Synthesis and chemistry of some pyridazine nucleosides related to certain 5-substituted pyrimidine nucleosides

Condensation of 3,4-dichloro-6-[(trimethylsilyl)oxy] pyridazine ( 3 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β- D -ribofuranose ( 4 ), by the stannic chloride catalyzed procedure, has furnished 3,4-dichloro-1-(2,3,5-tri-O-benzoyl-β- D -ribofuranosyl) pyridazin-6-one ( 5 ). Nucleophilic displacement of the chloro groups and removal of the benzoyl blocking groups from 5 has furnished 3-chloro-4-methoxy-, 3,4-dimethoxy-, 4-amino-3-chloro-, 3-chloro-4-methylamino-, 3-chloro-4-hydroxy-, and 4-hydroxy-3-methoxy-1-β- D -ribofuranosylpyridazin-6-one. An unusual reaction of 5 with dimethylamine is reported. Condensation of 4,5-dichloro-3-nitro-6-[(trimethylsilyl)oxy]pyridazine with 4 yielded 4,5-dichloro-3-nitro-1-(2,3,5-tri-O-benzoyl-β- D -ribofuranosyl)pyridazin-6-one ( 24 ). Nucleophilic displacement of the aromatic nitro groups from 24 is discussed. Condensation of 3 with 3,5-di-O-p-toluoyl 2-deoxy- D -erythro-pentofuranosyl chloride ( 28 ) afforded an α, β mixture of 2-deoxy nucleosides. The synthesis of certain 3-substituted pyridazine 2′-deoxy necleosides are reported.     

A comparison of two methods for the preparation of 3-Deazapurine ribonucleosides

The reaction of the trimethylsilyl derivative of 4,6-dichloroimidazo[4,5-c]pyridine with 2,3,5-tri-O-benzoyl- D -ribofuranosyl bromide gave four nucleosides-the α- and β-anomers of the 1-isomer and the α- and β-anomers of the 3-isomer (3.9:2.7:1.5:1). In contrast, the fusion reaction of 4,6-dichloroimidazo[4,5-c ]pyridine with 1,2,3,5-tetra-O-acetyl-β- D -ribofuranose gave a high yield of the 1-β-isomer, which was converted to the known 3-deazaadenosine (4-amino-l-β- D -ribofuranosylimidazo[4,5-c]pyridine).     

Synthesis of imidazo[4,5-d]pyridazine nucleosides related to inosine

Several imidazo[4,5-d]pyridazine nucleosides which are structurally similar to inosine were synthesized. Anhydrous stannic chloride-catalyzed condensation of persilylated imidazo[4,5-d]-pyridazin-4(5H)one (1) and imidazo[4,5-d]pyridazine-4,7(5H,6H)dione ( 16 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose ( 3 ) provided (after sodium methoxide deblocking) 6-β-D-ribo furanosylimidazo[4,5-d]pyridazin-4(5H)one (5) and 3,6-di-(β-D-ribofuranosyI)imidazo[4,5-d]pyridazin-4-one ( 7 ); and 1-(β-D-ribofuranosyl)imidazo[4,5-d]pyridazine-4,7(5H,6H)dione ( 19 ) and 1,5 or 6-di-(β-D-ribofuranosyl)imidazo[4,5-d ]pyridazine-4,7(5H or 6H)dione ( 21 ), respeeitvely. 4,7-Diehloro-1-β-D-ribofuranosylimidazo[4,5-d]pyridazine ( 12 ) and dimethyl 1-β-D-ribofuranosylimidazole-4,5-dicarboxylate ( 26 ), both prepared from stannic chloride-catalyzed ribosylations of the corresponding heterocycles, were converted in several steps to 3-β-D-ribo-furanosy limidazo[4,5-d]pyridazin-4(5H)one ( 14 ) and nucleosidc 19 , respectively. Acid-catalyzed isopropylidenation of mesomeric betaine 7 or nuclcoside 14 provided 3-(2,3-isopropylidene-β-D-ribofuranosyl)imidazo[4,5-d]pyrizin-4(5H)one ( 31 ). 1-β-D-Ribofuranosylimidazo[4,5-d]-pyridazine ( 29 ) was obtained in several steps from nueleoside 12 . The structure of the nucleosides was established by the use of carbon-13 and proton nmr.     

Synthesis and antiviral evaluation of some novel [1,2,4]triazolo[4,3-β][1,2,4]triazole nucleoside analogs

Ribosylation of 3-amino-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 1 ) with l-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose and stannic chloride resulted in the following protected nucleoside analogs: 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 4 ), 3-amino-1-(2,3,5-tri-O-benzoyl-α-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), and 3-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) amino-5H-[1,2,4]triazolo[4,3-b]-[1,2,4]triazole ( 7 ). Compounds 4–6 were deprotected to 3-amino-1-β-D-ribofuranosyl[1,2,4]triazolo[4,3-b][1,2,4]-triazole ( 3 ), 3-amino-1-α-D-ribofuranosyl[1,2,4]triazolo[4,5-b][1,2,4]triazole ( 8 ), and 3-imino-2H-2-β-D-ribo-furanosyl[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 9 ), while 7 could not be deprotected without decomposition. Compounds 1, 4, 6, 7 , and 9 were screened and found to have no antiviral activity.     

The synthesis of imidazo[4,5-c] - and v-triazolo[4,5-c] pyridazines

The parent imidazo[4,5-c]pyridazine (IV) has been prepared for the first time by three different routes. 1-Methylimidazo[4,5-c]pyridazine (XX) and 3-methylimidazo[4,5-c]pyridazine (XXVII) have been prepared by unequivocal syntheses. The constitution of the methylation product of imidazo[4,5-c]pyridazine-2-thiol (VIII) has been shown to be 2-methylthioimidazo[4,5-c]-pyridazine (IX) by the unequivocal syntheses of 1-methylimidazo[4,5-c]pyridazine-2-thiol (XXIII) and 3-methylimidazo[4,5-c]pyridazine-2-thiol (XXXIII). Likewise, the structure of the methylation product (XIII) was shown to be S-methylation by the unequivocal syntheses of 1-methyl-2-methylthio-6-chloroimidazo[4,5-c]pyridazine (XXIV) and 3-methyl-2-methylthio-6-chloroimidazo[4,5-c]pyridazine (XXXI), respectively. Several 7-substituted amino-v-triazolo-[4,5-c]pyridazines (XXXVIII) have been prepared from 7-chloro-v-triazolo[4,5-c]pyridazine (XXXVII).     

Pyrazolopyrimidine nucleosides. Part VII. The synthesis of certain pyrazolo [3,4-d] pyrimidine nucleosides related to the nucleoside antibiotics toyocamycin and sangivamycin

The condensation of 4-acetamido-3-cyanopyrazolo[3,4-d]pyrimidine ( 5 ) with crystalline 2,3,5-tri-O-acetyl-β- D -ribofuranosyl chloride ( 6 ) has furnished a good yield of nucleoside material ( 7 ) which on treatment with sodium methoxide in methanol provided a high yield of nucleoside which was subsequently established as methyl 4-amino-1-(β- D -ribofuranosyl)pyrazolo[3,4-d]-pyrimidine-3-formimidate monohydrate ( 11 ). The formimidate function of 11 was found to be highly reactive and 11 was readily converted into the corresponding carhoxamidine ( 8 ), carboxamidoxime ( 14 ) and carboxamidrazone ( 15 ) when treated with the appropriate nucleophiles. Treatment of the imidate ( 11 ) with sodium hydrogen sulfide gave a high yield of the thiocarboxamide ( 12 ) which was then readily converted into 4-amino-3-cyano-1-(β- D -ribofuranosyl)pyrazolo[3,4-d]pyrimidine ( 16 ). Aqueous base transformed 11 into 4-amino-1-(β- D -ribofuranosyl)-pyrazolo[3,4-d]pyrimidine-3-carboxamide ( 10 ) while more vigorous basic hydrolysis provided the corresponding carboxylic acid ( 9 ) in nearly quantitative yield. Decarboxylation of 9 proceeded smoothly in hot sulfolane to provide the known 4-amino-1-(β- D -ribofuranosyl)pyrazolo[3,4-d]pyrimidine ( 13 ) in 68% yield which unequivocally established the site of ribosylation and anomeric configuration for all nucleosides reported in this investigation.     

Pyrrolopyridazine nucleosides. The synthesis of certain 1-β-D-ribofuranosyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-ones

Nucleosides of pyrrolo[2,3-d]pyridazin-4(5H)-ones were prepared by the single-phase sodium salt glycosylation of appropriately functionalized pyrrole precursors. The glycosylation of the sodium salt of ethyl 4,5-dichloro-2-formyl-1H-pyrrole-3-carboxylate ( 4 ), or its azomethino derivative 7 , with 1-bromo-2,3,5-tri-O-benzoyl-D-ribofuranose in acetonitrile afforded the corresponding substituted pyrrole nucleosides ethyl 4,5-dichloro-2-formyl-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1H-pyrrole-3-carboxylate ( 5 ) and ethyl 4,5-dichloro-2-phenylazomethino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1H-pyrrole-3-carboxylate ( 8 ), respectively. The latter, upon treatment with hydrazine, afforded the annulated product 2,3-dichloro-1-β-D-ribofuranosyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one ( 6 ), in good yield. The unsubstituted analog 1-β-D-ribofuranosyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one ( 9 ), was obtained upon catalytic dehalogenation of 6 . This report represents the first example of the synthesis of nucleosides of pyrrolopyridazines.     

Synthesis and biodistribution of p-iodophenyl analogues of a naturally occurring imidazole ribonucleoside

A model iodophenyl imidazole ribonucleoside has been synthesized to study biodistribution properties in laboratory animals. The key intermediate 5-amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-[N-(p-iodophenyl)carboxamide] ( 5 ) was synthesized by coupling N-succinimidyl-5-amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxylate ( 4 ) and p-iodoaniline. Deacetylation of the intermediate compound gave 5-amino-1-β-D-ribofuranosylimidazole-4-[N-(p-iodophenyl)]carboxamide ( 6 ). Ring annulation via diazotization of 5 gave 7-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazo[4,5-d]-v-triazin-[3-N-(p-iodophenyl)]-4-one ( 7 ). Subsequent deacetylation of 7 afforded 7-β-D-ribofuranosylimidazo[4,5-d]-v-triazin-[3-N-(p-iodophenyl)]-4-one ( 8 ). The radiolabeled compounds, [¹²⁵I] 5 and [¹²⁵I] 6 were prepared in a manner similar to the corresponding unlabeled compounds except that p-[¹²⁵I]iodoaniline was used for coupling with 4 . Biodistribution studies of iodine-125-labeled 5 and 6 were performed in female Fischer rats and tumor bearing nude mice. Compound 6 showed uptake in the brain and proliferating tissues such as tumor and bone-marrow.     

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.     

Synthesis of β-D-ribo- and 2′-deoxy-β-D-ribofuranosyl derivatives of 6-aminopyrazolo[4,3-c]pyridin-4(5H)-one by a ring closure of pyrazole nucleoside precursors

6-Amino-1-(2-deoxy-β-D-erthro-pentofuranosyl)pyrazolo[4,3-c]pyridin-4(5H)-one ( 5 ), as well as 2-(β-D-ribofuranosyl)- and 2-(2-deoxy-β-D-ribofuranosyl)- derivatives of 6-aminopyrazolo[4,3-c]pyridin-4(5H)-one ( 18 and 22 , respectively) have been synthesized by a base-catalyzed ring closure of pyrazole nucleoside precursors. Glycosylation of the sodium salt of methyl 3(5)-cyanomethylpyrazole-4-carboxylate ( 6 ) with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose ( 8 ) provided the corresponding N-1 and N-2 glycosyl derivatives ( 9 and 10 , respectively). Debenzoylation of 9 and 10 with sodium methoxide gave deprotected nucleosides 14 and 16 , respectively. Further ammonolysis of 14 and 16 afforded 5(or 3)-cyanomethyl-1-(2-deoxy-β-D-erythro-pentofuranosyl)pyrazole-4-carboxamide ( 15 and 17 , respectively). Ring closure of 15 and 17 in the presence of sodium carbonate gave 5 and 22 , respectively. By contrast, glycosylation of the sodium salt of 6 with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide ( 11 ) or the persilylated 6 with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose gave mainly the N-2 glycosylated derivative 13 , which on ammonolysis and ring closure furnished 18 . Phosphorylation of 18 gave 6-amino-2-β-D-ribofuranosylpyrazolo[4,3-c]pyridin-4(5H)-one 5′-phosphate ( 19 ). The site of glycosylation and the anomeric configuration of these nucleosides have been assigned on the basis of ¹H nmr and uv spectral characteristics and by single-crystal X-ray analysis of 16 .     

Synthesis of 8-methyl-2-azainosine and related nucleosides

The synthesis of 6-methyl-7-(β-D-ribofuranosyl)imidazo[4,5-d]-v-triazin-4-one (8-methyl-2-azainosine ( 2) ) and 6-methyl-7-(β-D-glucopyranosyl)imidazo[4,5-d]-v-triazin-4-one ( 5 ) by diazotization of 5-amino-1-(β-D-ribofuranosyl)-2-methylimidazole-4-carboxamide ( 1 ) and diazotization of 5-amino-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-2-methylimidazole-4-carboxamide ( 3 ), followed by deacetylation of the resulting compound 4 , is described. The preparation of 6-methyl-5-(β-D-ribofuranosyl)imidazo[4,5-d]-v-triazin-4-one ( 10 ) and 6-methyl-5-(β-D-glucopyranosyl)imidazo[4,5-d]-v-triazin-4-one ( 11 ) by glycosylation of 6-methylimidazo[4,5-d]-v-triazin-4-one (8-methyl-2-azahypoxanthine, ( 7) ) is also described. Structural assignments were made on basis of analytical and ¹H-nmr and uv spectral data.     

The synthesis of ω-dialkylaminoalkylaminopyrazino[2,3-d]-, pyrido[2,3-d]-, imidazo[4,5-c]- and imidazo[4,5-d]pyridazines

The synthesis of 5-chloro-8-(ω-dialkylaminoalkylamino)pyrazino[2,3-d]pyridazine (II) proceeded smoothly when 5,8-dichloropyrazino[2,3-d]pyridazine (I) was allowed to react with ω-dialkylaminoalkylamines. Similarly, the reaction of 5,8-dichloropyrido[2,3-d]pyridazine (IV) with ω-dialkylaminoalkylamines gave the two expected products 8-chloro-5-(ω-dialkylaminoalkylamino)pyrido[2,3-d]pyridazine (V) and 5-chloro-8-(ω-dialkylaminoalkylamino)pyrido[2,3-d]pyridazine (VI) in a 2:3 ratio. 4,7-Dichloroimidazo[4,5-d]pyridazine (XII) was found to be much less reactive towards nucleophilic substitutions and more vigorous conditions resulted in disubstituted products (XIII). 7-Chloroimidazo[4,5-c]pyridazine (XVIII) was also found to be much less reactive towards nucleophilic substitution. In both of these cases one of the imidazole nitrogen atoms was blocked by a tetrahydropyranyl group which increased the reactivities and led to the desired monosubstituted products XVII from XII and in the latter case the expected products (XIX).     

The synthesis of 2-chloro-1-β-D-ribofuranosyl-5,6-dimethylbenzimidazole and (certain related derivatives

The synthesis of 2-chloro-1-(β-D -ribofuranosyl)-5,6-dimethylbenzimidazole (3b) has been accomplished by a condensation of 1-trimethylsilyl-2-chloro-5,6-dimethylbenzimidazole (1) with 2,3,5-tri-O-acetyl-D -ribofuranosyl bromide (2) followed by subsequent deacetylation. Nucleophilic displacement of the 2-chloro group from 3b has furnished several interesting 2-substituted-1-(β-D -ribofuranosyl)-5,6-dimethylbenzimidazoles. 1-(β-D -Ribofuranosyl)-5,6-dimethylbenzimidazole (5) and 1-(β-D -ribofuranosyl)-5,6-dimethylbenzimidazole-2-thione (4) were prepared from 3b. Alkylation of 4 furnished certain 2-alkylthio-1-(β-D -ribofuranosyl)-5,6-dirnethylbenzimidazoles and oxidation of 4 with alkaline hydrogen peroxide produced 1-(β-D -ribofuranosyl)-5,6-dimethylbenzimidazole-2-one D The assignment of anomeric configuration for all nucleosides reported is discussed.     

Synthesis and Properties of 6-Amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

We have established that when 5-chloro-6-[cyano(2,3-dihydro-1-R-benzo[d]azol-2-yl)methyl]-2,3-pyrazinedicarbonitriles are reacted with nucleophilic reagents (aliphatic and aromatic amines, hydrogen sulfide), annelation of the five-membered ring occurs on the [b] face of the pyrazine with formation of 6-amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles and 6-amino-7-(1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyrazine-2,3-dicarbonitrile respectively. Further heating with excess of acylating reagent leads to formation of a novel heterocyclic system 1H-benzo[4,5]imidazo[1,2-c]pyrazino[2',3':4,5]pyrrolo[3,2-e]pyrimidine. Reaction of vicinal dinitriles with hydrazine hydrate leads to the novel system 1H-pyrrolo[2',3':5,6]pyrazino[2,3-d]pyridazine.     

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.     

Novel Aspects of the Reaction of 3-(Benzimidazol-2-yl)-2-iminocoumarins with Aromatic Aldehydes

The reaction of 3-(benzimidazol-2-yl)-2-iminocoumarins with aromatic aldehydes has been studied. The condensation products 7-aryl-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines or 3-(benzimidazol-2-yl)coumarins are formed depending on the nature of the substituent in the starting 2-iminocoumarin and aldehyde. In DMF medium, 7-aryl-7H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines isomerize to the corresponding 7-aryl-14H-benzo[4,5]imidazo[1,2-c]benzopyrano[3,2-e]pyrimidines. The effect of the substituent on the isomerization process has been studied and the reaction mechanisms are discussed.     

Fused pyrimidines. 7. Nucleosides of pyrimidopyrimidinediones and pteridinediones as potential chemotherapeutic agents

Several nucleoside derivatives of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione 1 and 2,4{1H,3H-pteridinedione 2 were prepared. Treating the appropriate silylated nucleobase with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofura-nose 3 in the presence of trimethylsilyl Inflate gave 4 and 8 which, upon debenzoylation, gave 5 and 9 , respectively. Treatment of 4 with phosphorus pentasulfide afforded the sulfur substituted compound 6 . Again, deprotection gave 7 . The arabinose derivatives were obtained by treating 1-O-acetyl-2,3,5-tri-O-benzoyl-D-arabinofuranose 10 with the silylated nucleobases to give 11 and 13 . Debenzoylation gave the free arabinonucleosides 12 and 14 respectively. The deoxy derivative 16 was prepared by the reaction of 1 with 1-chloro-3,5-di-O-acetyl-2-deoxy-D-ribofuranose 15 . Deacetylation of 16 with methanolic ammonia gave the α-anomer 17 .     

Studies on imidazole derivatives and related compounds. 4. Synthesis of O-glycosides of 4-carbamoylimidazolium-5-olate

Ribosylation of trimethylsilyl derivative of 1-(4-nitrobenzyl)-5-carbamoylimidazolium-4-olate ( 5 ) with 1,2,3,5-tetra-O-acetyl-β- D -ribofuranose in the presence of stannic chloride and trimethylsilyl trifluoromethanesulfonate afforded no 5-O-glycosides but N-1 ribosylated compound ( 6 ). However, 5-O-riboside ( 7a ) and its orthoamide derivative ( 8 ) were given by glycosylation of tri-n-butylstannyl derivative of 5 with 2,3,5-tri-O-acetyl-β- D -ribofuranosyl chloride in the presence of silver trifluoromethanesulfonate. This procedure was successfully applied to other sugars and 5-O-glucuronide ( 11 ), a possible metabolite of 1 in vivo, was obtained as one of the 5-O-glycoside derivatives.     

Pyrrolopyrimidine nucleosides. IV. The synthesis of certain 4,5-disubstituted-7-(β-d-ribofuranosyl)pyrrolo[2,3-d]pyrimidines related to the pyrrolo[2,3-d]pyrimidine nucleoside antibiotics

The treatment of 4-chloro-7-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine ( 4 ) with N-bromoacetamide in methylene chloride has furnished the 5-bromo derivative of 4 which on subsequent deacetylation provided a good yield of 5-bromo-4-chloro-7-(β-D-ribo-furanosyl)pyrrolo[2,3-d] pyrimidine ( 6 ). Assignment of the halogen substituent to position 5 was made on the basis of pmr studies. Treatment of 6 with methanolic ammonia afforded 4-amino-5-bromo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d ]pyrimidine ( 8 , 5-bromotubercidin) and a subsequent study has revealed that the 4-chloro group of 6 was replaced preferentially in a series of nucleophilic displacement reactions. The analogous synthesis of 4,5-dichloro-7-(β-D-ribo-furanosyl)pyrrolo[2,3-d]pyrimidine ( 13b ) and 4-chloro-5-iodo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine ( 13a ) from 4 furnished 5-chlorotubercidin ( 15 ) and 5-iodotubercidin ( 14 ), respectively, on treatment of 13b and 13a with methanolic ammonia. The possible biochemical significance of these tubercidin derivatives is discussed.     

Pyridazines. XXXV. Preparation of some novel pyrimido[4,5-c]pyridazine derivatives from 3-alkylamino- and 3-arylamino-4-pyridazinecarboxamides

Facile syntheses of pyrimido[4,5-c]pyridazine-5,7(6H,8H)diones 4 , pyrimido[4,5-c]pyridazin-5(8H)-ones 7–10 , and dihydropyrimido[4,5-c]pyridazin-5(6H)ones 5,6 starting from 3-chloro-4-pyridazinecarbonitrile 1 via aminocarbonitriles 2 and aminocarboxamides 3 are described. In addition, a convenient access to the new aminopyridazinecarbonitrile 11 from the chloronitrile 1, employing the tetrazolo[1,5-b]pyridazine 12 as the key intermediate, is reported.