Synthesis of C-ribosyl imidazo[2,1-f  ][1,2,4]triazines as inhibitors of adenosine and AMP deaminases

Dudfield, Philip J.; Le, Van‐Duc; Lindell, Stephen D.; Rees, Charles W.

doi:10.1039/a904065j

Cited by 22 publications

(26 citation statements)

References 20 publications

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“…tert ‐Butyl (2‐chloroimidazo[2,1‐ f ][1,2,4]triazin‐4‐yl)(3,4‐dimethoxyphenyl)carbamate (18a) : To a solution of 2,4‐dichloroimidazo[2,1‐ f ][1,2,4]triazine (230 mg, 1.22 mmol) and 3,4‐dimethoxyaniline (373 mg, 2.43 mmol) in MeCN (5 mL) was added diisopropylethylamine (0.64 mL, 3.65 mmol) at RT resulting a clear solution which turned into a suspension after 30 min. The mixture was diluted with H 2 O.…”

Section: Methodsmentioning

confidence: 99%

Imidazotriazines: Spleen Tyrosine Kinase (Syk) Inhibitors Identified by Free‐Energy Perturbation (FEP)

et al. 2015

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There has been significant interest in spleen tyrosine kinase (Syk) owing to its role in a number of disease states, including autoimmunity, inflammation, and cancer. Ongoing therapeutic programs have resulted in several compounds that are now in clinical use. Herein we report our optimization of the imidazopyrazine core scaffold of Syk inhibitors through the use of empirical and computational approaches. Free-energy perturbation (FEP) methods with MCPRO+ were undertaken to calculate the relative binding free energies for several alternate scaffolds. FEP was first applied retrospectively to determine if there is any predictive value; this resulted in 12 of 13 transformations being predicted in a directionally correct manner. FEP was then applied in a prospective manner to evaluate 17 potential targets, resulting in the realization of imidazotriazine 17 (3-(4-(3,4-dimethoxyphenylamino)imidazo[1,2-f][1,2,4]triazin-2-yl)benzamide), which shows a tenfold improvement in activity relative to the parent compound and no increase in atom count. Optimization of 17 led to compounds with nanomolar cellular activity.

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Section: Methodsmentioning

confidence: 99%

Imidazotriazines: Spleen Tyrosine Kinase (Syk) Inhibitors Identified by Free‐Energy Perturbation (FEP)

et al. 2015

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“…In order to obtain these compounds the following synthetic approaches were previously proposed: the alkylation of the hydroxyl group in the corresponding position of the 1,2,4-triazine [1,[3][4][5][6], and the ipso-substitution of a chlorine atom [7][8][9], trichloromethyl group [10], methylthio group [11] or fluorine atom [12]. The ipso-substitution of a cyanogroup deserves a special attention because 5-cyano-1,2,4-triazines are highly affordable compounds due to previously developed convenient method of obtaining them by using the direct nucleophilic substitution of hydrogen in the series of 1,2,4-triazine-4-oxides [13].…”

Section: Resultsmentioning

confidence: 99%

“…Для получения этих соединений ранее были предложены следующие синтетические подходы: алкилирование гидроксигруппы в со-ответствующем положении триазина [1,[3][4][5][6], ипcо-замещение атома хло-ра [7][8][9], трихлорметильной группы [10], метилтиогруппы [11] или атома фтора [12]. Отдельного внимания за-служивает ипсо-замещение циано-группы, поскольку 5-циано-1,2,4-три-азины являются весьма доступными соединениями ввиду разработанного ранее удобного метода их получения с использованием методологии нук-леофильного замещения водорода в ряду 1,2,4-триазин-4-оксидов [13].…”

Section: In Russianunclassified

The synthesis of 1,2,4-triazines bearing the residues of higher alcohols in the 5-position via the ipso-substitution of cyano group under the solvent-free conditions

et al. 2017

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“…Bromoaniline could also be employed (entry 12) but the reaction failed with bromo-phenols (entries [13][14]. The phenate formation during the reaction thus seems detrimental to its efficiency.…”

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Efficient Pallado-Catalyzed C6-(het)arylation of Imidazo[1,2-b][1,2,4,5]Tetrazines under Microwave Irradiations

et al. 2010

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A versatile protocol for the preparation of a library of 5,6-(het)bisarylated imidazo[1,2-b][1,2,4,5]tetrazines is described. Target compounds were obtained in fairly good yields, starting from ethoxy-7-(4-methoxyphenyl)imidazo[1,2-b][1,2,4,5]tetrazine and a large panel of bromoaryl derivatives, using palladium catalysis under microwave irradiation. Compatibility with various chemical groups and heterocycles was proven. Steric and electronic effects do not have any effect on the efficiency of the reaction. Purifications were performed without any difficulties, and the structure of a final compound was proven by crystal X-ray diffraction studies.

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Synthesis of C-ribosyl imidazo[2,1-f ][1,2,4]triazines as inhibitors of adenosine and AMP deaminases

Cited by 22 publications

References 20 publications

Imidazotriazines: Spleen Tyrosine Kinase (Syk) Inhibitors Identified by Free‐Energy Perturbation (FEP)

Imidazotriazines: Spleen Tyrosine Kinase (Syk) Inhibitors Identified by Free‐Energy Perturbation (FEP)

The synthesis of 1,2,4-triazines bearing the residues of higher alcohols in the 5-position via the ipso-substitution of cyano group under the solvent-free conditions

Efficient Pallado-Catalyzed C6-(het)arylation of Imidazo[1,2-b][1,2,4,5]Tetrazines under Microwave Irradiations

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