Syntheses of five potential heterocyclic amine food mutagens

The syntheses of the potential heterocyclic amine food mutagens, 3,5,7-trimethyl-2-aminoimidazo-[4,5-b]pyridine, 1,4,7-trimethyl-2-aminoimidazo[4,5-c]pyridine, 1,6,7-trimethyl-2-aminoimidazo[4,5-c]-pyridine, 3,4,6-trimethyl-2-aminoimidazo[4,5-c]pyridine, and 1,4,6-trimethyl-7-aminoimidazo[4,5-c]-pyridine are described.     

Synthetic studies of potential antimetabolites. XIII. Synthesis of 7-amino-3-β-d-ribofuranosyl-3H-imidazo[4,5-b] pyridine (1-deazaadenosine) and related nucleosides

7-Amino-3-β-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine (III, 1-deazaadenosine) was synthesized in 32% yield from the diacetyl derivative prepared from 7-aminoimidazo[4,5-b ]pyridine (1-deazaadenine) and 1,2,3,5-tetra-O-acetyl-β-D-ribose by the fusion method. A synthesis of 7-amino-4-b?-D-ribofuranosyl-4H-imidazo[4,5-b]pyridine (IV) was also achieved.     

A facile synthesis of the 1,3-dithiolo[4,5-b]pyridine ring system via pyridylthiocyanates

2-Chloro-3-thiocyanatopyridine reacted with thioacetic acid and thiobenzoic acid to yield 2-acetylimino-1,3-dithiolo[4,5-b]pyridine and 2-benzoylimino-1,3-dithiolo[4,5-b]pyridine respectively. 2,5,6-Trihalo-3-thiocyanatopyridine under the same conditions gave only the corresponding 3-S-acetyl-3-thio or 3-S-benzoyl-3-thiopyridine.     

New cascade reaction of azides with malononitrile dimer to polyfunctional [1,2,3]triazolo[4,5-b]pyridine

A new cascade reaction of azides with malononitrile dimer yielding polyfunctional [1,2,3]triazolo[4,5-b]pyridine was found. It was established that during the reaction of aryl azides with malononitrile dimer, under base catalysis, the formed intermediate triazole underwent spontaneous cyclization leading to the pyridine ring annulation. The obtained products have provided a new entry to [1,2,3]triazolo[4,5-b]pyridine.     

Recent progress in the chemistry of heterocycles incorporated oxazolo[4,5-b]pyridine and oxazolo[5,4-b]pyridine skeletons

Abstract

The present study describes recent advances in the chemistry of heterocycles incorporated oxazolo[4,5-b]pyridine and oxazolo[5,4-b]pyridine skeletons. The main sections included the synthesis of the investigated compounds from readily accessible aminopyridinol derivatives or aminopyridines. The reactivity of substituents attached to ring carbon or nitrogen atoms were discussed. In addition, the synthetic and biological evaluation of the inspected oxazolopyridines were highlighted. The purpose of this review is to discuss the chemistry of the title so far. The present study will support researchers in the fields of organic and medicinal chemistry to design and develop new protocols for the construction of new biological components.     

Synthesis of New Imidazo[4,5-b]pyridine Derivatives

New imidazo[4,5-b]pyridine derivatives with various substituents in the 2-position (,-unsaturated ketones, imines, ²-pyrazolines, pyrimidines, 1,2,3,4-tetrahydropyrimidines) and derivatives of the new pyrido[3',2':4,5]imidazo[1,2-d][1,2,4]triazine ring system were synthesized. Biological data for selected compounds are presented.     

Derivatives of Condensed Pyridopyrimidines. 3. Synthesis of Condensed Imidazo[4,5-b]pyridine and also 4-Oxo- and 2,4-Dioxopyrido[2,3-d]pyrimidines

A convient methods has been developed for the synthesis of condensed imidazo[4,5-b]pyridine and also 4-oxo- and 2,4-dioxopyrido[2,3-d]pyrimidines. The optimum conditions for the Curtius rearrangement of 2-amino-3-azidocarbonyl derivative of pyrano[4,3-b]pyridine have been established.     

The synthesis of 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles,11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles and 1,2,4-triazolo[3,4-f]-1,2,4-triazino[4,5-a]indoles

This paper describes the synthesis of the previously unknown 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles (2) and 11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles (3) from 4-hydrazino-5H-pyridazino[4,5-b]indoles (1) , as well as the synthesis of 1,2,4-triazolo[3,4-f]-1,2,4-triazino-[4,5-a]indoles (10) from 2-indolecarbohydrazide (4) . Compounds 2 were obtained by acylation of compounds 1 , followed of thermal cyclization and compounds 3 by treating compounds 1 with nitrous acid. The reactions of compound 4 with formic acid or ethyl orthoformiate gave 1,2-dihydro-1-oxo-1,2,4-triazino[4,5-a]indole (6) . Treating this last compound with phosphorus oxychloride or phosphorus pentasulfide, followed by hydrazine, gave 1-hydrazino-1,2,4-triazino-[4,5-a]indole (9) . Acylation of this last compound, followed of cyclization gave compounds 10 . All the compounds were characterized by elemental analysis and ir and ¹H-nmr spectra.     

Convenient synthesis and anticancer evaluation of novel pyrazolyl-thiophene,thieno[3,2-b]pyridine,pyrazolo[3,4-d]thieno[3,2-b]pyridine and pyrano[2,3-d]thieno[3,2-b]pyridine derivatives

The newly synthesized 3-(3-amino-5-(phenylamino)-4-(phenylcarbamoyl)thiophen-2-yl)-3-oxopropanoate was utilized as a precursor for the synthesis of pyrazolyl-thiophene derivative, which undergoes cyclization upon treatment with benzaldehyde derivatives to provide pyrazolo[3,4-d]thieno[3,2-b]pyridines. Basic treatment of pyrazolyl-thiophene derivative with phenyl isothiocyanate followed by subsequent addition of chloroacetone and/or ethyl bromoacetate yielded the thiazolylidene-pyrazolyl thiophenes. In addition, the building block 3-(3-amino-5-(phenylamino)-4-(phenylcarbamoyl)thiophen-2-yl)-3-oxopropanoate was converted into the corresponding thieno[3,2-b]pyridine compounds through its reactions with (DMF-DMA) and/or heating in sodium ethoxide. Moreover, the reaction of 7-hydroxy-5-oxo-N-phenyl-2-(phenylamino)-4,5-dihydrothieno[3,2-b]pyridine-3-carboxamide with 2-arylidenemalononitrile produced the new annulated pyrano[2,3-d]thieno[3,2-b]pyridines. The prepared thiophene-based compounds were evaluated against HepG2, PC3, and MCF-7 cancer cells, and normal fibroblast cell (WI38). The pyrazolo[3,4-d]thieno[3,2-b]pyridine and pyrano[2,3-d]thieno[3,2-b]pyridine compounds substituted with chlorophenyl group presented promising cytotoxic activities against HepG2 cancer cell line without any human toxicity. Docking study for the synthesized thiophene compounds delivered valuable insights about the binding interactions with the crystal structure of NS5B enzyme with PDB ID (4TLR).     

Synthesis of Some New Imidazo[4,5-B]Pyridine Derivatives Using 2-Cyanomethyl-1-Methyl-1H-Imidazo[4,5-B]Pyridine

Abstract

The reactions of 2-cyanomethyl-1-methyl-1H-imidazo[4,5-b]pyridine with isothiocyanates, nitroso compounds, acid chlorides, and thioglycolic acid were investigated. New imidazo[4,5-b]pyridine derivatives with various substituents in 2-position and derivatives of the new pyrrolo[2′,1′:2,3]imidazo[4,5-b]pyridine ring system were synthesized. The compounds obtained were tested in vitro for their tuberculostatic activity.     

Studies on the chemical synthesis of potential antimetabolites. 30. Regioselective introduction of a chlorine atom into the imidazo[4,5-b]pyridine nucleus

Reactions of some imidazo[4,5-b]pyridine 4-oxides with phosphoryl chloride are described. Treatment of N-1-substituted imidazo[4,5-b]pyridine 4-oxides with phosphoryl chloride led to the predominant formation of 7-chloro derivatives. This feature was successfully applied to the preparation of a chloroimidazo[4,5-b]pyridine nucleoside, which served as an important precursor of 1-deazaadenosine.     

Reduction of Imidazo[4,5-c]pyridine and [1,2,3]Triazolo[4,5-c]pyridine Derivatives to Spinaceamines and 2-Azaspinaceamines

Reduction of 1-substituted [1,2,3]triazolo[4,5-c]pyridines with nickel-aluminum alloy in aqueous alkali gave 2-azaspinaceamines. Reduction of imidazo[4,5-c]pyridine and [1,2,3]triazolo[4,5-c]pyridine derivatives with formic acid in the presence of triethylamine resulted in formation of 5-formylspinaceamines and 2-azaspinaceamines. The 5-formyl group in the latter can be removed by acid hydrolysis. Unsubstituted 2-azaspinaceamine, an aza analog of natural spinaceamine, was synthesized for the first time.     

The preparation of the benzo[4,5]cyclohepta[1,2-b]pyrazine and benzo[4,5]cyclohepta[1,2-b]quinoxaline systems

Benzo[4,5]cyclohepta[1,2-b]quinoxaIine 2 , benzo[4,5]cyclohepta[1,2-b]pyrazine 3a and benzo[4,5]cyclohepta[1,2-b]quinoxaline 4 were prepared from 4,5-benzotropolone and 1,2-phenylenediamine, ethylenediamine and 1,2-diaminocyclohexane, respectively. Compound 3a was methylated to 3b .     

Synthesis of 6,7,8,9-tetrahydro-5H-pyrimido-[4,5-b][1,4]diazepine-6,8-diones

The sodium ethoxide catalyzed condensation of 4,5-diaminopyrimidine ( 3 ) with diethyl malonate afforded 6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 4 ). Methylation of 6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 4 ) using sodium hydride and two equivalents of iodomethane gave 5,9-dimethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 5 ) which on further methylation using sodium hydride and one equivalent iodomethane yielded 6,7,8,9-tetrahydro-5,7,9-trimethyl-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 6 ). Reaction of 6,7,8,9-tetrahydro-5H-pyrirnido[4,5-b][1,4]diazepine-6,8-dione ( 4 ) with 4.2 equivalents of sodium hydride and 4.1 equivalents of iodomethane afforded 6,7,8,9-tetrahydro-5,7,7, 9-tetramethyl-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 7 ). 6,7,8,9-Tetrahydro-5,7,7,9-tetramethyl-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 7 ) exhibited weak anticonvulsant activities in the subcutaneous pentylenetetrazole and maximal electroshock anticonvulsant screens indicating it is a partial bioisostere of the anticonvulsant drug clobazam ( 2 ).     

Synthesis of derivatives of a new heterocyclic system pyrazolo[3,4-b]pyrido[1′,2′: 1,2]imidazo[4,5-d]pyridine

1-[4-Aminoarylpyrazolo[3,4-b]pyridin-5-yl]pyridinium chlorides undergo cyclization under reflux in tert-butanol in the presence of an excess of potassium tert-butoxide to form tetracyclic derivatives of pyrazolo[3,4-b]pyrido[1′,2′:1,2]imidazo[4,5-d]pyridine. The reaction scheme of the processes is proposed. The structures of the reaction products were confirmed by physicochemical methods. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 710–714, April, 2006.     

Synthesis of 4,10-dihydro-4,10-dioxo-1H-[1]-benzopyrano[3,2-b]pyridine, 4,5-Dihydro-4,5-dioxo-1H-[1]-benzopyrano[2,3–6]pyridine and 1,5-Dihydro-1,5-dioxo-4H-[1]-benzopyrano[3,4-b]pyridine derivatives from aminobenzopyrones

3-Aminochromone and 3-aminocoumarin were condensed with diethyl ethoxymethylenemalonate and with dimethyl acetylenedicarboxylate to give intermediates, which were thermally cyclized to give 4,10-dihydro-4,10-dioxo-lH-[1]-benzopyrano[3,2-b]pyridinecarboxylates and 1,5-dihydro-1,5-dioxo-4H-[1]-benzopyrano-[3,4-b]pyridinecarboxylates. 2-Aminochromone was converted to 4,5-dihydro-4,5-dioxo-1H-[1]-benzopyrano-[2,3-b]pyridinecarboxylate via an intermediate condensation product with diethyl ethoxymethylenemalonate. These esters were hydrolyzed to the corresponding carboxylic acids (21, 30, 36, 50, and 60). Attempts to prepare 4,5-dihydro-4,5-dioxo-1H-[1]-benzopyrano[4,3-b]pyridinecarboxylates from 4-aminocoumarin were unsuccessful.     

Synthesis of New Fused Pirano[4,3-b]pyridine Derivatives

A method was developed for the synthesis of pyrano[4,3-b]thieno[3,2-e]pyridine derivatives based on the reaction of 3-amino-7-ethyl-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]thieno[3,2-e]pyridine-2-carboxylic acid ethyl ester with chloroacetic acid chloride, triethyl orthoformate, hydrazine hydrate, and also phenyl chloroformate. The synthesis of various new representatives of pyrano[2″,3″:5′,6′]pyrido[3′,2′:4,5]thieno[3,2-dl-pyrimidine series was carried out.

     

New process for the synthesis of imidazo[4,5-b]pyridine derivatives as potent orally active thromboxane a2 receptor antagonists

A new synthetic route to prepare the 4-[3-(4-chlorophenyl)methyl-6-chloroimidazo[4,5-b]pyridin-2-yl]-3,3-dimethylbutanoic acid (UP 116-77) is described. UP 116-77 is a potent orally active TXA₂/PGH₂ receptor antagonist currently under pharmacological investigation. Its development needed a suitable synthesis for industrial processing. The cyclization of 3-amino-5-chloro-2-(4-chlorophenyl)methylaminopyridine 4 with 3,3-dimethylglutaric anhydride in refluxing acetic acid affords a new efficient and simple way to UP 116-77 and subsequently to various 2-substituted imidazo[4,5-b]pyridine derivatives.     

Quaternary salts and polymethine dyes from 2-(methylpyridyl)-X-azolo[4,5-b]pyridine

If picoline and X-azolo[4,5-b]pyridine are linked, an assembled system arises which has a particular behaviour towards various quaternizing agents. As soon as picolinium salts could be obtained, the corresponding styryl dyes were prepared. The structures of bases, salts and dyes were clarified and their physical and spectroscopic data were correlated and compared with those of similar systems previously studied.     

Halogenation of 2-Unsubstituted and 2-Methylimidazo[4,5-<Emphasis Type="Italic">b</Emphasis>]pyridine Derivatives

Halogenation of 2-unsubstituted and 2-methylimidazo[4,5-b]pyridines and their N-methyl derivatives with bromine and chlorine in acetic acid takes different pathways, depending on the acetic acid concentration. The bromination in 50% aqueous acetic acid gives only 6-bromoimidazo[4,5-b]pyridines; bromination and chlorination of 2-unsubstituted imidazo[4,5-b]pyridines in glacial acetic acid leads to 5,6-dibromo(dichloro)imidazo[4,5-b]pyridin-2-ones, and bromination of 2-methylimidazo[4,5-b]pyridines in glacial acetic acid involves both the pyridine ring and the 2-methyl group to afford the corresponding 6-bromo-2-tribromomethylimidazo[4,5-b]pyridines.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 3, 2005, pp. 457–461.Original Russian Text Copyright © 2005 by Yutilov, Lopatinskaya, Smolyar, Gres’ko.