- Highly efficient, chemoselective syntheses of 2-methoxy-4-substituted pyrimidines
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Three 2-methoxy-4-substituted pyrimidine compounds were chemoselectively synthesized by diazotization, using 2,4-dichloropyrimidine as the starting material. In nonaqueous diazotization reaction system, halo-substituted 6 and 7 were efficiently prepared, and in aqueous medium, hydrolysis product 8 was afforded.
- Xu, Chunyan,Cheng, Chuanjie,Liu, Hongtao,Liu, Bo
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- Synthesis and biological evaluation of novel flexible nucleoside analogues that inhibit flavivirus replication in vitro
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Flaviviruses, such as Dengue (DENV) and Zika (ZIKV) viruses, represent a severe health burden. There are currently no FDA-approved treatments, and vaccines against most flaviviruses are still lacking. We have developed several flexible analogues (“fleximers”) of the FDA-approved nucleoside Acyclovir that exhibit activity against various RNA viruses, demonstrating their broad-spectrum potential. The current study reports activity against DENV and Yellow Fever Virus (YFV), particularly for compound 1. Studies to elucidate the mechanism of action suggest the flex-analogue triphosphates, especially 1-TP, inhibit DENV and ZIKV methyltransferases, and a secondary, albeit weak, effect on the DENV RNA-dependent RNA polymerase was observed at high concentrations. The results of these studies are reported herein.
- Thames, Joy E.,Waters, Charles D.,Valle, Coralie,Bassetto, Marcella,Aouadi, Wahiba,Martin, Baptiste,Selisko, Barbara,Falat, Arissa,Coutard, Bruno,Brancale, Andrea,Canard, Bruno,Decroly, Etienne,Seley-Radtke, Katherine L.
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- Phototransformation of Chlorimuron-ethyl in Aqueous Solution
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Chlorimuron-ethyl is relatively stable in water buffered to pH 7.0 and 9.0, but hydrolyzes readily (half-life, 14 d) in water buffered to pH 4.0. In addition, chlorimuron-ethyl photodegrades rapidly and extensively in aqueous solution. The predominant photoproducts are 4-methoxy-6-chloro-2-aminopyrimidine, ethyl 2-aminosulfonylbenzoate, N-(4-methoxy-6-chloropyrimidin-2-yl)methyl urea, and o-benzoic sulfimide (saccharin). A minor deesterified product (chlorimuron) was evident. The decrease in chlorimuron-ethyl concentration in aqueous solutions followed first-order kinetics. The rate of degradation in different types of water followed the order irrigation water > tap water > distilled water. Chlorimuron-ethyl photodegraded in pH 4, 7, and 9 buffer solutions under both UV and sunlight. A faster degradation rate in pH 4.0 buffer solution was observed.
- Choudhury, Partha P.,Dureja, Prem
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- C2-Selective, Functional-Group-Divergent Amination of Pyrimidines by Enthalpy-Controlled Nucleophilic Functionalization
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Synthesis of heteroaryl amines has been an important topic in organic chemistry because of their importance in small-molecule discovery. In particular, 2-Aminopyrimidines represent a highly privileged structural motif that is prevalent in bioactive molecules, but a general strategy to introduce the pyrimidine C2-N bonds via direct functionalization is elusive. Here we describe a synthetic platform for site-selective C-H functionalization that affords pyrimidinyl iminium salt intermediates, which then can be transformed into various amine products in situ. Mechanism-based reagent design allowed for the C2-selective amination of pyrimidines, opening the new scope of site-selective heteroaryl C-H functionalization. Our method is compatible with a broad range of pyrimidines with sensitive functional groups and can access complex aminopyrimidines with high selectivity.
- Ham, Won Seok,Choi, Hoonchul,Zhang, Jianbo,Kim, Dongwook,Chang, Sukbok
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supporting information
p. 2885 - 2892
(2022/02/23)
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- 2-MORPHOLIN-4,6-DISUBSTITUTED PYRIMIDINE DERIVATIVE, AND PREPARATION METHOD AND PHARMACEUTICAL USE THEREOF
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Disclosed is a 2-morpholin-4,6-disubstituted pyrimidine derivative as shown in formula (I) below, and a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and a pharmaceutical composition thereof and a use thereof, wherein the definition of each group is as shown in the description. The compound has a PI3K kinase inhibition activity, and has a relatively high inhibitive ability and a low cytotoxicity against PIK3CA mutant breast cancer cell strains T47D and MCF-7.
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Paragraph 0108
(2017/11/11)
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- Peptide deformylase inhibitors
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The present invention relates to a compound of Formula (I): or a pharmaceutically acceptable salt thereof, corresponding pharmaceutical compositions, compound preparation and treatment methods directed to bacterial infections and inhibition of bacterial peptide deformylase (PDF) activity.
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(2014/12/09)
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- DIBENZOOXEPIN DERIVATIVE
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A dibenzoxepin derivative represented by the following general formula (I) wherein Y is a hydrogen atom and the like, RA is a hydrogen atom and the like, X is the formula (b3) wherein RB is a hydrogen atom and the like, and the like,
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Paragraph 0372
(2014/06/24)
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- PEPTIDE DEFORMYLASE INHIBITORS
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The present invention relates to a compound of Formula (I): or a pharmaceutically acceptable salt thereof, corresponding pharmaceutical compositions, compound preparation and treatment methods directed to bacterial infections and inhi-bition of bacterial peptide deformylase (PDF) activity
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(2014/02/15)
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- SUBSTITUTED IMIDAZO[1,2-A]PYRIMIDINES AND -PYRIDINES
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Compounds of formula (I) which are effective inhibitors of the Pi3K/Akt pathway, processes for their production and their use as pharmaceuticals.
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Page/Page column 90; 91
(2012/02/02)
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- Synthesis and evaluation of novel monosubstituted sulfonylurea derivatives as antituberculosis agents
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A series of novel monosubstituted sulfonylurea derivatives 10a-y were synthesized and characterized by 1H NMR, 13C NMR and HRMS. These compounds were evaluated against Mycobacterium tuberculosis H37Rv in vitro. The results showed compounds 10f, 10k and 10s exhibited moderate antituberculosis activities with MIC values in the range of 20-100 mg/L. Compounds 10b and 10o displayed good antituberculosis activities (MIC 10 mg/L), which were comparable with that of the sulfometuron methyl. Both of the two compounds showed little cytotoxicities, with an IC50 against THP-1 cells greater than 100 mg/L.
- Pan, Li,Jiang, Ying,Liu, Zhen,Liu, Xing-Hai,Liu, Zhuo,Wang, Gang,Li, Zheng-Ming,Wang, Di
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experimental part
p. 18 - 26
(2012/07/01)
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- Systematic structure modifications of imidazo[1,2-a]pyrimidine to reduce metabolism mediated by aldehyde oxidase (AO)
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N-{trans-3-[(5-Cyano-6-methylpyridin-2-yl)oxy]-2,2,4,4- tetramethylcyclobutyl}imidazo[1,2-a]pyrimidine-3-carboxamide (1) was recently identified as a full antagonist of the androgen receptor, demonstrating excellent in vivo tumor growth inhibition in castration-resistant prostate cancer (CRPC). However, the imidazo[1,2-a]pyrimidine moiety is rapidly metabolized by aldehyde oxidase (AO). The present paper describes a number of medicinal chemistry strategies taken to avoid the AO-mediated oxidation of this particular system. Guided by an AO protein structure-based model, our investigation revealed the most probable site of AO oxidation and the observation that altering the heterocycle or blocking the reactive site are two of the more effective strategies for reducing AO metabolism. These strategies may be useful for other drug discovery programs.
- Linton, Angelica,Kang, Ping,Ornelas, Martha,Kephart, Susan,Hu, Qiyue,Pairish, Mason,Jiang, Ying,Guo, Chuangxing
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supporting information; experimental part
p. 7705 - 7712
(2012/01/13)
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- Phase transfer-catalyzed, one-pot synthesis of some novel N-pyrimidinyl-N'-nicotinyl thiourea derivatives
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A new series of acyl thiourea derivatives were synthesized in one-pot using PEG-600 as the phase transfer catalyst (PTC). The structures of title compounds were characterized by 1H NMR, IR, MS, and elemental analysis. In addition, the fungicidal activity of the acyl thiourea derivatives were tested, which showed that most of them exhibit moderate activity. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Copyright Taylor & Francis Group, LLC.
- Liu, Xing-Hai,Tan, Cheng-Xia,Weng, Jian-Quan
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body text
p. 552 - 557
(2011/05/07)
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- Identification of NVP-BKM120 as a potent, selective, orally bioavailable class i PI3 kinase inhibitor for treating cancer
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Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
- Burger, Matthew T.,Pecchi, Sabina,Wagman, Allan,Ni, Zhi-Jie,Knapp, Mark,Hendrickson, Thomas,Atallah, Gordana,Pfister, Keith,Zhang, Yanchen,Bartulis, Sarah,Frazier, Kelly,Ng, Simon,Smith, Aaron,Verhagen, Joelle,Haznedar, Joshua,Huh, Kay,Iwanowicz, Ed,Xin, Xiaohua,Menezes, Daniel,Merritt, Hanne,Lee, Isabelle,Wiesmann, Marion,Kaufman, Susan,Crawford, Kenneth,Chin, Michael,Bussiere, Dirksen,Shoemaker, Kevin,Zaror, Isabel,Maira, Sauveur-Michel,Voliva, Charles F.
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supporting information; experimental part
p. 774 - 779
(2011/12/03)
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- TRIAZINE COMPOUNDS AS KINASE INHIBITORS
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The present invention relates to triazine compounds that are useful as kinase inhibitors. More particularly, the present invention relates to morpholino substituted triazines, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative disorders including tumours and cancers as well as other disorders or conditions related to or associated with mTOR kinases or PI3 kinases. The compounds are of the formula (I)
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- PHOSPHOINOSITIDE 3-KINASE INHIBITOR COMPOUNDS AND METHODS OF USE
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Compounds of Formulas Ia-d where X is S or O, mor is a morpholine group, and R3 is a monocyclic heteroaryl group, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for modulating the activity of lipid kinases including PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula Ia-d for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed. [Insert Formula Ic and Id]
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(2008/12/06)
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- PI 3-KINASE INHIBITORS AND METHODS OF THEIR USE
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Phosphatidylinositol (PI) 3-kinase inhibitor compounds, their pharmaceutically acceptable salts, and prodrugs thereof; compositions of the new compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of diseases characterized by the abnormal activity of growth factors, protein serine/threonine kinases, and phospholipid kinases, including proliferative diseases, inflammatory and obstructive airways diseases, allergic conditions, auutoimmune and cardiovascular diseases.
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- PYRIMIDINE DERIVATIVES USED AS PI-3 KINASE INHIBITORS
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Phosphatidylinositol (PI) 3-kinase inhibitor compounds (I), their pharmaceutically acceptable salts, and prodrugs thereof ; compositions of the new compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases characterized by the abnormal activity of growth factors, protein serine/threonine kinases, and phospholipid kinases.
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(2010/11/28)
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- New base pairing motifs. The synthesis and thermal stability of oligodeoxynucleotides containing imidazopyridopyrimidine nucleosides with the ability to form four hydrogen bonds
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The synthesis and thermal stability of oligodeoxynucleotides (ODNs) containing imidazo[5′,4′: 4,5]pyrido[2,3-d]pyrimidine nucleosides 1-4 (NN, OO, NO, and ON, respectively) with the aim of developing two sets of new base pairing motifs consisting of four hydrogen bonds (H-bonds) is described. The proposed four tricyclic nucleosides 1-4 were synthesized through the Stille coupling reaction of a 5-iodoimidazole nucleoside with an appropriate 5-stannylpyrimidine derivative, followed by an intramolecular cyclization. These nucleosides were incorporated into ODNs to investigate the H-bonding ability. When one molecule of the tricyclic nucleosides was incorporated into the center of each ODN (ODN I and II, each 17mer), no apparent specificity of base pairing was observed, and all duplexes were less stable than the duplexes containing natural G:C and A:T pairs. On the other hand, when three molecules of the tricyclic nucleosides were consecutively incorporated into the center of each ODN (ODN III and IV, each 17mer), thermal and thermodynamic stabilization of the duplexes due to the specific base pairings was observed. The melting temperature (Tm) of the duplex containing the NO:ON pairs showed the highest Tm of 84.0 °C, which was 18.2 and 23.5 °C higher than that of the duplexes containing G:C and A:T pairs, respectively. This result implies that NO and ON form base pairs with four H-bonds when they are incorporated into ODNs. The duplex containing NO:O N pairs was markedly stabilized by the assistance of the stacking ability of the imidazopyridopyrimidine bases. Thus, we developed a thermally stable new base pairing motif, which should be useful for the stabilization and regulation of a variety of DNA structures.
- Minakawa, Noriaki,Kojima, Naoshi,Hikishima, Sadao,Sasaki, Takashi,Kiyosue, Arihiro,Atsumi, Naoko,Ueno, Yoshihito,Matsuda, Akira
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p. 9970 - 9982
(2007/10/03)
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- Fluorinated Heterocyclic Compounds. 2. 2,4-Difluoro and 4-Amino-2-fluoropyrimidines, Nucleoside Base Analogs
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Nucleoside base analogs in which fluoro substituents replace the enolic hydroxy groups of uracil, thymine and cytosine have been prepared.Improved methods for the preparation and isolation of the known 2,4-difluoropyrimidine, 2,4-difluoro-6-methylpyrimidine and the new 2,4-difluoro-5-methylpyrimidine, 2-fluoro-4-aminopyrimidine, 4-fluoro-2-aminopyrimidine, and other alkylaminofluoropyrimidines are described.
- Svirskaya, Polina I.,Yedidia, Varda,Leznoff, Clifford C.,Miller, Jack M.
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p. 149 - 153
(2007/10/02)
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