- Identification and Optimization of Novel Cathepsin C Inhibitors Derived from EGFR Inhibitors
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In the course of developing the biochemistry to chemistry activity-based protein profiling (BTC-ABPP) method, we herein unexpectedly discovered that the epidermal growth factor receptor irreversible inhibitor WZ4002 also functioned as a low micromolar inhibitor of cathepsin C (CatC), a promising target for the treatment of numerous inflammatory and autoimmune diseases. Building on from this discovery, and following structure-activity relationship investigations guided by computational modeling, a novel series of pyridine scaffold compounds were developed as irreversible CatC inhibitors, further culminated in identifying a highly potent and selective inhibitor 22, which displays good metabolic stability and oral bioavailability. In vivo studies revealed that compound 22 clearly displays the ability to inhibit CatC, consequently leading to efficient inhibition of downstream neutrophil serine proteases in both bone marrow and blood. The overall excellent profile of compound 22 made it an interesting candidate for further preclinical investigation.
- Hou, Weijie,Sun, Huan,Ma, Yongfen,Liu, Chunyan,Zhang, Zhiyuan
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Read Online
- A concise approach to a gelsemine core structure using an oxygen to carbon bridge swapping strategy
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(Chemical Equation Presented) A tricyclic core structure 2 related to gelsemine 1 was synthesized from an oxabicyclo[3.2.1]octanone 4 by a three-step bridge swapping strategy involving elimination of the bridging ether oxygen and intramolecular Michael addition of a tethered cyanoacetamide unit.
- Tchabanenko, Kirill,Simpkins, Nigel S.,Male, Louise
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Read Online
- Quantification of CH...π interactions: Implications on how substituent effects influence aromatic interactions
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Attractive interactions between a substituted benzene ring and an α-substituted acetate group were determined experimentally by using the triptycene model system. The attractive interaction correlates well with the Hammett constants σm (R2=0.90), but correlates much better with the acidity of the α-protons (R2=0.98). A predominant CH...π interaction was found to control the conformational preference of model compounds 1a-g. Despite the predominance of the CH...π interaction in compounds 1a-g, a Hammett plot displays a fairly straight line for the substituent effect. These results show that when using Hammett plots in a simplified model system, a system designed to study the effect of X...π interactions could capture the X-H...π interaction instead.
- Gung, Benjamin W.,Emenike, Bright U.,Lewis, Michael,Kirschbaum, Kristin
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Read Online
- Alternating copolymerization of cyclohexene oxide and CO2 catalyzed by zinc complexes with new 3-amino-2-cyanoimidoacrylate ligands
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New 3-amino-2-cyanoimidoacrylate ligands with varying steric demands have been synthesized. Zinc acetate complexes of these ligands catalyze the copolymerisation of CO2 and cyclohexene oxide, showing high activities (TOF up to over 200 h -1).
- Kroeger, Mario,Folli, Cristina,Walter, Olaf,Doering, Manfred
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Read Online
- Stable enols of amides ArNHC(OH)=C(CN)CO2R. E/Z enols, equilibria with the amides, solvent effects, and hydrogen bonding
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The structures of anilido cyano(fluoroalkoxycarbonyl)methanes ArNHCOCH(CN)CO2R, where r = CH2CF3 or CH(CF3)2, Ar = p-XC6H4, and X = MeO, Me, H, or Br, were investigated. In the solid state, all exist as the enols ArNHC(OH)=C(CN)CO2R 7 (R = CH2CF3) and 9 (R = CH(CF3)2) with cis arrangement of the hydrogen-bonded ROC=O...HO moiety and a long C1=C2 bond. The product composition in solution is solvent dependent. In CDCl3 solution, only a single enol is observed, whereas in THF-d8 and CD3CN, two enols (E and Z) are the major products, and the amide is the minor product or not observed at all (KEnol 1.04-9 (CD3CN, 298 K) and 3 to ≥100 (THF, 300 K)). The percentage of the amide and the Z-enol increase upon an increase in temperature. In all solvents, the percent enol is higher for 9 than for 7. In CD3CN, more enol is observed when the aryl group is more electron-donating. The spectra in DMSO-d6 and DMF-d7 indicate the presence of mostly a single species, whose spectra do not change on addition of a base and is ascribed to the anion of the ionized carbon acid. Comparison with systems where the CN is replaced by a CO2R group (R = CH2CF3, CH(CF3)2) shows a higher percentage of enol for the CN-substituted system. Intramolecular (to CO2R) and intermolecular hydrogen bonds determine, to a significant extent, the stability of the enols, their Z/E ratios (e.g., Z/E (THF, 240 K) = 3.2-4.0 (7) and 0.9-1.3 (9)), and their δ(OH) in the 1H spectra. The interconversion of Z- and E-enol by rotation around the C=C bond was studied by DNMR, and ΔG? values of ≥15.3 and 14.1 ± 0.4 kcal/mol for Z-7 and Z-9 were determined. Features of the NMR spectra of the enols and their anions are discussed.
- Lei, Yi Xiong,Casarini, Daniele,Cerioni, Giovanni,Rappoport, Zvi
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- Synthesis of functionally substituted cyanoacetates
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Some mew cyanoacetates were synthesized and characterized.They are precursors for α-cyanoacrylates used as rapidly polymerized, cold-hardening adhesives.
- Guseva, T. I.,Senchenya, N. G.,Gol'ding, I. P.,Mager, K. A.,Gololobov, Yu. G..
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- Cyanoketene: The microwave spectrum and structure of an unstable molecule
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The unstable molecule cyanoketene has been prepared by pyrolysis in a flow system, and the microwave spectra of five isotopic species, a- and b-type, have been measured in the frequency range from 8 to 40 GHz. Precise rotational constants and centrifugal distortion parameters up to the sixth order were obtained. The molecule has been shown to be planar, and a reliable structure was derived, Also the N-quadrupole coupling constants and the dipole moment components have been determined. The results could be a basis for interstellar spectroscopy of this molecule.
- Hahn,Bodenseh,Ferner
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Read Online
- A synthesis of bredinin (Mizoribine) from an acyclic precursor
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Bredinin (4-carbamoyl-1-β-d-ribofuranosylimidazolium-5-olate, 1) was synthesised by the formation of a malonamate from 2,3-isopropylidene-d- ribofuranosylamine and ethyl malonyl chloride, followed by a sequence involving amination, via reduction of an oxime, heterocycle formation and then deprotection.
- Humble, Robert W.,Middleton, Danielle F.,Banoub, Joseph,Ewing, David F.,Boa, Andrew N.,MacKenzie, Grahame
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- CHEMICAL COMPOUNDS
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The present disclosure describes novel compounds, or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of the disclosure have activity as Janus kinase (JAK) inhibitors and are useful in the treatment or control of inflammation, auto-immune diseases, cancer, and other disorders and indications where modulation of JAK would be desirable. Also described herein are methods of treating inflammation, auto-immune diseases, cancer, and other conditions susceptible to inhibition of JAK by administering a compound herein described.
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Paragraph 0414-0416
(2021/04/02)
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- KRAS MUTANT PROTEIN INHIBITORS
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The invention relates to a KRAS mutant protein inhibitor, a composition containing the inhibitor and the use thereof.
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Paragraph 0201; 0203
(2021/04/02)
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- KRAS MUTANT PROTEIN INHIBITOR
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Provided herein are a KRAS mutant protein inhibitor, as shown by formula (I), a composition containing the inhibitor and the use thereof.
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Page/Page column 51-52; 55-56
(2021/05/15)
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- KRAS MUTANT PROTEIN INHIBITORS
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The invention relates to a KRAS mutant protein inhibitor shown as formula (I), a composition containing the inhibitor and the use thereof.
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Page/Page column 38-39
(2021/06/26)
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- SUBSTITUTED BICYCLIC COMPOUNDS USEFUL AS T CELL ACTIVATORS
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Disclosed are compounds of Formula (I): or a salt thereof, wherein: X is CR6 or N; Y is CR3 or N; R1, R2, R3, R4, R5, R6, R7, and m are defined herein. Also disclosed are methods of using such compounds to inhibit the activity of one or both of diacylglycerol kinase alpha (DGKα) and diacylglycerol kinase zeta (DGKζ), and pharmaceutical compositions comprising such compounds. These compounds are useful in the treatment of viral infections and proliferative disorders, such as cancer.
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Paragraph 0475; 0476
(2021/06/26)
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- Fused pyrimidine derivative, and preparation method thereof and application of fused pyrimidine derivative in medicine
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The invention relates to a fused pyrimidine derivative, and a preparation method thereof and application of the fused pyrimidine derivative in medicine. Specifically, the invention relates to a fused pyrimidine derivative shown in a general formula (I), a preparation method of the fused pyrimidine derivative, a pharmaceutical composition containing the derivative and application of the fused pyrimidine derivative as a therapeutic agent, especially application of the fused pyrimidine derivative as an ATR kinase inhibitor and application of the fused pyrimidine derivative in preparation of drugs for treating or preventing hyperproliferative diseases.
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Paragraph 0271-0276
(2021/07/21)
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- Preparation process of continuous-flow teriflunomide
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To the preparation process, cyanoacetic acid is used as a starting material, cyanoacetyl chloride is prepared by chlorination, and a tertamine intermediate is synthesized by cyanacetyl chloride and p-trifluoromethylaniline, and an intermediate is synthesized with acetyl chloride. The invention has high safety. The utility model has the advantages of low cost, low energy consumption and high production yield.
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Paragraph 0041-0045; 0053-0057; 0065-0069
(2021/11/21)
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- NAPHTHYRIDINONE COMPOUNDS USEFUL AS T CELL ACTIVATORS
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Disclosed are compounds of Formula (I): or a salt thereof, wherein: R1, R2, R3, and R4 are defined herein. Also disclosed are methods of using such compounds to inhibit the activity of one or both of diacylglycerol kinase alpha (DGK α) and diacylglycerol kinase zeta (DGKζ ), and pharmaceutical compositions comprising such compounds. These compounds are useful in the treatment of viral infections and proliferative disorders, such as cancer.
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Page/Page column 114-115
(2020/01/24)
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- Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors
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Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1β and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent reactivity of the active-site cysteine has resulted in reported inhibitors that act by covalent labeling. In this study, structure-activity relationship (SAR) elaboration of the reported GSTO1-1 inhibitor C1-27 was undertaken. Compounds were evaluated for inhibitory activity toward purified recombinant GSTO1-1 and for indicators of target engagement in cell-based assays. As covalent inhibitors, the kinact/KI values of selected compounds were determined, as well as in vivo pharmacokinetics analysis. Cocrystal structures of key novel compounds in complex with GSTO1-1 were also solved. This study represents the first application of a biochemical assay for GSTO1-1 to determine kinact/KI values for tested inhibitors and the most extensive set of cell-based data for a GSTO1-1 inhibitor SAR series reported to date. Our research culminated in the discovery of 25, which we propose as the preferred biochemical tool to interrogate cellular responses to GSTO1-1 inhibition.
- Xie, Yiyue,Tummala, Padmaja,Oakley, Aaron J.,Deora, Girdhar Singh,Nakano, Yuji,Rooke, Melissa,Cuellar, Matthew E.,Strasser, Jessica M.,Dahlin, Jayme L.,Walters, Michael A.,Casarotto, Marco G.,Board, Philip G.,Baell, Jonathan B.
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p. 2894 - 2914
(2020/04/08)
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- Benzopyridone heterocyclic compound and application thereof
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The invention relates to a benzopyridone heterocyclic compound and an application thereof. The compound is a compound represented by a formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, and R1, R2, R3, R4 and R5 and an A group are as defined in the specification. The compound disclosed by the invention can be used for preparing a medicine for treating and/or preventing cancers.
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Paragraph 0096; 0099; 0102-0103
(2020/08/18)
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- Identification and Optimization of Novel Small c-Abl Kinase Activators Using Fragment and HTS Methodologies
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Abelson kinase (c-Abl) is a ubiquitously expressed, nonreceptor tyrosine kinase which plays a key role in cell differentiation and survival. It was hypothesized that transient activation of c-Abl kinase via displacement of the N-terminal autoinhibitory "myristoyl latch", may lead to an increased hematopoietic stem cell differentiation. This would increase the numbers of circulating neutrophils and so be an effective treatment for chemotherapy-induced neutropenia. This paper describes the discovery and optimization of a thiazole series of novel small molecule c-Abl activators, initially identified by a high throughput screening. Subsequently, a scaffold-hop, which exploited the improved physicochemical properties of a dihydropyrazole analogue, identified through fragment screening, delivered potent, soluble, cell-active c-Abl activators, which demonstrated the intracellular activation of c-Abl in vivo.
- Simpson, Graham L.,Bertrand, Sophie M.,Borthwick, Jennifer A.,Campobasso, Nino,Chabanet, Julien,Chen, Susan,Coggins, Julia,Cottom, Josh,Christensen, Siegfried B.,Dawson, Helen C.,Evans, Helen L.,Hobbs, Andrew N.,Hong, Xuan,Mangatt, Biju,Munoz-Muriedas, Jordi,Oliff, Allen,Qin, Donghui,Scott-Stevens, Paul,Ward, Paris,Washio, Yoshiaki,Yang, Jingsong,Young, Robert J.
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p. 2154 - 2171
(2019/02/26)
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- Design, synthesis and biological study of potent and covalent HER-2 tyrosine kinase inhibitors with low cytotoxicity in vitro
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The discovery and development of a novel HER-2 tyrosine kinase inhibitor for the treatment of HER2-positive breast cancer are presented in this article. EGFR family has been recognized as a crucial meditator in the cancer progression; HER-2 tyrosine kinase was one of the members among them. In the effort to explore potent HER-2 inhibitors, a novel series of 4-anilino-3-cyanoquinoline derivatives have been designed, synthesized and evaluated. Most compounds possessed modest proliferation inhibition on SK-BR-3 cell line and HER-2 kinase. Compound 16 appeared to be the most potent compound (HER-2 kinase IC50: 19.4?nM, SK-BR-3 IC50: 94?nM). In the experiment of cellular cytotoxicity assay, compound 16 shows a much lower cytotoxicity than neratinib on Beas-2b cell line (Human bronchial epithelial cells). In conclusion, compound 16 would be a promising lead compound for further anti-breast cancer drug discovery.
- Jin, Shuyu,Sun, Xiuyun,Liu, Dan,Xie, Hua,Rao, Yu
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p. 1333 - 1345
(2019/05/06)
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- Cobalt-Catalyzed Allylic Alkylation Enabled by Organophotoredox Catalysis
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Co-catalyzed allylic substitution reactions have received little attention, arguably because of the lack of any known advantage of Co catalysis over either Rh or Ir catalysis. Described here is a general and regioselective Co-catalyzed allylic alkylation using an in situ catalyst activation by organophotoredox catalysis. This noble-metal-free catalytic system exhibits unprecedentedly high reactivities and regioselectivities for the allylation with an allyl sulfone, for the first time, representing the unique synthetic utility of the Co-catalyzed method compared to the related Rh- and Ir-catalyzed reactions.
- Takizawa, Koji,Sekino, Tomoyuki,Sato, Shunta,Yoshino, Tatsuhiko,Kojima, Masahiro,Matsunaga, Shigeki
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supporting information
p. 9199 - 9203
(2019/06/04)
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- Small Molecule Inhibition of MicroRNA miR-21 Rescues Chemosensitivity of Renal-Cell Carcinoma to Topotecan
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Chemical probes of microRNA (miRNA) function are potential tools for understanding miRNA biology that also provide new approaches for discovering therapeutics for miRNA-associated diseases. MicroRNA-21 (miR-21) is an oncogenic miRNA that is overexpressed in most cancers and has been strongly associated with driving chemoresistance in cancers such as renal cell carcinoma (RCC). Using a cell-based luciferase reporter assay to screen small molecules, we identified a novel inhibitor of miR-21 function. Following structure-activity relationship studies, an optimized lead compound demonstrated cytotoxicity in several cancer cell lines. In a chemoresistant-RCC cell line, inhibition of miR-21 via small molecule treatment rescued the expression of tumor-suppressor proteins and sensitized cells to topotecan-induced apoptosis. This resulted in a >10-fold improvement in topotecan activity in cell viability and clonogenic assays. Overall, this work reports a novel small molecule inhibitor for perturbing miR-21 function and demonstrates an approach to enhancing the potency of chemotherapeutics specifically for cancers derived from oncomir addiction.
- Naro, Yuta,Ankenbruck, Nicholas,Thomas, Meryl,Tivon, Yaniv,Connelly, Colleen M.,Gardner, Laura,Deiters, Alexander
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p. 5900 - 5909
(2018/08/04)
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- Preparation method and application of novel quinolone compound
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The invention discloses a novel quinolone compound, a preparation method and application. The novel quinolone compound provided by the invention has the following structure: a formula is shown in thedescription. An experiment proves that the novel quinolone compound disclosed by the invention has the advantages of good antibacterial activity, wide antibacterial spectrum, strong targeting performance, good biocompatibility, high bioavailability and low toxicity; the preparation method is simple and rapid, has a high yield and is suitable for large-scale industrial production.
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Paragraph 0040; 0074; 0075
(2018/12/14)
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- Discovery of a Highly Selective Cell-Active Inhibitor of the Histone Lysine Demethylases KDM2/7
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Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell-permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure–activity relationships, leading to the development of a small molecule with around 75-fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations.
- Gerken, Philip A.,Wolstenhulme, Jamie R.,Tumber, Anthony,Hatch, Stephanie B.,Zhang, Yijia,Müller, Susanne,Chandler, Shane A.,Mair, Barbara,Li, Fengling,Nijman, Sebastian M. B.,Konietzny, Rebecca,Szommer, Tamas,Yapp, Clarence,Fedorov, Oleg,Benesch, Justin L. P.,Vedadi, Masoud,Kessler, Benedikt M.,Kawamura, Akane,Brennan, Paul E.,Smith, Martin D.
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supporting information
p. 15555 - 15559
(2017/12/02)
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- SPIROCYCLIC HAT INHIBITORS AND METHODS FOR THEIR USE
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Compounds having a structure of Formula (IX) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b, R3a, R3b, R4a, R4b, Q1----Q2, R6, R7, A, B, W, x, and y are as defined herein and are provided. Pharmaceutical compositions comprising such compounds and methods for treating various HAT-related conditions or diseases, including cancer, by administration of such compounds are also provided.
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Page/Page column 691
(2016/04/10)
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- Nonpeptidic Selective Inhibitors of the Chymotrypsin-Like (β5 i) Subunit of the Immunoproteasome
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Elevated expression of the immunoproteasome has been associated with autoimmune diseases, inflammatory diseases, and various types of cancer. Selective inhibitors of the immunoproteasome are not only scarce, but also almost entirely restricted to peptide-based compounds. Herein, we describe nonpeptidic reversible inhibitors that selectively block the chymotrypsin-like (β5i) subunit of the human immunoproteasome in the low micromolar range. The most potent of the reversibly acting compounds were then converted into covalent, irreversible, nonpeptidic inhibitors that retained selectivity for the β5i subunit. In addition, these inhibitors discriminate between the immunoproteasome and the constitutive proteasome in cell-based assays. Along with their lack of cytotoxicity, these data point to these nonpeptidic compounds being suitable for further investigation as β5i-selective probes for possible application in noncancer diseases related to the immunoproteasome.
- Sosi?, Izidor,Gobec, Martina,Brus, Boris,Knez, Damijan,?ivec, Matej,Konc, Janez,Le?nik, Samo,Ogrizek, Mitja,Obreza, Ale?,?igon, Du?an,Jane?i?, Du?anka,Mlinari?-Ra??an, Irena,Gobec, Stanislav
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supporting information
p. 5745 - 5748
(2016/05/09)
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- PSORALEN DERIVATIVES AS NON-PEPTIDIC INHIBITORS OF CHYMOTRYPSIN-LIKE ACTIVITY OF THE IMMUNOPROTEASOME
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This invention relates to new inhibitors of chymothrypsin-like activity of the immunoproteasome (inhibitors of β5? or LMP7 subunit) with the general formula (I), where substituents are described in patent description. Compounds can be in the form of pure enantiomers or as racemic mixtures, or in the form of pharmaceutically acceptable salts. The present invention relates to the use of these inhibitors for the treatment of diseases where immunoproteasome activity is increased.
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Paragraph 0192; 0193; 0194; 0195
(2016/10/11)
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- POLYCYCLIC DERIVATIVES, PREPARATION PROCESS AND PHARMACEUTICAL USE THEREOF
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Disclosed in the present invention are polycyclic derivatives as represented by general formula (I), the preparation method thereof, pharmaceutical compositions containing the derivatives and uses thereof as therapeutic agents, especially the GPR40 agonist and in preparation of drugs for treating diseases such as diabetes and metabolic disorders, etc., wherein each substituent in the general formula (I) has the same definition as in the description.
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Paragraph 0275; 0276
(2015/02/05)
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- Synthesis of diversely functionalised 2,2-disubstituted oxetanes: Fragment motifs in new chemical space
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Di-, tri- and tetra-substituted oxetane derivatives with combinations of ester, amide, nitrile, aryl, sulfone and phosphonate substituents are prepared as fragments or building blocks for drug discovery. The synthesis of these novel oxetane functional groups, in new chemical space, is achieved via rhodium-catalysed O-H insertion and C-C bond forming cyclisation.
- Davis, Owen A.,Croft, Rosemary A.,Bull, James A.
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supporting information
p. 15446 - 15449
(2015/10/20)
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- DEUBIQUITINASE INHIBITORS
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Described herein are compounds that are deubiquitinase inhibitors, methods of making pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from inhibition of deubiquitinase activity.
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Paragraph 00388
(2016/02/09)
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- IRE-1α INHIBITORS
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PROBLEM TO BE SOLVED: To provide compounds which directly inhibit inositol requiring enzyme 1 (IRE-1α activity) in vitro, prodrugs, and pharmaceutically acceptable salts thereof. SOLUTION: The present invention provides a compound represented by formula (A) [R3 and R4 are H or the like; Q5-Q8, together with the benzene ring to which they are attached, form a benzofused ring, where at least one of Q5-Q8 is a heteroatom selected from N, O, and S. COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 1357; 1358
(2016/10/07)
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- IMIDAZOLIDINONES AND ANALOGS EXHIBITING ANTI-CANCER AND ANTI-PROLIFERATIVE ACTIVITIES
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Described are compounds of Formula I which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-1R), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.
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Paragraph 0548
(2014/10/29)
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- A diversity-oriented synthesis of caroverine derivatives via TEMPO-promoted aerobic oxidative C-N bond formation
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A concise method has been developed for the synthesis of caroverine and its derivatives. The quinoxalinone scaffold of these compounds was constructed via the tandem nitrosation/aerobic oxidative CN bond formation reaction of N-(2-chloroethyl)-2-cyano-N-phenylacetamide, followed by sequential Grignard, Finkelstein and nucleophilic substitutions reactions to give several different derivatives. Herein, we describe the development of this strategy in terms of the optimization of each step as well as the effect of different additives on the individual reactions.
- Kobayashi, Yusuke,Suzuki, Yusuke,Ogata, Tokutaro,Kimachi, Tetsutaro,Takemoto, Yoshiji
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supporting information
p. 3299 - 3301
(2014/06/09)
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- THE PRESENT INVENTION RELATES TO PROCESS FOR THE PREPARATION OF TOFACITINIB AND INTERMEDIATES THEREOF.
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The present invention relates to process for the preparation of tofacitinib and intermediates thereof.
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Paragraph 0293
(2014/07/21)
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- In situ-generated iodonium ylides as safe carbene precursors for the chemoselective intramolecular buchner reaction
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A chemoselective intramolecular Buchner reaction employing iodonium ylides as safe carbene precursors has been developed. Iodonium ylides are generated in situ from N-benzyl-2-cyanoacetamides and PhI(OAc)2 in the presence of base and undergo intramolecular Buchner reaction under catalysis from Cu(OAc)2·H2O, affording fused cyclohepta-1,3,5-triene derivatives in up to 85% yield. The N,N-dibenzyl-2-cyanoacetamides with two different benzyl groups undergo intramolecular Buchner reaction on their electron-rich benzyl groups selectively. The reaction is not sensitive to air and moisture and uses a safe alternative version of the corresponding diazo starting materials. The overall transformation involving the carbene pathway has been verified.
- Mo, Shanyan,Li, Xinhao,Xu, Jiaxi
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p. 9186 - 9195
(2014/12/11)
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- POLYCYCLIC DERIVATIVES, PREPARATION METHOD AND MEDICAL USES THEREOF
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Disclosed in the present invention are polycyclic derivatives as represented by general formula (I), the preparation method thereof, pharmaceutical compositions containing the derivatives and uses thereof as therapeutical agents, especially the GPR40 agonist and in preparation of drugs for treating diseases like diabetes and metabolic disorders, etc., wherein each substituent in the general formula (I) has the same definition as in the description.
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Paragraph 0179; 0180
(2014/12/09)
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- A class of 5-nitro-2-furancarboxylamides with potent trypanocidal activity against Trypanosoma brucei in vitro
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Recently, the World Health Organization approved the nifurtimox- eflornithine combination therapy for the treatment of human African trypanosomiasis, renewing interest in nitroheterocycle therapies for this and associated diseases. In this study, we have synthesized a series of novel 5-nitro-2-furancarboxylamides that show potent trypanocidal activity, ~1000-fold more potent than nifurtimox against in vitro Trypanosoma brucei with very low cytotoxicity against human HeLa cells. More importantly, the most potent analogue showed very limited cross-resistance to nifurtimox-resistant cells and vice versa. This implies that our novel, relatively easy to synthesize and therefore cheap, 5-nitro-2-furancarboxylamides are targeting a different, but still essential, biochemical process to those targeted by nifurtimox or its metabolites in the parasites. The significant increase in potency (smaller dose probably required) has the potential for greatly reducing unwanted side effects and also reducing the likelihood of drug resistance. Collectively, these findings have important implications for the future therapeutic treatment of African sleeping sickness.
- Zhou, Linna,Stewart, Gavin,Rideau, Emeline,Westwood, Nicholas J.,Smith, Terry K.
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supporting information
p. 796 - 806
(2013/03/28)
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- α-Diazo-β-ketonitriles: Uniquely reactive substrates for arene and alkene cyclopropanation
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An investigation of the intramolecular cyclopropanation reactions of α-diazo-β-ketonitriles is reported. These studies reveal that α-diazo-β-ketonitriles exhibit unique reactivity in their ability to undergo arene cyclopropanation reactions; other similar acceptor-acceptor- substituted diazo substrates instead produce mixtures of C-H insertion and dimerization products. α-Diazo-β-ketonitriles also undergo highly efficient intramolecular cyclopropanation of tri- and tetrasubstituted alkenes. In addition, the α-cyano-α-ketocyclopropane products are demonstrated to serve as substrates for SN2, SN2′, and aldehyde cycloaddition reactions.
- Nani, Roger R.,Reisman, Sarah E.
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supporting information
p. 7304 - 7311
(2013/06/27)
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- ARYL DIHYDROPYRIDINONE AND PIPERIDINONE MGAT2 INHIBITORS
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The present invention provides compounds of Formula (I): or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are monoacylglycerol acyltransferase type 2 (MGAT2) inhibitors which may be used as medicaments.
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Paragraph 0610; 0611
(2013/06/26)
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- Optically active thiophenes via an organocatalytic one-pot methodology
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A general methodology for the synthesis of trisubstituted, optically active thiophenes by an organocatalytic one-pot reaction cascade is presented. The target products are synthesized in good yields (up to 92%) and with excellent enantioselectivities (up to 98% ee). Importantly, based on practical and easily available starting materials, the presented methodology can be conducted under mild reaction conditions. To further elucidate the generality, the synthesis of optically active thienoindoles, as well as selenophenes, is also demonstrated.
- Ransborg, Lars Krogager,Albrecht, Lukasz,Weise, Christian F.,Bak, Jesper R.,Jorgensen, Karl Anker
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supporting information; experimental part
p. 724 - 727
(2012/04/11)
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- Stereoselective control in the Staudinger reactions involving monosubstituted ketenes with electron acceptor substituents: Experimental investigation and theoretical rationalization
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The stereoselectivity of the Staudinger reactions involving monosubstituted ketenes with electron acceptor substituents was investigated experimentally by determination of the product stereochemistry and theoretically via DFT calculations. The results indicate that imines preferentially attack the less sterically hindered exo-side of the ketenes to generate zwitterionic intermediates. Subsequently, for cyclic imines, the intermediates undergo a conrotatory ring closure directly to produce β-lactams, while for linear imines, the imine moiety of the intermediates isomerizes to more stable intermediates, which further undergo a conrotatory ring closure to afford trans-β-lactams. The steric hindrance and the isomerization, rather than the torquoelectronic effect, play crucial roles in controlling the stereoselectivity in the practical Staudinger reactions involving monosubstituted ketenes with electron acceptor substituents, although the unaccessible borylketene with a powerful electron acceptor group controls the stereoselectivity torquoelectronically, in theory.
- Qi, Hengzhen,Li, Xinyao,Xu, Jiaxi
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supporting information; experimental part
p. 2702 - 2714
(2011/05/19)
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- Highly efficient synthesis of quinoxalinone-N-oxide via tandem nitrosation/aerobic oxidative C-N bond formation
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An efficient method for constructing quinoxalinone-N-oxides from cyanoacetanilides has been developed. This transformation can be achieved using inexpensive reagents and molecular oxygen under mild conditions, thus offering a practical pathway to quinoxalinone-containing pharmaceuticals such as ataquimast and opaviraline.
- Kobayashi, Yusuke,Kuroda, Mami,Toba, Natsuki,Okada, Mari,Tanaka, Rie,Kimachi, Tetsutaro
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supporting information; experimental part
p. 6280 - 6283
(2012/01/06)
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- Novel irreversible epidermal growth factor receptor inhibitors by chemical modulation of the cysteine-trap portion
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Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATPcompetitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and a warhead, generally an acrylamide or propargylamide fragment that binds covalently to Cys797 within the kinase domain of EGFR. We performed a systematic exploration of the role for the warhead group, introducing different cysteine-trapping fragments at position 6 of a traditional 4-anilinoquinazoline scaffold. We found that different reactive groups, including epoxyamides (compounds 3-6) and phenoxyacetamides (compounds 7-9), were able to irreversibly inhibit EGFR. In particular, at significant lower concentrations than gefitinib (1), (2R,3R)N-(4-(3-bromoanilino)quinazolin-6-yl)- 3 -(piperidin-1 -ylmethyl)oxirane-2-carboxamide (6) inhibited EGFR autophosphorylation and downstream signaling pathways, suppressed proliferation, and induced apoptosis in gefitinib-resistant NSCLC H1975 cells, harboring the T790M mutation in EGFR.
- Carmi, Caterina,Cavazzoni, Andrea,Vezzosi, Stefano,Bordi, Fabrizio,Vacondio, Federica,Silva, Claudia,Rivara, Silvia,Lodola, Alessio,Alfieri, Roberta R.,La Monica, Silvia,Galetti, Maricla,Ardizzoni, Andrea,Petronini, Pier Giorgio,Mor, Marco
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experimental part
p. 2038 - 2050
(2010/08/20)
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- A concise and versatile synthesis of viridicatin alkaloids from cyanoacetanilides
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The efficient synthesis of 3-hydroxy-4-arylquinolin-2(1H)-ones through one-pot Knoevenagel condensation/epoxidation of cyanoacetanilides followed by decyanative epoxide-arene cyclization is described. A convergent assembly with functionalized aldehydes allows for rapid synthesis with diverse substitution patterns. Isolation of 3-hydroxy-4-arylquinolin-2(1H)-ones is readily accomplished by precipitation and filtration.
- Kobayashi, Yusuke,Harayama, Takashi
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supporting information; experimental part
p. 1603 - 1606
(2009/08/07)
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- Structure-based design, synthesis, and characterization of inhibitors of human and Plasmodium falciparum dihydroorotate dehydrogenases
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Pyrimidine biosynthesis is an attractive drug target in a variety of organisms, including humans and the malaria parasite Plasmodium falciparum. Dihydroorotate dehydrogenase, an enzyme catalyzing the only redox reaction of the pyrimidine biosynthesis pathway, is a well-characterized target for chemotherapeutical intervention. In this study, we have applied SPROUT-LeadOpt, a software package for structure-based drug discovery and lead optimization, to improve the binding of the active metabolite of the anti-inflammatory drug leflunomide to the target cavities of the P. falciparum and human dihydroorotate dehydrogenases. Following synthesis of a library of compounds based upon the SPROUT-optimized molecular scaffolds, a series of inhibitors generally showing good inhibitory activity was obtained, in keeping with the SPROUTLeadOpt predictions. Furthermore, cocrystal structures of five of these SPROUT-designed inhibitors bound in the ubiquinone binding cavity of the human dihydroorotate dehydrogenase are also analyzed.
- Davies, Matthew,Heikkil?, Timo,McConkey, Glenn A.,Fishwick, Colin W. G.,Parsons, Mark R.,Johnson, A. Peter
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supporting information; experimental part
p. 2683 - 2693
(2010/01/16)
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- INHIBITORS OF PROTEIN KINASES
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The present invention is directed to compounds of formula (I)-(II) and pharmaceutically acceptable salts, esters, and prodrugs thereof which are inhibitors of syk and/or JAK kinase. The present invention is also directed to intermediates used in making such compounds, the preparation of such a compound, pharmaceutical compositions containing such a compound, methods of inhibition syk and/or JAK kinase activity, methods of inhibition the platelet aggregation, and methods to prevent or treat a number of conditions mediated at least in part by syk and/or JAK kinase activity, such as undesired thrombosis and Non Hodgkin's Lymphoma.
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Page/Page column 167-168
(2009/12/05)
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- AMPK MODULATORS
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The present invention relates to compounds and pharmaceutically acceptable salts, esters and prodrugs of Formula (I) or (II), which are useful as AMPK modulators effective in treating diabetes, obesity and cancer in a subject.
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Page/Page column 33
(2009/10/09)
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- Comparative reactivity of N′-(5-benzoyl/ethoxycarbonyl)thiazol-2-yl- N,N-dimethylformamidines with ketenes
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The comparative account of the reactivities of N′-[(5-benzoyl and ethoxycarbonyl)thiazol-2-yl]-N,N-dimethylformamidines (1a and 1b), tremendously influenced by the electronic nature of the substituents on C-5 of the thiazolic ring with various monosubstituted and conjugated ketenes is reported herein. The DA cycloadditions of the dienyl pyrimidinone 3h with both symmetrical as well as unsymmetrical dienophiles leading to the formation of various thiazolic pyrimidinone derivatives are also reported.
- Singh, Parvesh,Marwaha, Alka,Singh, Harmeet,Mahajan, Mohinder P.
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p. 11999 - 12005
(2007/10/03)
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- Enols of Amides Activated by the 2,2,2-Trichloroethoxycarbonyl Group
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Reaction of isocyanates XNCO (X = Ar, i-Pr, t-Bu) with CH 2(Y)CO2CH2CCl3 (Y = CO 2Me, CO2-CH2CCl3, CN) gave 15 amides XNHCOCH(Y)CO2CH2CCl3 (6) or enols of amides XNHC(OH)=C(Y)-CO2CH2CCl3 (5) systems. The amide/enol ratios in solution depend strongly on the substituent Y and the solvent and mildly on the substituent X. The percentage of enol for group Y increases according to Y = CN > CO2CH2CCl3 > CO2Me and decreases with the solvent according to CCl 4 > C6D6 > CDCl3 > THF-d8 > CD3CN > DMSO-d6. With the most acidic systems (Y = CN) amide/enol exchange is observed in moderately polar solvents and ionization to the conjugate base is observed in DMSO-d 6. The solid-state structure of the compound with Y = CN, X = i-Pr was found to be that of the enol. The reasons for the stability of the enols were discussed in terms of polar and resonance effects. Intramolecular hydrogen bonds result in a very low δ(OH) and contribute to the stability of the enols and are responsible for the higher percentage of the E-isomers when Y = CO2Me and the Z-isomers when Y = CN. The differences in δ(OH), δ(NH), Kenol, and E/Z enol ratios from the analogues with CF3 instead of CCl3 are discussed.
- Basheer, Ahmad,Rappoport, Zvi
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p. 1151 - 1160
(2007/10/03)
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- Synthesis and preparative resolution of the trans-cyclohexane analogues of phenylalanine
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Different approaches to the synthesis of enantiomerically pure (1R,2S)- and (1S,2R)-1-amino-2-phenylcyclohexanecarboxylic acids (trans-c6Phe) through a racemic pathway followed by semi-preparative HPLC of a racemic precursor have been studied. The complete diastereoselectivity of the Strecker reaction and the high efficiency of the subsequent transformations into the amino acid favour this method in comparison to the Diels-Alder route. The relative stereochemistry of the amino acid and its precursors has been unambiguously assigned. The preparation of the final enantiomerically pure amino acids and their corresponding N-Boc derivatives was carried out by HPLC resolution of one of the intermediates using a cellulose-derived chiral stationary phase. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Cativiela, Carlos,Lopez, Pilar,Lasa, Marta
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p. 3898 - 3908
(2007/10/03)
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- Synthesis and herbicidal activity of 2-cyano-3-substituted-pyridinemethylaminoacrylates
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Two series of 2-cyano-3-substituted-pyridinemethylaminoacrylates, namely 12 new (Z)-2-cyano-3-methylthio-3-substituted-pyridinemethaneaminoacrylates and 10 new (Z)-2-cyano-3-alkyl-3-substituted-pyridinemethaneaminoacrylates, were synthesized as herbicidal inhibitors of photosystem II (PSII) electron transport. All of these compounds were confirmed by 1H NMR, elemental, IR, and mass spectrum analyses. Their herbicidal activities were evaluated. Some compounds exhibited excellent herbicidal activities, even at a dose of 75 g/ha. A suitable substituent at the 2-position of the pyridine ring and the well-fit group at the 3-position of acrylate were essential for high herbicidal activity. 2-Cyanoacrylates containing a substituted pyridine ring provide higher herbicidal activities than parent compounds containing phenyl. These PSII inhibitor herbicides are safe to corn, which is a major crop in China.
- Wang, Qingmin,Sun, Huikai,Cao, Huanyan,Cheng, Muru,Huang, Runqiu
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p. 5030 - 5035
(2007/10/03)
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