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.     

Synthesis of arylamino-substituted pyrazolo[3,4-d][1,2,4]triazolo[4,3-a]pyrimidinones,pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinones,and their thermal isomerization

The reaction of 1-(4-oxo-1-R-5H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-arylthiosemicarbazides with methyl iodide gave rise to 1,2,4-triazolo-pyrazolopyrimidinones of linear structure, and with dicyclohexylcarbodiimide the products had angular and linear structure. The heating of compounds obtained higher than their melting point resulted in their isomerization into 7-aryl-amino-1-R-1,8-dihydro-4H-pyrazolo[3,4-d]-[1,2,4]triazolo[1,5-a]pyrimidin-4-ones.     

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.     

Synthesis and alkylation of pyrazolo[3,4-c]isoquinolines and hexahydrocyclohepta[d]pyrazolo[3,4-b]pyridines

The condensation of 1-acyl-2-(morpholin-4-yl)cycloalkenes with 3-amino-1-phenyl-1H-pyrazol-5(4H)-ones gave the corresponding 2,3,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinoline and 3,6,7,8,9,10-hexahydrocyclohepta[ d]pyrazolo[3,4-b]pyridine derivatives. Alkylation of 2,3,6,7,8,9-hexahydropyrazolo[3,4-c]-isoquinolines with alkyl halides occurred at the nitrogen atom in the 3-position. The structure of 7-methyl-2,5-diphenyl-2,3,6,7,8,9-hexahydro-1H-pyrazolo[3,4-c]isoquinolin-1-one was proved by X-ray analysis.     

1H-pyrazolo[3,4-d]thieno[2,3-b]pyridine and its derivatives

The synthesis of the parent ring system and some of the derivatives of 1H-pyrazolo[3,4-d]thieno[2,3-b]pyridine are described.     

Synthesis of pyrano[3,4-c]pyrazole and pyrazolo[3,4-d][1,2]diazepine derivatives

By the action of thionyl chloride on 3(5)-R-4-phenacylpyrazole-5(3)-carboxylic acid ( 3c,d ), 3-R-5-phenylpyrano[3,4-c]pyrazole-7-(1H)ones ( 4c,d ) were obtained. When 4c,d were treated with hydrazine hydrate followed by refluxing in ethanol containing acetic acid, 4,7-dihydro-3-R-5-phenylpyrazolo[3,4-d][1,2]-diazepin-8-(1H)ones ( 6c,d ) were formed. Compounds 6c,d , in turn, were refluxed in ethanol saturated with hydrochloric acid to yield 6-amino-1,6-dihydro-3-R-5-phenyl-7H-pyrazolo[3,4-c]pyridin-7-ones ( 7c,d ). Compounds 7c,d could be obtained directly from 5c,d. The starting materials 3c,d were prepared by hydrolysis of the oxime of 3(5)-R-4-phenacyl-5(3)carboalcoxypyrazoles ( 1a,b ). Structural assignments rested on correct elemental analysis, molecular weights determined by mass spectrometry, and spectroscopic evidence.     

Synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines

Starting from 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones, a synthesis pathway to the tricyclic pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines is described. Reaction of 1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-ones with phosphoryl chloride afforded the corresponding 4-chloro-1H-pyrazolo[3,4-d]pyrimidines. Treatment of these compounds with hydrazine hydrate at reflux temperature gave the hydrazino derivatives, which were subsequently cyclized to the titled compounds on heating with orthoesters in ethanol.     

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.     

Synthesis of 1H-pyrazolo[3,4-e]-s-triazolo[3,4-c]-as-triazines, 8H-pyrazolo[3,4-e]tetrazolo[5,1-c]-as-triazine and 1,7-dihydro-8H-pyrazolo[3,4-e]-as-triazine derivatives

3-Hydrazino-7-methyl-5-phenyl-5H-pyrazolo[3,4-c]-as-triazine 1 underwent ring closure and/or condensation reaction with formic acid, acetic acid, acetic anhydride and benzoyl chloride to afford 1H-pyrazolo-[3,4-d]-s-triazolo[3,4-c]-as-triazines 2, 5 and 7a and/or N-acyl derivatives 3, 4 and 6 . N-Acyl derivatives 3 and 6 underwent cyclisation reaction on treatment with phosphoryl chloride to give 5 and 7a . 3-Methyl-1-phenyl-8-aryl-1H-pyrazolo[3,4-e]-s-triazolo[34,-c]-as-triazines 7 were also prepared by the reaction of the hydrazono derivatives 8 wit thionyl chloride. On treatment of 1 with nitrous acid gave the 8H-pyrazolo[3,4-e]tetrazolo-[5,1-c]-as-triazine 9 . Compound 1 underwent ring closure with carbon disulphide or ethyl chloroformate to 1,7-dihydro-8H-pyrazolo[3,4-e]-s-triazolo[3,4-c]-as-triazine derivatives 10 and 12 . Reaction of 1 with ethyl acetoacetate or acetylacetone gave 3-pyrazolo derivatives 13 and 14 .     

Synthesis of pyrazolo[4,3-d]oxazoles

1-Phenyl-3-methyl-5-pyrazolone-4-oxime reacted with benzylamine, methylamine, methyl- and ethyl ioides to give 3-methyl-1,5-diphenyl-1H-, 3-methyl-1-phenyl-1H- and 3,5-dimethyl-1-phenyl-1H-pyrazolo[4,3-d]oxazoles I, II. The structure of I was elucidated authentically through other routes by interaction of 1-phenyl-3-methyl-4,5-dioxopyrazolone with benzylamine and/or benzaldehyde and ammonium acetate. Various 3-meth-yl-5-aryl-1-phenyl-1H-pyrazolo[4,3-d]oxazoles IV were synthesized by the reaction of 4,5-dioxopyrazolone with aromatic aldehydes in the presence of ammonium acetate. Also, the structure of I was elucidated authentically via other routes by the reaction of 1-phenyl-3-methyl-4-imino-5-pyrazolone with each of benzylcyanide, benzylamine, benzaldehyde and benzalaniline.     

Synthesis of 2-hetaryl-6H-pyrazolo[3,4-d]-1,2,3-triazoles

A novel efficient synthesis of 2-hetaryl-4-methyl-6-phenyl-6H-pyrazolo[3,4-d]-1,2,3-triazoles was achieved by the reaction of 5-amino-3-methyl-4-nitroso-1-phenyl-1H-pyrazole with heterocyclic amines followed by air oxidation in the presence of cupric acetate.     

Synthesis of pyrazolo[4,3-<Emphasis Type="Italic">e</Emphasis>][1,2,4]triazolo[4,3-<Emphasis Type="Italic">c</Emphasis>]pyrimidines

Starting from 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones, a synthesis pathway to the tricyclic pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines is described. Reaction of 1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-ones with phosphoryl chloride afforded the corresponding 4-chloro-1H-pyrazolo[3,4-d]pyrimidines. Treatment of these compounds with hydrazine hydrate at reflux temperature gave the hydrazino derivatives, which were subsequently cyclized to the titled compounds on heating with orthoesters in ethanol. Correspondence: Abolghasem Davoodnia, Department of Chemistry, School of Sciences, Islamic Azad University, Mashhad Branch, Mashhad 91735-413, Iran.     

1,3-Dipolar cycle-addition of 2-diazoalkanes to pyridazin-3(2H)-one derivatives. The formation of 3H-pyrazolo[3,4-d]pyridazin-4(5H)-one and 3H-pyrazolo[3,4-d]pyridazin-7(6H)-one derivatives

1,3-Dipolar cycloadditions of diazoalkanes to pyridazin-3(2H)-ones 1–7 and pyridazin-3(2H)-thiones 8 and 9 are regioselective producing 3H -pyrazolo[3,4-d]pyridazin-4(5H)-ones 15–19, 27–29 and 34–38 as the major products. In some instances, the isomeric 3H-pyrazolo[3,4-d]pyridazin-7(6H)-ones, such as 20 and 23 were isolated as the minor products. From 3 and 6 the primary 3a,7a-dihydro cycloadducts 25 and 26 , and rearranged 1,2-dihydro intermediate 31 were isolated. From 10 and 1-diazoindane the isomeric exo- and endospiro products 39 and 40 were formed.     

Potential antitumor agents. III. Synthesis of pyrazolo[3,4-e]pyrrolo[3,4-g]indolizine and 1H-pyrazolo[3,4-e]indolizine derivatives

The preparation of 5-dimethylaminoethyl-4,6-dioxo-1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]pyrrolo-[3,4-g]indolizine, a derivative of the still unknown tetracyclic parent ring pyrazolo[3,4-e]pyrrolo[3,4-g]indolizine, is reported starting from 1-phenyl-5-(1-pyrryl)pyrazole-4-acetonitrile by PPA catalyzed double cyclization of the related oxalylcyanomethyl derivative and subsequent alkylation. The synthesis of 4,5-bis(isopro-pylaminocarbonyloxymethyl) and 4,5-bis-(cyclohexylaminocarbonyloxymethyl) derivatives of 1-phenyl-1H-pyrazolo[3,4-e]indolizine is also described. The new tricyclic and tetracyclic derivatives were tested as potential antitumor agents.     

Some transformations of 3-amino-4-alkoxycarbonyl-6-hydroxy-2H-1-benzopyran-2-ones. The synthesis of [1] benzopyrano[3,4-d]-[1,3]oxazine and [1] benzopyrano[3,4-d]pyrimidine derivatives

Acylation of 4-alkoxycarbonyl-3-amino-6-hydroxy-2H-1-benzopyran-2-one derivatives 3 and 4 gave under mild conditions the O-substituted derivatives 5–10, N,O -disubstituted derivative 11 and N,N-disubstituted derivative 12 . The compound 4 was transformed with benzoyl chloride under more drastic conditions into 13 , a derivative of a new heterocyclic system 2-benzopyrano[3,4-d][1,3]oxazine. The derivatives of 1-benzopyrano-[3,4-d]pyrimidine 19 and 20 were prepared either from 3 and 4 through the corresponding N-heteroarylformamidines 14 and 15 and N-heteroarylformamide oximes 17 and 18 or by cyclization of thiourea derivative 20 .     

Synthesis and tautomeric structure of some 2H-pyrazolo[3,4-d]pyridazines

A number of substituted 2H-pyrazolo[3,4-d]pyridazines, pyridazin-7(6H)ones, and -pyrid-azine-4,7(5H,6H)diones have been prepared from the 3,4-diacyl-, 3-carbethoxy-4-acyl-, 3-carbethoxy-4-cyano-, and 3,4-dicarbethoxy-pyrazole derivatives and hydrazine hydrate. The structures of the compounds prepared were inferred from their elemental analyses and spectral data. On the basis of spectroscopic data it was concluded that pyrazolopyridazinones have the oxo form, whereas the monohydroxymono oxo structure is preferred for pyrazolopyridazine-diones.     

Reaction of 6-hydrazino-3,4-dimethyl-1H-pyrazolo[3,4-d]pyrimidine with pregnenolone derivatives

New androsteno[17,16-d]pyrazoles and -pyrazolines with pyrazolo[3,4-d]pyrimidine fragments were synthesized. A reaction of 3β-hydroxypregna-5,16-dien-20-one and its 3-O-acetyl derivative with 6-hydrazino-3,4-dimethyl-1H-pyrazolo[3,4-d]pyrimidine led to hydrazones at position 20 of the pregnenolone molecule, a possibility of their cyclization was studied. Upon melting, the hydrazones cyclize with the formation of pyrazoline ring annulated with ring D of the steroid at positions 16 and 17. Reflux of the hydrazones in mesitylene with AcOH leads to a mixture of two reaction products: androsteno[17,16-d]pyrazole and a dodecahydro-13H-phenanthro[1′,2′:5,6]pyrano[2,3-d]pyrazole derivative. Apparently, this transformation proceeds through the corresponding epoxide with subsequent rearrangement, which leads to the ring D expansion.     

Facile Synthesis of 2′-Deoxyribofuranosides of Allopurinol and 4-Amino-1H-pyrazolo[3,4-d]pyrimidine via Phase-Transfer Glycosylation

Phase-transfer glycosylation of 4-methoxy-1H-pyrazolo[3,4-d]pyrimidine with the 2-deoxyribofuranosyl chloride 9 formed the N(1)-β-nucleoside 10a as main product (39%). As by-products the α-D -anomer 11a (7%) and the N(2)-isomer 12a (18%) were isolated. Assignment of these isomers was made on the basis of their ¹H- and ¹³C-NMR spectra. Removal of the sugar-protecting groups yielded the 4-methoxy-nucleosides 10b, 11b , and 12b , respectively. Nucleophilic displacement of the 4-MeO-group gave the 2-deoxyribofuranosides 1–4 of allopurinol and 4-amino-1H-pyrazolo[3,4-d]pyrimidine.     

Preparation and regiochemical assignments of new pyrazolo[3,4-c] [2,1]benzodiazepines

The preparation of new pyrazolo[3,4-c][2,1]benzothiazepines substituted at the nitrogen atoms of the pyrazole moiety is described. It was carried out by reaction of the 4,9-dihydro-9-methyl-4,10,10-trioxo-1(2)H-pyrazolo[3,4-c][2,1]benzothiazepine ( 1 ) with several alkylating agents under both classical and phase-transfer catalysis (PTC) conditions. Assignments of the N-alkyl regioisomers obtained were performed by study of their ¹H nmr spectra and NOE experiments.     

A convenient synthesis of novel pyridazino[3,4-b]quinoxaline and pyrazolo[3,4-b]quinoxaline utilizing 1,3-dipolar cycloaddition reaction

The reaction of 2,6-dichloroquinoxaline 4-oxide 4 with methylhydrazine gave 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5, whose reaction with dimethyl acetylenedicarboxylate or 2-chloroacrylonitrile resulted in the 1,3-dipolar cycloaddition reaction to afford 7-chloro-3,4-bismethoxycarbonyl-1-methyl-1,2-dihydropyridazino[3,4-b]quinoxaline 6 or 6-chloro-3-hydroxymethylene-1-methyl-2,3-dihydro-1H-pyrazolo[3,4-b] quinoxaline hydrochloride 7, respectively.