- A practical and step-economic route to Favipiravir
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A practical and step-economic route to Favipiravir, an antiviral drug, was developed. Favipiravir was synthesized in only six steps from 3-aminopyrazine-2-carboxylic acid with an overall yield of about 22.3%. Key intermediates 3 and 6 were obtained in excellent purity via recrystallization from optimized solvents, which was beneficial to large-scale production. In the key synthetic reaction, 3,6-dichloropyrazine-2-carbonitrile (6) was reacted sequentially, in one pot, with KF and 30% H2O2 to give (after crystallization from 95% EtOH) favipiravir as colorless crystals, with a 60% yield for this final step of the synthesis.
- Liu, Feng-Liang,Li, Cui-Qin,Xiang, Hao-Yue,Feng, Si
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Read Online
- Application of the Curtius rearrangement in a convenient preparation of 3-amino-pyrazinecarboxylic acid, methyl ester
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An efficient and convenient synthesis of 3-aminopyrazinecarboxylic acid, methyl ester (7) has been achieved through the use of a Curtius rearrangement.
- Chen,Hinkley,Wise,Townsend
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Read Online
- Derivatives of 3-Aminopyrazine-2-carboxamides: Synthesis, antimicrobial evaluation, and in vitro cytotoxicity
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We report the design, synthesis, and in vitro antimicrobial activity of a series of N-substituted 3-aminopyrazine-2-carboxamides with free amino groups in position 3 on the pyrazine ring. Based on various substituents on the carboxamidic moiety, the series is subdivided into benzyl, alkyl, and phenyl derivatives. The three-dimensional structures of the title compounds were predicted using energy minimization and low mode molecular dynamics under AMBER10:EHT forcefield. Compounds were evaluated for antimycobacterial, antibacterial, and antifungal activities in vitro. The most active compound against Mycobacterium tuberculosis H37Rv (Mtb) was 3-amino-N-(2,4-dimethoxyphenyl)pyrazine-2-carboxamide (17, MIC = 12.5 μg/mL, 46 μM). Antimycobacterial activity against Mtb and M. kansasii along with antibacterial activity increased among the alkyl derivatives with increasing the length of carbon side chain. Antibacterial activity was observed for phenyl and alkyl derivatives, but not for benzyl derivatives. Antifungal activity was observed in all structural subtypes, mainly against Trichophyton interdigitale and Candida albicans. The four most active compounds (compounds 10, 16, 17, 20) were evaluated for their in vitro cytotoxicity in HepG2 cancer cell line; only compound 20 was found to exert some level of cytotoxicity. Compounds belonging to the current series were compared to previously published, structurally related compounds in terms of antimicrobial activity to draw structure activity relationships conclusions.
- Bouz, Ghada,Semelková, Lucia,Jand’ourek, Ond?ej,Kone?ná, Klára,Paterová, Pavla,Navrátilová, Lucie,Kubí?ek, Vladimír,Kune?, Ji?í,Dole?al, Martin,Zitko, Jan
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- Discovering a new class of antifungal agents that selectively inhibits microbial carbonic anhydrases
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Infections caused by pathogens resistant to the available antimicrobial treatments represent nowadays a threat to global public health. Recently, it has been demonstrated that carbonic anhydrases (CAs) are essential for the growth of many pathogens and their inhibition leads to growth defects. Principal drawbacks in using CA inhibitors (CAIs) as antimicrobial agents are the side effects due to the lack of selectivity toward human CA isoforms. Herein we report a new class of CAIs, which preferentially interacts with microbial CA active sites over the human ones. The mechanism of action of these inhibitors was investigated against an important fungal pathogen, Cryptococcus neoformans, revealing that they are also able to inhibit CA in microbial cells growing in vitro. At our best knowledge, this is the first report on newly designed synthetic compounds selectively targeting β-CAs and provides a proof of concept of microbial CAs suitability as an antimicrobial drug target.
- Annunziato, Giannamaria,Giovati, Laura,Angeli, Andrea,Pavone, Marialaura,Del Prete, Sonia,Pieroni, Marco,Capasso, Clemente,Bruno, Agostino,Conti, Stefania,Magliani, Walter,Supuran, Claudiu T.,Costantino, Gabriele
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p. 1537 - 1544
(2018/10/15)
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- Method for synthesis of favipiravir
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The invention discloses a method for synthesis of favipiravir. The method comprises an esterification reaction of 3-aminopyrazine-2-carboxylic acid and an alcohol, a bromination reaction, a diazotization reaction, an ammonolysis reaction, a chlorination-dehydration reaction, a one-pot series connection aromatic ring fluorination reaction, a cyan-hydrolysis reaction, an aromatic ring hydroxyl substitution reaction, and purification treatment so that favipiravir is obtained. The method utilizes 3-amino-2-carboxypyrazine as a raw material to synthesize favipiravir through 8-step reactions and has a total yield of 26%. The key intermediates 3 and 6 in the method are purified by recrystallization so that column chromatography separation in the literature is avoided. The final three reactions are finished by a one-pot method so that the operation is simplified. The synthesis method improves a yield, realizes a low cost and green economy and is conducive to industrial production.
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Paragraph 0137; 0138; 0139; 0140
(2017/07/19)
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- Aminopyrazine Pathway to the Moco Metabolite Dephospho Form A
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An efficient synthesis of the molybdopterin/molybdenum cofactor (Moco) oxidation product dephospho Form A is described that assembles the pteridinone system starting from an iodinated aminopyrazine. The sodium salt of dephospho Form A could be purified by precipitation from methanol, which paved the way to the title compound in the 100 mg range. By HPLC, the synthetic material was compared with a sample isolated from a recombinant Moco containing protein. Analysis of dephospho Form A is the only method that allows the quantification of the Moco content of crude cell extracts and recombinant protein preparations.
- Klewe, Anne,Kruse, Tobias,Lindel, Thomas
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p. 11230 - 11233
(2017/08/26)
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- Preparation method for pyrazine derivative
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The invention discloses a preparation method for a pyrazine derivative 3-amino-6-(3-chloro-5-methylphenyl)pyrazine-2-carboxamide. The method comprises the following steps: 3-aminopyrazine-2-carboxylic acid is used as a starting raw material, an esterification reaction is performed, an amidation reaction is performed, a bromination reaction is performed, a coupling reaction is performed, and therefore the objective product is obtained. The compound is an important pharmaceutical intermediate.
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Paragraph 0021; 0022
(2018/03/24)
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- Azaindole synthesis through dual activation catalysis with N-heterocyclic carbenes
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A convergent, transition-metal-free synthesis of 2-aryl-azaindoles has been developed. The interception of a reactive aza-ortho-azaquinone methide intermediate by an acyl anion equivalent generated through carbene catalysis provides high yields, a wide substrate scope, and the synthesis of previously inaccessible azaindoles.
- Sharma, Hayden A.,Todd Hovey,Scheidt, Karl A.
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supporting information
p. 9283 - 9286
(2016/07/25)
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- Pyrazine-based Syk kinase inhibitors
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A series of aminopyrazines as inhibitors of Syk kinase activity and showing inhibition of LAD2 cells degranulation is described. Optimization of the carboxamide motif with aminomethylpiperidines provided high potency inhibiting Syk but low cellular activity. Amides of cis and trans adamantanol showed good inhibitory activity against Syk as well as remarkable activity in LAD2 cells degranulation assay.
- Forns, Pilar,Esteve, Cristina,Taboada, Lorena,Alonso, Juan Antonio,Orellana, Adelina,Maldonado, Mónica,Carre?o, Cristina,Ramis, Isabel,López, Manel,Miralpeix, Montserrat,Vidal, Bernat
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scheme or table
p. 2784 - 2788
(2012/05/20)
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- Synthesis of N-substituted-6-alkoxypteridin-4-amine
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A novel seven-step methodology for the synthesis of N-substituted-6- alkoxypteridin-4-amine has been developed with the total yields of 35.4-41%. Twenty new compounds were synthesized by heterocyclization of easily prepared 3-amino-6-bromopyrazine-2-carboxamide, subsequent alkoxylation, chlorination, and nucleophilic substitution. Their structures were confirmed by 1H-NMR, 13C-NMR, ESI-MS, and elemental analysis. The structure of N-(3-chloro-4-fluorophenyl)-6-ethoxypteridin-4-amine was further determined by X-ray crystallographic analysis. It was found that different chlorinating reagents gave different products. The possible chlorination mechanism was discussed.
- Duan, Chonggang,Jia, Jiong,Zhu, Rongxiu,Wang, Jianwu
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p. 865 - 872
(2012/10/29)
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- Design, synthesis, and antidiabetic activity of 4-phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists
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4-Phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists are reported. Several 4-phenoxynicotinamide derivatives were found to activate human and mouse TGR5 (hTGR5 and mTGR5) with EC50 values in the low nanomolar range. Compound 23g, with an EC50 value of 0.72 nM on hTGR5 and an EC 50 value of 6.2 nM on mTGR5, was selected for further in vivo efficacy studies. This compound exhibited a significant dose-dependent glucagon-like peptide-1 (GLP-1) secretion effect. A single oral dose of 23g (50 mg/kg) significantly reduced blood glucose levels in db/db mice and caused a 49% reduction in the area under the blood glucose curve (AUC)0-120min following an oral glucose tolerance test (OGTT) in imprinting control region (ICR) mice. However, 23g stimulated gallbladder filling, which might result in side effects to the gallbladder.
- Duan, Hongliang,Ning, Mengmeng,Chen, Xiaoyan,Zou, Qingan,Zhang, Liming,Feng, Ying,Zhang, Lina,Leng, Ying,Shen, Jianhua
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supporting information
p. 10475 - 10489
(2013/02/22)
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- NOVEL IMMUNE SYSTEM MODULATORS
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The present invention relates to a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein the symbols are as defined in the specification; a pharmaceutical composition comprising the same; and a method for treating or preventing autoimmunity disease using the same.
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Page/Page column 111
(2013/02/28)
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- Discovery of a series of imidazopyrazine small molecule inhibitors of the kinase MAPKAPK5, that show activity using in vitro and in vivo models of rheumatoid arthritis
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MAPKAPK5 has been proposed to play a role in regulation of matrix metalloprotease expression and so to be a potential target for intervention in rheumatoid arthritis. We present here the identification of a series of compounds against this target which are effective in both biochemical and cell assays. The expansion of the series is described, along with early SAR and pharmacokinetics for some representative compounds.
- Andrews, Martin J.I.,Andrew Clase,Bar, Gregory,Tricarico, Giovanni,Edwards, Paul J.,Brys, Reginald,Chambers, Mark,Schmidt, Wolfgang,MacLeod, Angus,Hirst, Kim,Allen, Vivienne,Birault, Veronique,Le, Joelle,Harris, John,Self, Andrew,Nash, Kevin,Dixon, Graham
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scheme or table
p. 2266 - 2270
(2012/05/04)
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- Anthranilic acid-based inhibitors of phosphodiesterase: Design, synthesis, and bioactive evaluation
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Our previous studies identified two 2-benzoylaminobenzoate derivatives 1, which potently inhibited superoxide (O2-) generation induced by formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP) in human neutrophils. In an attempt to improve their activities, a series of anthranilic acid derivatives were synthesized and their anti-inflammatory effects and underlying mechanisms were investigated in human neutrophils. Of these, compounds 17, 18, 46, 49, and 50 showed the most potent inhibitory effect on FMLP-induced release of O2- in human neutrophils with IC50 values of 0.20, 0.16, 0.15, 0.06, and 0.29 μM, respectively. SAR analysis showed that the activities of most compounds were dependent on the ester chain length in the A ring. Conversely, a change in the linker between the A and B ring from amide to sulfonamide or N-methyl amide, as well as exchanges in the benzene rings (A or B rings) by isosteric replacements were unfavorable. Further studies indicated that inhibition of O2- production in human neutrophils by these anthranilic acids was associated with an elevation in cellular cAMP levels through the selective inhibition of phosphodiesterase 4. Compound 49 could be approved as a lead for the development of new drugs in the treatment of neutrophilic inflammatory diseases.
- Cheng, Yih-Dih,Hwang, Tsong-Long,Wang, Han-Hsiang,Pan, Tai-Long,Wu, Chin-Chung,Chang, Wen-Yi,Liu, Yi-Ting,Chu, Tzu-Chi,Hsieh, Pei-Wen
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experimental part
p. 7113 - 7125
(2011/11/04)
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- Structural characterisation of 2,3-disubstituted pyrazines: NMR and X-ray crystallography
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2-Formyl-3-aminopyrazine (1), 2-acetyl-3-aminopyrazine (2) and 2-benzoyl-3-aminopyrazine (3) have been studied by multinuclear magnetic resonance spectroscopy in solution and in solid state. Amino-imine tautomerism in such derivatives has been discussed on the basis of the calculated stabilities of the different tautomers by the hybrid B3LYP/6-31G** method. The crystalline structure of compound 3 has been solved, it belongs to the monoclinic P21/n space group, and shows supramolecular architectures involving N-H?O and N-H?N-pyrazine intermolecular hydrogen bonds.
- Farrán, M. ángeles,Claramunt, Rosa M.,López, Concepción,Pinilla, Elena,Torres, M. Rosario,Elguero, José
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- Central and peripheral analgesic agents: Chemical strategies for limiting brain penetration in Kappa-opioid agonists belonging to different chemical classes
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Over the past decade there has been great interest by the pharmaceutical industry in the development of novel analgesics which act by activation of central x-opioid receptors. However, in view of the spectrum of unwanted CNS effects associated with such agents, recent efforts have been focused on peripherally-selective compounds with limited ability to cross the blood-brain barrier (BBB). In this review, the authors consider the chemical strategies and associated synthetic procedures employed by various research groups to produce hydrophilic compounds with retained x-opioid agonist activity. Physico-chemical (clogP, ΔlogP) and biological methods (antinociception following administration by peripheral and central routes; ex-vivo binding to detect plasma and brain levels of the drugs) utilized to assess brain penetration are described and compared. Overall, in-vivo ratios correlate better with ΔlogP values than with clogP.
- Giardina,Clarke,Grugni,Sbacchi,Vecchietti
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p. 405 - 418
(2007/10/02)
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- Dihalogentriphenylphosphoranes in the synthesis of heterocycles, 29. A simple synthesis of pteridin-4-ones, from methyl-3-amino-2-pyrazinecarboxylate and pyrazino[3,1]oxazin-4-ones
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Methyl 3-amino-2-pyrazinecarboxylate (3) affords the synthetically useful 3-aroylaminopyrazin-2-carboxylates 5a-f with aroyl chlorides, which are converted with dibromotriphenylphosphorane into 2-arylpyrazino[2,3-d][3,1]oxazin-4-ones 6a-f. Nucleophilic attack at the carbonyl function of these oxazinones results in ring cleaved amides which can be recyclized with dibromotriphenylphosphorane to afford 2-arylpteridin-4-ones 7a-f.
- Wamhoff,Kroth
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p. 405 - 410
(2007/10/02)
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- (2-imidazolin-2-yl) fused heteropyridine compounds, intermediates for the preparation of and use of said compounds as herbicidal agents
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There are provided novel (2-imidazolin-2-yl) fused heteropyridine compounds, and intermediate compounds for the preparation thereof, and a method for controlling a wide variety of annual and perennial plant species therewith.
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- A CONVENIENT SYNTHESIS OF 3-(ARYL)SUBSTITUTED 2,4(1H,3H)-PTERIDINEDIONES AND THEIR ABSORPTION AND FLUORESCENCE SPECTROSCOPIC CHARACTERISTICS
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3-(Aryl)substituted 2,4(1H,3H)-pteridinediones are synthesized in high yields by addition and simultaneous cyclization of methyl 3-amino-2-pyrazinecarboxylate with isocyanates.The remarcable difference in the reactivity is observed among heterocumulenes.The absorption and fluorescence spectroscopic characteristics of the titled compounds are also discussed.
- Katoh, Akira,Ohkanda, Junko,Sato, Hiroshi,Sakamoto, Tsuyosi,Mitsuhashi, Keiryo
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p. 949 - 954
(2007/10/02)
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- HOMOLYTIC CARBAMOYLATION AND ALKOXYCARBONYLATION OF 2-AMINOPYRAZINE
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3-Amino-2-pyrazinecarboxylic acid amide and methyl and ethyl esters have been prepared by respective homolytic carbamoylation and alkoxycarbonylation.The identity of products has been confirmed by the mass and NMR spectroscopies.
- Vontor, Tomas,Palat, Karel,Lycka, Antonin
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p. 1306 - 1310
(2007/10/02)
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