- First synthesis of piperazine-derived [1,2,4]triazolo[1,5-a]pyrazine as an adenosine A2a receptor antagonist
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Synthesis of piperazine-derived 2-furan-2-yl-[1,2,4]triazolo[1,5-a] pyrazines was achieved using methyl 3-amino-2-pyrazinecarboxylate. Introduction of the piperazine to the pyrazine template was achieved through a pteridin-4-one intermediate (7). Cyclization of the [1,2,4]triazolo[1,5-a]pyrazine ring was accomplished by amination of pyrazine (8) followed by condensation with 2-furaldehyde. Curtius rearrangement installed the amine to afford template (11). As one example of derivatizing 11, 6N-(4-(2,4,6-trifluorobenzyl)piperazin-1-yl)-2-(furan-2-yl)-[1,2,4]triazolo-[1,5-a]pyrazin-8-amine (12) showed moderate adenosine A2a receptor binding affinity and selectivity over the A1 receptor.{A figure is presented}.
- Peng, Hairuo,Sha, Li,Chang, He Xi,Vessels, Jeffery T.,Haque, Serajul,Conlon, Patrick R.,Dowling, James E.,Wang, Joy,Engber, Thomas M.,Kumaravel, Gnanasambandam,Scott, Daniel M.,Petter, Russell C.
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Read Online
- A french pulls Wei synthetic method
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The invention belongs to the field of medicinal chemistry and particularly relates to a new synthesis method of Favipiravir. The method comprises the following steps: carrying out carboxyl protection on raw material shown in the formula (II) to generate a compound (III); carrying out diazotization hydrolysis reaction in the presence of concentrated sulfuric acid and sodium nitriteto generate a compound (IV); carrying out benzyl protection reaction to generate a compound (V), and then generating a compound (VI) in the presence of potassium fluoride and tetrabutylammonium bromide; removing a benzyl protection group to generate a compound (VII); and then adding an aminating agent to carry out amination to generate Favipiravir shown in the formula I. The method disclosed by the invention has the advantages that the reaction cycle is short, the operation is simple, the production cost is low, and the product is high in quality; therefore, the method is suitable for industrial production.
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Paragraph 0041; 0042; 0043; 0044; 0045
(2017/08/25)
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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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- 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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p. 2153 - 2158
(2017/09/30)
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- BCR-ABL kinase inhibitor and its application (by machine translation)
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The present invention relates to the field of chemical medicines, in particular to compounds as represented by formula I having BCR-ABL kinase inhibitory activity, or pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and pharmaceutical composition containing the compounds, and application of the compounds or compositions in drug preparation. The compounds of the present invention have strong inhibitory effect on BCR-ABL kinase, and can be used to treat diseases such as tumors.
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Paragraph 0067
(2017/03/28)
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- SUBSTITUTED BENZOFURAN COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
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The present invention relates to compounds of formula I that are useful as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system. (I)
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Page/Page column 66-67
(2015/01/16)
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- SUBSTITUTED BENZOFURAN COMPOUNDS AND METHODS OF USE THEREOF FOR TREATMENT OF VIRAL DISEASES
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Disclosed are compounds of formula (I) that are useful as hepatitis C virus (HCV) NSSB polymerise inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NSSB polymerise activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.
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Page/Page column 70
(2015/01/16)
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- Aminopyrazinamides: Novel and specific GyrB inhibitors that kill replicating and nonreplicating mycobacterium tuberculosis
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Aminopyrazinamides originated from a high throughput screen targeting the Mycobacterium smegmatis (Msm) GyrB ATPase. This series displays chemical tractability, robust structure-activity relationship, and potent antitubercular activity. The crystal structure of Msm GyrB in complex with one of the aminopyrazinamides revealed promising attributes of specificity against other broad spectrum pathogens and selectivity against eukaryotic kinases due to novel interactions at hydrophobic pocket, unlike other known GyrB inhibitors. The aminopyrazinamides display excellent mycobacterial kill under in vitro, intracellular, and hypoxic conditions.
- Shirude, Pravin S.,Madhavapeddi, Prashanti,Tucker, Julie A.,Murugan, Kannan,Patil, Vikas,Basavarajappa, Halesha,Raichurkar, Anandkumar V.,Humnabadkar, Vaishali,Hussein, Syeed,Sharma, Sreevalli,Ramya,Narayan, Chandan B.,Balganesh, Tanjore S.,Sambandamurthy, Vasan K.
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p. 519 - 523
(2013/05/08)
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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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p. 2266 - 2270
(2012/05/04)
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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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p. 2784 - 2788
(2012/05/20)
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- INHIBITORS OF JAK
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The present invention relates to the use of novel compounds of Formula I, wherein the variables m, n, p, q, Q, r, R, R′, X, X′, Y, Z1, Z2, and Z3 are defined as described herein, which inhibit JAK and are useful for the treatment of auto-immune and inflammatory diseases.
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Page/Page column 84-85
(2011/04/18)
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- Discovery of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase as Potential Anticancer Agents
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DNA-damaging agents are among the most frequently used anticancer drugs. However, they provide only modest benefit in most cancers. This may be attributed to a genome maintenance network, the DNA damage response (DDR), that recognizes and repairs damaged DNA. ATR is a major regulator of the DDR and an attractive anticancer target. Herein, we describe the discovery of a series of aminopyrazines with potent and selective ATR inhibition. Compound 45 inhibits ATR with a Ki of 6 nM, shows >600-fold selectivity over related kinases ATM or DNA-PK, and blocks ATR signaling in cells with an IC50 of 0.42 μM. Using this compound, we show that ATR inhibition markedly enhances death induced by DNA-damaging agents in certain cancers but not normal cells. This differential response between cancer and normal cells highlights the great potential for ATR inhibition as a novel mechanism to dramatically increase the efficacy of many established drugs and ionizing radiation.
- Charrier, Jean-Damien,Durrant, Steven J.,Golec, Julian M. C.,Kay, David P.,Knegtel, Ronald M. A.,MacCormick, Somhairle,Mortimore, Michael,O'Donnell, Michael E.,Pinder, Joanne L.,Reaper, Philip M.,Rutherford, Alistair P.,Wang, Paul S. H.,Young, Stephen C.,Pollard, John R.
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scheme or table
p. 2320 - 2330
(2011/06/17)
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- PYRAZINES USEFUL AS INHIBITORS OF ATR KINASE
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The present invention relates to pyrazine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula II; (Formula (II) wherein the variables are as defined herein.
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Page/Page column 44
(2011/12/02)
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present invention relates to pyrazine and pyridine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula (IV): (Formula (IV)) wherein the variables are as defined herein.
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Page/Page column 37-38
(2011/12/02)
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present invention relates to pyrazine and pyridine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula (V): (Formula (v)) wherein the variables are as defined herein.
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Page/Page column 52
(2011/12/02)
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- Efficient three-step one-pot synthesis of a novel 2,3,5-substituted pyrazine library
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The partnership between rational synthesis design and mass-triggered preparative LCMS is a powerful one, capable of furnishing very large libraries in a selective manner in a very short space of time. Herein, we communicate one example of possibly a perfect marriage between the synthetic chemistry and the subsequent purification method employed, affording a ～1000-member library supplying 50 mg on average of final compound in less than a month.
- Delvare, Christian,Harris, Craig S.,Hennequin, Laurent,Koza, Patrice,Lambert-Van Der Brempt, Christine,Pelleter, Jacques,Willerval, Olivier
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scheme or table
p. 449 - 452
(2011/11/29)
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- PYRAZINE DERIVATIVES
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The invention concerns pyrazine derivatives of the Formula (I) or pharmaceutically-acceptable salts thereof; wherein each of n, m and R has any of the meanings defined hereinbefore in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use in the treatment of bone-related disorders or conditions
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Page/Page column 67
(2011/08/08)
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- COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE
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The present disclosure relates to pyrazine compounds of formula (I) wherein L, n, R1, and R2 are as described in the specification. These compounds are useful as inhibitors of ATR protein kinase. The disclosure also relates to pharmaceutically acceptable compositions comprising the compounds of the disclosure; methods of treating of various diseases, disorders, and conditions using the compounds of the disclosure; processes for preparing the compounds of the disclosure; intermediates for the preparation of the compounds of the disclosure; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.
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Page/Page column 90
(2010/06/11)
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- HETEROCYCLIC INHIBITORS OF c-MET AND USES THEREOF
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The present invention provides compounds useful as inhibitors of c-Met tyrosine kinase. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various proliferative disorders
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Page/Page column 45
(2008/06/13)
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- NEW COMPOUNDS
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The present invention relates to compounds of formula (I) [Chemical formula should be inserted here. Please see paper copy] as well as pharmaceutically acceptable salts and pharmaceutical compositions including the compounds are prepared or thereof: wherein, A1, A2, R1, R2, R3, R4, and R5 and n are as defined in the specification. The compounds of formula (I) are useful in therapy.
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Page/Page column 71
(2008/06/13)
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- TRIAZOLOPYRAZINES AND METHODS OF MAKING AND USING THE SAME
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The invention is based on the discovery that compounds of formula (I) possess unexpectedly high affinity for the A2a adenosine receptor, and can be useful as antagonists thereof for preventing and/or treating numerous diseases, including Parkinson's disease. In one embodiment, the invention features a compound of formula I (See formula on paper copy)
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- Preparation and diuretic properties of novel amiloride analogues
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Fifteen novel amiloride analogues were synthesized and their diuretic properties compared to amiloride and triamterene in white wistar rats. Whereas none of the 6-substituted derivatives exhibited significant natriuretic and antikaliuretic effects, five of the compounds modified in the 2-position were found equal or better than standards. The results are discussed with respect to chemical structure and physicochemical properties.
- Russ,Ried,Ullrich,Mutschler
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p. 761 - 767
(2007/10/02)
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