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.     

Studies on the chemistry of 5-propynyloxy- and 5-propynylthiopyrimidines: New syntheses of furo- and thieno[3,2-d]pyrimidines

The utility of certain 5-alkynyloxy-, 5-alkynylthio, and 5-alkynylsulfinyl-pyrimidines as precursors of 7-substituted furo[3,2-d]- and thieno[3,2-d]pyrimidines has been examined. When treated with sodium methoxide in warm methyl sulfoxide, 1,3-dimethyl-5-(2-propynyloxy)uracil ( 6 ) cyclizes to afford 1,3,7-tri-methylfuro[3,2-d]pyrimidine-2,4-(1H,3H)-dione ( 12 ) in 52% yield, possibly via the allenic ether 9 (R = H). The corresponding 5-(2-butynyloxy)pyrimidine ( 7 ), obtained in good yield by treating 6 with methyl iodide and sodium hydride in methyl sulfoxide, fails to undergo an analogous cyclization. However, compound 7 does undergo a normal alkynyl Claisen rearrangement and cyclization when heated at 130°, giving the 8-methylpyrano[3,2-d]pyrimidine 8 in methyl sulfoxide and the 6,7-dimethylfuro[3,2-d]pyrimidme 11 in dimethylformamide. The 5-(2-propynylthio)pyrimidine 15 affords the allene 19 and the 1-propyne 22 when treated with various bases, but none of the 7-methylthieno[3,2-d]pyrimidine 16. At 145° in methyl sulfoxide, 15 undergoes a thio-Claisen rearrangement process to afford the 6-methylthieno[3,2-d]pyrimidine 17 together with substantial amounts of a product 20 that bears a 7-thiomethoxymethyl substituent derived from the solvent. Heating the 5-(2-propynylsulfinyl)pyriniidine 23 at 105° in methyl sulfoxide, followed by acidification of the reaction mixture, affords 1,3-dimethyl-7-formylthieno[3,2-d]pyrimidine-2,4-(1H,3H)-dione ( 29 ) in 47% yield. Deuterium labelling studies established that the aldehyde proton of 29 is derived from the 3′-proton of 23 . This finding is consistent with a mechanism that involves sequential [2,3] and [3,3] sigma-tropic rearrangements, and the intermediacy of a dihydrothieno[3,2-d]pyrimidine such as compound 30.     

α-Thioureidoalkylation of functionally substituted ureas: I. Tandem cyclization and esterification in reactions of <Emphasis Type="Italic">N</Emphasis>-(carboxyalkyl)ureas with 1,3-dialkyl-4,5-dihydroxy-4,5-diphenylimidazolidine-2-thiones in alcohols

Acid-catalyzed reactions of N-(carboxyalkyl)ureas with 1,3-dialkyl-4,5-dihydroxy-4,5-diphenylimidazolidine-2-thiones in methanol or propan-2-ol led to the formation of previously unknown ω-(4,6-dialkyl-2-oxo-3a,6a-diphenyl-5-thioxooctahydroimidazo[4,5-d]imidazol-1-yl)alkanoic acids and their methyl and isopropyl esters. The structure of some esters was proved by X-ray analysis. Methyl (4,6-diethyl-2-oxo-3a,6adiphenyl-5-thioxooctahydroimidazo[4,5-d]imidazol-1-yl)acetate showed anxiolytic effect.     

Polycyclic N-Heterocyclic Compounds,Part 77: Synthesis of [1]Benzothieno[3′,2′:2,3]oxepino[4,5-d]pyrimidines and Evaluation of Their Antiplatelet Aggregation Activity

Reaction of 3-(3-cyanopropoxy)[1]benzothiophene-2-carbonitrile with sodium hydride gave 5-amino-1,2-dihydro[1]benzothieno[3,2-d]furo[2,3-b]pyridine and 5-amino-2,3-dihydro[1]benzothieno[3,2-b]oxepin-4-carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles [1]benzothieno[3′,2′:2,3]oxepino[4,5-d]pyrimidines and the parent 1,2,4,5-tetrahydro[1]benzothieno[2′,3′:6,7]oxepino[4,5-e]imidazo[1,2-c]pyrimidine heterocyclic system. The new compounds described in this report were evaluated as inhibitors of platelet aggregation in vitro.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

A novel synthesis of 2-arylaminothiazolo[4,5-d]pyridazinones

The reaction of 5(4)-amino-4(5)-chloropyridazin-3(2H)-ones 1 (9 ) with methyl dithiocarbamates 2 gave 2-arylaminothiazolo[4,5-d]pyridazinones 3 (10 ). Treatment of 5(4)-alkylamino-4(5)-chloropyridazin-3(2H)-ones 5 (12 ) with 2 afforded the corresponding 2-aryliminothiazolo[4,5-d]pyridazinones 6 (13 ). Cyclization of 1a with phenylisothiocyanate produced 2-amino- and 2-iminothiazolo[4,5-d]pyridazinones 3a and 16 .     

The synthesis of azahomotryptophane derivatives. The transformation of N-trifluoroacetyl-5-bromo-4-oxonorvaline methyl ester into 4-(imidazo[1,2-a]azinyl-3)-4-oxohomoalanine derivatives

Azatryptophane homologues, 4-(imidazo[1,2-a]pyridinyl-3)- 9a-9f and 4-(imidazo[1,2-a]pyrimidinyl-3)-4-oxohomoalanine derivatives 9g-91 , were prepared from N,N-dimethyl-N′-(pyridinyl-2)- 6a-6f and N,N-dimethyl-N-(pyriniidinyl-2)formamidines 6g-6i , and (S)-N-trifluoroacetyl-5-bromo-4-oxonorvaline methyl ester ( 2 ) and its (R,S)-isomer.     

Synthesis and Biological Evaluation of New Fused Thiazolo[4,5-d] Pyridazine Derivatives

The synthesis of thiazolo[4,5-d]pyridazines and the unknown ring systems, thiazolo[4,5-d]-1,2,4-triazolo- and tetrazolo[4,3-b]pyridazines as well as thiazolo(4,5-d]pyridazino[2,3-c]2H triazines, has been achieved according to different pathways. Biological testing of the new tricyclic heterocycles revealed that some of these compounds possess remarkable antibacterial activity.     

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 and anticonvulsant activity of 3H-imidazo[4,5-c]-pyridazine, 1H-imidazo[4,5-d]pyridazine and 1H-benzimidazole analogues of 9-(2-fluorobenzyl)-6-methylamino-9H-purine

The 3H-imidazo[4,5-c]pyridazine, 1H-imidazo[4,5-d]pyridazine, and 1H-benzimidazole analogues of the potent anticonvulsant purine 9-(2-fluorobenzyl)-6-methylamino-9H-purine (1, 78U79) were synthesized and tested for anticonvulsant activity. The 3H-imidazo[4,5-c]pyridazines 8 and 9 were prepared in five stages from 3,4,5-trichloropyridazine (2) . The 1H-imidazolo[4,5-d]pyridazine 15 was synthesized in four stages from 5-[(benzyloxy)methyl]-1,5-dihydro-4H-imidazo[4,5-d] pyridazin-4-one (10a) . The benz-imidazole analogues 18 and 20 were prepared from 2,6-dinitroaniline in three stages. These compounds were one-tenth or less as active as 1 in protecting rats against maximal electroshock-induced seizures.     

Synthesis and S-methylation of 2-thioxopyrido[3′,2′:4,5]thieno[3,2-d]-pyrimidin-4(3H)-ones with and without a phase transfer catalyst

A number of 2-thioxopyrido[3′,2′:4,5]thieno[3,2-H]pyrimdin-4(3H-ones (5) have been synthesized by cyclocondensation of 2-carbethoxy-3-amino-4-phenyl-6-substituted-thieno[2,3-b]pyridines (3) with various isothiocyanates. Compounds 5 were S-methylated routinely and the reactions compared under solid-liquid phase transfer conditions to obtain 2-methylthiopyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-^ones (6). The new triheterocyclic pyridothienopyrimidines were prepared with the objective to study their pharmacological properties.     

α-Thioureidoalkylation of functionally substituted ureas: II. Synthesis of thio analogs of N-hydroxyalkyl-1,5-diphenylglycolurils

Reactions of N-(hydroxyalkyl)ureas with 4,5-dihydroxy-4,5-diphenylimidazolidine-2-thiones gave previously unknown 4,6-dialkyl-1-hydroxyalkyl-3a,6a-diphenyl-5-thioxooctahydroimidazo[4,5-d]imidazol-2-ones which may be regarded as thio analogs of N-(hydroxyalkyl)glycolurils.     

1,4-disubstituted pyridazino[4,5-d] pyridazines

1,4-Bis(methyIthio)pyridazino[4,5-d]pyridazine (IV) was synthesized from 4,5-pyridazinedi-carboxylic acid in three steps. By employing IV as an intermediate, various 1,4-disubstituted pyridazino[4,5-d]pyridazine derivatives of classes 1,4-N,S; 1,4-N,O; 1,4-O,S; and 1,4-O,O were prepared by one-step or two-step nucleophilic substitution reactions. Steric, polar and resonance effects were observed in some of these reactions and are discussed.     

The synthesis of 2-azainosine and related derivatives by ring annulation of imidazole nucleosides

The synthesis of 7-(β-D-ribofuranosyl)imidazo[4,5-d]-v-triazin-4-one ( 6b , 2-azainosine) and 5-(β-D-ribofuranosyl)imidazo[4,5-d]-v-triazin-4-one ( 4b ) have been achieved for the first time by direct diazotization of AICA riboside ( 5b ) and iso-AICA riboside ( 3b ), respectively. The conditions required for cyclization of the model methyl bases, 3a and 5a , as well as the nucleosides 3b , 5b , and 7 are described.     

On the formation and reactivity of N(2),N(2′)-tetrasubstituted 2,4-diamino-5-(2-amino-4-thiazolyl)thiazoles

By the reaction of weak bases with N(2)-disubstituted 2-amino-4-thiazoliniminium chlorides 3, easily available by the reaction of thioureas 1 with α-chloroacetonitrile 2, N(2),N(2′)-persubstituted 2,4-diamino-5-(2-amino-4-thiazolyl)thiazoles 8 are formed. These new bis-thiazoles react, as exemplified with the dimorpholino derivative 8a, with different electrophilic reagent, such as phenyl isothiocyanate 9, 4-nitro-phenyldiazonium salt 11, or 4-dialkylaminobenzaldehydes 13 at their 5H-substituted thiazole moieties to give the corresponding thioanilides 10, azo compounds 12, and methine dyes 14, respectively. With sodium nitrite and the Vilsmeier reagent the thiazole 8a is transformed, via unstable intermediates, into the tricyclic 2,7-dimorpholinothiazolo[4,5-c]thiazolo[4,5-e]pyridazine 16 and 2,7-dimorpholinothiazolo[4,5-b]thiazolo[4,5-d]pyridine 19, respectively.     

Solvent Moisture-Controlled Self-Assembly of Fused Benzoimidazopyrrolopyrazines with Different Ring’s Interposition

This article shows that two extremely important families of fused heterocyclic assemblies, namely 6-methylbenzo[4,5]imidazo[1,2-a]pyrrolo[2,1-c]pyrazine and 5a-methyl-5a,6-dihydro-5H,12H-benzo[4,5]imidazo[1,2-a]pyrrolo[1,2-d]pyrazine, can be synthesized from only two available building blocks (N-allenylpyrrole-2-carbaldehyde and o-phenylenediamine) by controlling only one reaction parameter (water content of the medium). It should be emphasized that the latter class of compounds (with an a/d arrangement) is previously unknown. If the allene group is introduced not into the starting compound, but during the reaction (in superbase media), a heterocyclic ensemble, 5-methylbenzo[4,5]imidazo[1,2-a]pyrrolo[2,1-c]pyrazines, with a different position of the methyl group is formed.     

Reactions with diazoazoles. Part VI. Unequivocal synthesis of 3-methyl-3h-azolotetrazoles. Correction of the formerly described 3-methylazolotetrazoles in favour of mesoionic 2-methylazolotetrazoles

3-Methyl-3H-pyrazolo[1,5-d]tetrazoles 2 and 3-methyl-6-phenyl-3H-1,2,4-triazolo[1,5-d]tetrazole (4) have been unequivocally synthesized by annulation of the tetrazole moiety to the pyrazole resp. 1,2,4-triazole system. The constitution of some N-methyl substituted azolotetrazoles, formerly described as 3-methyl-3H-pyrazolo[1,5-d]tetrazoles 2, 3-methyl-6-phenyl-3H-1,2,4-triazolo[1,5-d]tetrazole (4) and 1-methyl-6-phenyl-1H-1,2,4-triazolo[4,3-d]tetrazole (5), has to be revised in favour of the corresponding mesoionic 2-methyl derivatives 2′, 4′, 5′. The structures of 3-methyl-3H- as well as of 2-methyl-2H-pyrazolo[1,5-d]tetrazole derivatives 2a, 2c, 2′a have been determined by X-ray analyses. The azapentalenic system is aromatic in all three measured compounds and mesoionic in the case of the 2-methyl-2H- substitution pattern. The phenyl and ester substituents are coplanar with the azapentalene system. 3-, 2-, and 1-Methylpyrazolo[1,5-d]tetrazoles exhibit different behaviour when allowed to react with stannous chloride or sodium ethoxide. Azolotetrazoles with a methyl substituent at N-1, N-2 or N-3 of the tetrazole moiety can be distinguished by a combination of ¹H and ¹³C nmr with respect to the chemical shifts of the N-methyl group and the bridgehead carbon. Results of semiempirical calculations of the pyrazolo[1,5-d]tetrazole anion and of its N-methyl derivatives are discussed.     

Thiazolo-N-hydroxyuracils

The partial Lossen degradation of the hydroxamic acid group at C-4 or C-5 of sodium 4,5-thiazoledicarbohydroxamate (IIIb) and its 2-methyl analog (IIIe) initiated a multicoursed reaction which furnished a mixture of thiazolo[4,5-d]- and thiazolo[5,4-d]-N-hydroxyuracils. The isomer distribution was sensitive to the solvent systems in which these reactions were carried out. The structure of the isomers so obtained was established by chemical and spectral methods.     

Synthesis of new thiazolo[2,3-b]pyrimidine derivatives of pharmaceutical interest

2H-5-Amino-6-cyano-3,7-dioxothiazolo[2,3-b]pyrimidine was subjected to ring formation affording thiazolo[2,3-b]pyrimidine derivatives. 2H-5-Amino-6-cyano-3,7-dioxo-2-phenylmethylenethiazolo[2,3-b]pyrimidine was also subjected to ring formation affording pyrimido[4,5-d]-, pyrano[2,3-d]-, and pyrido[2,3-d]thiazolo[2,3-b]pyrimidine derivatives. 2-Anilinothiocarbonyl-3,9-dioxo-8-imino-7-phenyl-6-thioxothiazolo[2,3-b]pyrimido[4,5-d]pyrimidine and 8-amino-3,9-dioxo-6-thioxothiazolo[2,3-b]pyrimido[4,5-d]pyrimidine reacted with α-haloactive-methylene compounds to afford heterocyclic compounds containing two, fused and isolated, thiazole moieties, respectively.     

Acetylation of indolobenzo[b]furans,pyrrolocarbazole, pyrrolophenothiazine dioxide and pyrroloacridine under Vilsmeier reaction conditions

The course of the Vilsmeier acetylation of new heterocyclic systems, namely, indolo[4,5-d]-, indolo[6,5-d]-, indolo[5,6-d]-, indolo[5,4-d]benzo[b]furans, 3H-pyrrolo[2,3-c]carbazole, 3H-pyrrolo[2,3-c]pheno-thiazine 11,11-dioxide, and 3H-pyrrolo[2,3-c]acridine depends on the type of fusion of the pyrrole ring. Angular heterocycles are acetylated at the -position of the pyrrole ring, while linear heterocycles under analogues conditions give dimerization products with a substituent at the nitrogen atom of the hydrogenated part of the dimer molecule. 3H-Pyrrolo[2,3-c]phenothiazine 11,11-dioxide and 3H-pyrrolo[2,3-c]acridine are not acetylated under Vilsmeier reaction conditions.Georgian Technical University, 380075 Tbilisi, Georgia. D. E. Mendeleev Russian Chemical Engineering University, 125047 Moscow. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1331–1336, October, 1996. Original article submitted August 19, 1996.     

The synthesis of several imidazo[4,5-d]isothiazoles. Derivatives of a new ring system

Several derivatives of the new imidazo[4,5-d]isothiazole ring system have been synthesized from the appropriately substituted isothiazolediamines. The reaction of 3-methyl-4,5-diaminoisothiazole ( 4a ) with diethoxy-methyl acetate gave a low yield of 3-methylimidazo[4,5-d]isothiazole ( 5a ). However, the analogous reaction of 4,5-diaminoisothiazole ( 4b ) with diethoxymethyl acetate failed to yield the parent imidazo[4,5-d]isothiazole ring system. The diamines 4a and 4b were readily cyclized with thiocarbonyldiimidazole to give the unstable thiones 6a and 6b , which were alkylated in situ to afford good yields of the corresponding 5-methylthioimidazo[4,5-d]isothiazoles 7a and 7b , respectively. Neither of these compounds could be reduced to the corresponding 5-unsubstituted derivatives via treatment with Raney nickel. To the best of our knowledge, this is the first report of the imidazo[4,5-d]isothiazole ring system.