant activity

The imidazo[4,5-d]-1,2,3-triazine and pyrazolo[3,4-d]-1,2,3-triazine analogues of the potent anticonvul-sant purine, BW 78U79 (9-(2-fluorobenzyl)-6-methylamino-9H-purine, 1 ), were synthesized and tested for anticonvulsant activity. The imidazo[4,5-d]-1,2,3-triazines 11–13 were prepared in four steps from 5-aminoimidazole-4-carboxamide (2) and the pyrazolo[3,4-d]-1,2,3-triazines 18–21 were synthesized starting with 5-amino-1-(2-fluorobenzyl)pyrazole-4-carbonitrile (14) . The intermediate 1,2,3-triazin-4-ones 6 and 16 were converted to the 4-substituted targets via the 4-(4-dimethylaminopyridinium) salts 10 and 17 . Imidazotriazine 11 had potent anticonvulsant activity against maximal electroshock-induced seizures, but its propensity to cause emesis precluded further development.     

Synthesis of 4,6-disubstituted-7-β-D-ribofuranosyl- and arabinofuranosylpyrazolo[3,4-d]pyrimidines and certain related ribonucleosides

Several disubstituted pyrazolo[3,4-d]pyrimidine, pyrazolo[1,5-a]pyrimidine and thiazolo[4,5-d]pyrimidine ribonucleosides have been prepared as congeners of uridine and cytidine. Glycosylation of the trimethylsilyl (TMS) derivative of pyrazolo[3,4-d]pyrimidine-4,6(1H,5H,7H)-dione ( 4 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose ( 5 ) in the presence of TMS triflate afforded 7-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)pyrazolo-[3,4-d]pyrimidine-4,6(1H,5H)-dione ( 6 ). Debenzoylation of 6 gave the uridine analog 7-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-4,6(1H,5H)-dione ( 3 ), identical with 7-ribofuranosyloxoallopurinol reported earlier. Thiation of 6 gave 7 , which on debenzoylation afforded 7-β-D-ribofuranosyl-6-oxopyrazolo[3,4-d]pyrimidine-4(1H,5H)-thione ( 8 ). Ammonolysis of 7 at elevated temperature gave a low yield of the cytidine analog 4-amino-7-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-6(1H)-one ( 11 ). Chlorination of 6 , followed by ammonolysis, furnished an alternate route to 11 . A similar glycosylation of TMS-4 with 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride ( 12 ) gave mainly the N7-glycosylated product 13 , which on debenzylation provided 7-β-D-arabinofuranosylpyrazolo[3,4-d]pyrimidine-4,6(1H,5H)-dione ( 14 ). 4-Amino-7-β-D-arabinofuranosyl-pyrazolo[3,4-d]pyrimidin-6(1H)-one ( 19 ) was prepared from 13 via the C4-pyridinium chloride intermediate 17 . Condensation of the TMS derivatives of 7-hydroxy- ( 20 ) or 7-aminopyrazolo[1,5-a]pyrimidin-5(4H)-one ( 23 ) with 5 in the presence of TMS triflate gave the corresponding blocked nucleosides 21 and 24 , respectively, which on deprotection afforded 7-hydroxy- 22 and 7-amino-4-β-D-ribofuranosylpyrazolo[1,5-a]pyrimidin-5-one ( 25 ), respectively. Similarly, starting either from 2-chloro ( 26 ) or 2-aminothiazolo[4,5-d]pyrimidine-5,7-(4H,6H)-dione ( 29 ), 2-amino-4-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine-5,7(6H)-dione ( 28 ) has been prepared. The structure of 25 was confirmed by single crystal X-ray diffraction studies.     

Building libraries of skeletally diverse scaffolds from novel heterocyclic active methylene compound through multi-component reactions

Libraries of skeletally diverse potential bioactive polycyclic/spirocyclic heterocyclic compounds; 2-amino-7,9-dimethyl-5-oxo-4-aryl-4,5,6,7-tetrahydropyrano[2,3-d]pyrazolo[3,4-b]pyridine-3-carbonitrile, 2′-amino-7′,9′-dimethyl-2,5′-dioxo-6′,7′-dihydro-5′H-spiro[indoline-3,4′-pyrano[2,3-d]pyrazolo[3,4-b]pyridine]-3′-carbonitrile, and 5,5′-(arylmethylene)bis(4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one) have been synthesized through a multi-component reaction using novel heterocyclic active methylene compound 4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-6(7H)-one as one of the building blocks. This protocol can be considered to be an efficient and eco-friendly strategy for diversity oriented synthesis.     

Synthesis of 3-aryl-6H-isoxazolo[3,4-d]pyrazolo[3,4-b]pyridines and 3-aryl-6H-isoxazolo[5,4-d]pyrazolo[3,4-b]pyridines

The synthesis and characterization of a number of 3-aryl-6H-isoxazolo[3,4-d]pyrazolo[3,4-b]pyridines and 3-aryl-6H-isoxazolo[5,4-d]pyrazolo[3,4–6]pyridines from common precursors, 5-benzoyl-4-chloro-1H-pyrazolo-[3,4-b]pyridines, has been described. The structures were determined by unambiguous chemical synthesis and by isolation and ¹³C nmr analysis of some key, isolated, intermediates. The ability of these compounds to displace [3H]flunitrazepam from CNS binding sites was also observed.     

Regioselective formylation of pyrazolo[3,4-b]pyridine and pyrazolo[1,5-a]pyrimidine systems using Vilsmeier-Haack conditions

Regioselective formylation behavior has been found in the reaction of pyrazolo[3,4-b]pyridines and pyrazolo[1,5-a]pyrimidines via Vilsmeier-Haack conditions. While the 4,5- and 6,7-dihydro derivatives afforded pyrazolo[3,4-b]pyridine-5-carbaldehydes and 4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbaldehydes, respectively, the aromatic analogs rendered the pyrazolo[1,5-a]pyrimidine-3-carbaldehyde only, and no reaction took place at the pyrazolopyridine derivatives.     

Pyrazoles as building blocks in heterocyclic synthesis: Synthesis of pyrazolo [3,4-d]pyrimidine, pyrazolo[3,4-e][1,4]diazepine, pyrazolo [3,4-d][1,2,3]triazine and pyrolo [4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives

Several new pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-e][1,4]diazepine, pyrazolo[3,4-d][1,2,3]triazine and pyrolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives were prepared by the reaction of the corresponding 5-amino-pyrazole-4-carbonitrile derivative with different organic reagents under different reaction conditions. Using IR, ¹H NMR, and mass spectra we have characterized all new compounds.     

Synthesis of new 1-(3,4-dimethylphenyl)-1,5-dihydropyrazolo[3,4-<Emphasis Type="Italic">d</Emphasis>]pyrimidin-4-one derivatives

New substituted pyrazolo[3,4-d]pyrimidin-4-ones have been synthesized as a result of a series of transformations including hydrolysis of ethyl 5-amino-1H-pyrazole-4-carboxylates, cyclization of the carboxylic acids thus obtained to pyrazolo[3,4-d][1,3]oxazin-4(1H)-ones, and treatment of the latter with substituted anilines. The final pyrazolo[3,4-d]pyrimidin-4-one derivatives can also be synthesized from 5-(arylamido)-1H-pyrazole-4-carboxylic acids in the presence of a catalytic amount of anhydrous zinc(II) chloride.     

Synthesis and Antibacterial Evaluation of New Pyrazolo[3,4-d]pyrimidines Kinase Inhibitors

Pyrazolo[3,4-d]pyrimidines represent an important class of heterocyclic compounds well-known for their anticancer activity exerted by the inhibition of eukaryotic protein kinases. Recently, pyrazolo[3,4-d]pyrimidines have become increasingly attractive for their potential antimicrobial properties. Here, we explored the activity of a library of in-house pyrazolo[3,4-d]pyrimidines, targeting human protein kinases, against Staphylococcus aureus and Escherichia coli and their interaction with ampicillin and kanamycin, representing important classes of clinically used antibiotics. Our results represent a first step towards the potential application of dual active pyrazolo[3,4-d]pyrimidine kinase inhibitors in the prevention and treatment of bacterial infections in cancer patients.     

Regiocontrolled synthesis of 3- and 5-aminopyrazoles,pyrazolo[3,4-d]pyrimidines,pyrazolo[3,4-b]pyridines and pyrazolo[3,4-b]quinolinones as MAPK inhibitors

Microwave irradiation of a hydrazine and 3-methoxyacrylonitrile, ethoxymethylenemalononitrile or ethyl acetoacetate provides rapid access to 3- or 5-substituted pyrazoles in excellent yield and with total regiocontrol in a process that can be switched from one regioisomer to the other by choice of conditions. Subsequent reaction, either by microwave-assisted hydrolysis and cyclocondensation with formamide, Hantzsch-type three-component reaction with an aldehyde and ketone, or by cyclocondensation with 2-nitrobenzaldehyde, provides the pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-b]pyridine or pyrazolo[3,4-b]quinolin-4-one framework, respectively, of inhibitors of mitogen-activated protein kinases.     

Synthesis of certain pyrazolo[3,4-d]pyrimidin-3-one nucleosides

Synthesis of the pyrazolo[3,4-d]pyrimidin-3-one congeners of guanosine, adenosine and inosine is described. Glycosylation of 3-methoxy-6-methylthio-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 13 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose ( 16 ) in the presence of boron trifluoride etherate gave 3-methoxy-6-methylthio-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 17 ) which, after successive treatments with 3-chloroperoxybenzoic acid and methanolic ammonia, afforded 6-amino-3-methoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)one ( 18 ). The guanosine analog, 6-amino-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-3,4(2H,5H)-dione ( 21 ), was made by sodium iodide-chlorotrimethylsilane treatment of 6-amino-3-methoxy-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)one ( 19 ), followed by sugar deprotection. Treatment of the adenine analog, 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one ( 11 ), according to the high temperature glycosylation procedure yielded a mixture of N-1 and N-2 ribosyl-attached isomers. Deprotection of the individual isomers afforded 4-amino-3-hydroxy-1-βribofuranosylpyrazolo-[3,4-d]pyrimidine ( 26 ) and 4-amino-2-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-3(7H)-one ( 27 ). The structures of 26 and 27 were established by single crystal X-ray diffraction analysis. The inosine analog, 1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-3,4(2H,5H)-dione ( 28 ), was synthesized enzymatically by direct ribosylation of 1H-pyrazolo[3,4-d]pyrimidine-3,4(2H,5H)-dione ( 8 ) with ribose-1-phosphate in the presence of purine nucleoside phosphorylase, and also by deamination of 26 with adenosine deaminase.     

Isatins 3-C annulation vs ring-opening: Two different pathways for synthesis of spiro compounds via multicomponent reactions

An efficient synthesis of spiro compounds via two different pathways from the reactions of isatins, 3-phenylisoxazol-5(4H)-one (3-ethylisoxazol-5(4H)-one), and pyrazol-5-amine (6-aminopyrimidine-2,4(1H,3H)-dione) were reported. The catalyst Amberlyst-15 could be easy recycled and reused for many time without any appreciable loss in catalytic activity. The new type spiro compounds were gained through the ring-opening of isatins process. The structures of spiro[indoline-3,4′-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo[5,4-b]quino line-4,5′-pyrrolo[2,3-d]pyrimidine]-2′,4′,6′(1′H,3′H,7′H)-trione, and spiro[indoline-3,4′-pyrazolo[3,4-b]pyridine]-2,6′(5′H)-dione were successfully confirmed by ¹H NMR, ¹³C NMR, HRMS, and X-ray crystal diffraction analysis.     

Reactions of 4-oxobenz[1,3-e]oxazinium perchlorates with α-aminoazoles

Reactions of 4-oxo benz[1,3-e]oxazinium perchlorates with 1-R¹-3-R²-5-aminopyrazoles lead to the formation of derivatives of pyrazolo[3,4-d]pyrimidine and pyrazolo[1,5-a]1,3,5]triazine series, and with 3-amino-1,2,4-triazole, to [1,2,4]triazolo[1,5-a][1,3,5]triazines.     

Cyclic guanidines: Synthesis of 4,6,7,8-tetrahydro-1H-imidazo[1,2-a]pyrazolo[3,4-d]pyrimidin-7-ones and 1,4,6,7,8,9-hexahydropyrazolo[3′,4′:4,5]pyrimido[2,1-c] [1,2,4]triazin-7-ones

The synthesis of potential platelet aggregation inhibitors 4,6,7,8-tetrahydroimidazo[1,2-a]pyrazolo[3,4-d]-pyrimidin-7-ones and 1,4,6,7,8,9-hexahydropyrazolo[3′,4′:4,5]pyrimido[2,1-c] [1,2,4]triazin-7-ones derivatives is described starting from 4,6-dichloropyrazolo[3,4-d]pyrimidines.     

N-bromosuccinimide in heterocyclic synthesis. Synthesis of pyrazolo[3,4-d]pyrimidines,Pyrimido[5,4-e]-as-triazines,and pyrimido[4,5-c]pyridazines from 6-arylidenehydrazino-1,3-dimethyluracil derivatives

Reactions of 6-arylidenehydrazino-1,3-dimethyluracil derivatives with N-bromosuccinimide leading to pyrazolo[3,4-d]pyrimidines, pyrimido[5,4-e]-as-triazines, and pyrimido[4,5-c]pyridazines are described.     

Synthesis of pyrimido [4,5-c] pyridazine (4-deazafervenulin), pyrazolo[3,4-d] pyrimidine and 6-(pyrazino-1-yl)pyrimidine derivatives

The synthesis of several pyrimido[4,5-c]pyridazine (4-deazafervenulin) ( 1 ), pyrazolo[3,4-d]-pyrimidine ( 2 ) and 6-(pyrazino-1-yl)pyrimidine ( 9 ) analogs has been accomplished from 6-hydrazinouracil ( 3 ). This compound could not be used as starting material for the preparation of indolo[3,2-c]pyridazino[3,4-d]pyrimidine derivatives ( 8 ) because it yielded the corresponding hydrazones ( 7 ).