- Regioselective Radical Arene Amination for the Concise Synthesis ofortho-Phenylenediamines
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The formation of arene C-N bonds directly from C-H bonds is of great importance and there has been rapid recent development of methods for achieving this through radical mechanisms, often involving reactiveN-centered radicals. A major challenge associated with these advances is that of regiocontrol, with mixtures of regioisomeric products obtained in most protocols, limiting broader utility. We have designed a system that utilizes attractive noncovalent interactions between an anionic substrate and an incoming radical cation in order to guide the latter to the areneorthoposition. The anionic substrate takes the form of a sulfamate-protected aniline and telescoped cleavage of the sulfamate group after amination leads directly toortho-phenylenediamines, key building blocks for a range of medicinally relevant diazoles. Our method can deliver both free amines and monoalkyl amines allowing access to unsymmetrical, selectively monoalkylated benzimidazoles and benzotriazoles. As well as providing concise access to valuableortho-phenylenediamines, this work demonstrates the potential for utilizing noncovalent interactions to control positional selectivity in radical reactions.
- Gillespie, James E.,Morrill, Charlotte,Phipps, Robert J.
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supporting information
p. 9355 - 9360
(2021/07/19)
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- Biomimetic alloxan-catalyzed intramolecular redox reaction with O2: One-pot atom-economic synthesis of sulfinyl-functionalized benzimidazoles
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Given the necessity of sacrificial reductants in various biomimetic aerobic oxygenations, alloxan-catalyzed aerobic redox system for one-pot atom-economic synthesis of sulfinyl-functionalized benzimidazoles was developed by ingeniously binding both the substrate sulfide and sacrificial reductant. This mild and transition-metal-free protocol undergoes two oxidations without additional sacrificial reagents, except for the environmentally benign molecular oxygen.
- Zhang, Shiqi,Yi, Dong,Li, Guangxun,Li, Ling,Zhao, Gang,Tang, Zhuo
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- TREX1 INHIBITORS AND USES THEREOF
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Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds for inhibiting three prime repair exonuclease 1 ("TREX1").
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- Enantioselective Epoxidation of Electron-Deficient Alkenes Catalyzed by Manganese Complexes with Chiral N4 Ligands Derived from Rigid Chiral Diamines
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A series of tetradentate sp2N/sp3N hybrid chiral N4 ligands derived from rigid chiral diamines were synthesized, which enabled the first manganese-catalyzed enantioselective epoxidation of electron-deficient alkenes with hydrogen peroxide (H2O2) as an oxidant. The reaction furnishes enantiomerically pure epoxy amides, epoxy ketones as well as epoxy esters in good yields and excellent enantioselectivities (up to 99.9% ee) with lower catalyst loading. Preliminary studies on structure–activity relationship demonstrated that maintaining comparatively lower electron-donating ability of the sp3N and relatively higher electron-donating ability of sp2N of the N4 ligands is beneficial to getting higher activity and selectivity, thus providing us a new view to understand epoxidation with H2O2. (Figure presented.).
- Chen, Xiangning,Gao, Bao,Su, Yijin,Huang, Hanmin
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supporting information
p. 2535 - 2541
(2017/08/16)
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- Rapid construction of imidazopyridines from ortho-haloaminopyridines
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A practical strategy for the preparation of imidazopyridine derivatives from ortho-haloaminopyridines utilizing a two-step C-N coupling/cyclization reaction sequence has been developed. This procedure provides rapid and efficient access to many medicinally interesting imidazopyridine compounds and related imidazopyrazine/purine heterocycles.
- Li, Chaomin,Chen, Lily,Steinhuebel, Dietrich,Goodman, Andrew
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supporting information
p. 2708 - 2712
(2016/06/09)
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- Synthetic, structural, and computational investigations of N-alkyl benzo-2,1,3-selenadiazolium iodides and their supramolecular aggregates
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Despite their versatility, the application of telluradiazoles as supramolecular building blocks is considerably constrained by their sensitivity to moisture. Albeit more robust, their selenium analogues form weaker supramolecular interactions. These, however, are enhanced when one nitrogen atom is bonded to an alkyl group. Here we investigate general methods for the synthesis of such derivatives. Methyl, iso-propyl and tert-butyl benzo-2,1,3-selenadiazolium cations were prepared by direct alkylation or cyclo-condensation of the alkyl-phenylenediamine with selenous acid. While the former reaction only proceeds with the primary and tertiary alkyl iodides, the latter is very efficient. Difficulties reported in earlier literature are attributable to the formation of adducts of benzoselenadiazole with its alkylated cations and side reactions initiated by aerobic oxidation of iodide. However, the cations themselves are resilient to oxidation and stable in acidic to neutral aqueous medium. X-ray crystallography was used in the identification and characterization of the following compounds: [C6H4N2(R)Se]+X-, (R = CH(CH3)2, C(CH3)3; X = I-, I3-], [C6H4N2(CH3)Se]+I-, and [C6H4N2Se][C6H4N2(CH3)Se]2I2. Formation of Se?N secondary bonding interactions (chalcogen bonds) was only observed in the last structure as anion binding to selenium is a strong competitor. The relative strengths of those forces and the structural preferences they enforce were assessed with DFT-D3 calculations supplemented by AIM analysis of the electron density.
- Lee, Lucia M.,Corless, Victoria B.,Tran, Michael,Jenkins, Hilary,Britten, James F.,Vargas-Baca, Ignacio
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p. 3285 - 3293
(2016/03/05)
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- Blue phosphorescent nitrile containing C^C* cyclometalated NHC platinum(ii) complexes
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Since C^C* cyclometalated Pt(ii) complexes with N-heterocyclic carbene (NHC) ligands have been identified as potential emitter materials in organic light-emitting devices (OLEDs), very promising results regarding quantum yields, colour and stability have
- Tronnier, Alexander,Metz, Stefan,Wagenblast, Gerhard,Muenster, Ingo,Strassner, Thomas
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p. 3297 - 3305
(2014/03/21)
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- Synthetic modification of acyclic bent allenes (carbodicarbenes) and further studies on their structural implications and reactivities
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The paper describes the synthetic development of Bertrand-type acyclic carbodicarbene scaffolds derived from an unsymmetrical bis(benzimidazol-2-yl) methane bearing two sterically demanding pendant arms, isopropyl (6a) or cyclohexyl (6b). X-ray crystallographic analysis shows that the impact of these pendant arms on the overall structural parameters of carbodicarbenes is minimal. The chemical reactivity of the carbodicarbenes was evaluated with iodomethane to afford compound 7, illustrating its nucleophilic properties. Finally, experiments were also undertaken to investigate the coordination ability of carbodicarbene toward the formation of rhodium carbonyl (10) and palladium allyl complexes (11). The crystal structures of the metal complexes have been determined, revealing that their metal-carbene distances are elongated only slightly, this fact was rationalized on the basis of geometrical steric considerations with regard to the ligand.
- Chen, Wen-Ching,Hsu, Yu-Chen,Lee, Ching-Yu,Yap, Glenn P. A.,Ong, Tiow-Gan
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p. 2435 - 2442
(2013/06/27)
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- Indole RSK inhibitors. Part 2: Optimization of cell potency and kinase selectivity
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A series of inhibitors for the 90 kDa ribosomal S6 kinase (RSK) based on an 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide scaffold were optimized for cellular potency and kinase selectivity. This led to the identification of compound 24, BIX 02565, an attractive candidate for use in vitro and in vivo to explore the role of RSK as a target for the treatment heart failure.
- Kirrane, Thomas M.,Boyer, Stephen J.,Burke, Jennifer,Guo, Xin,Snow, Roger J.,Soleymanzadeh, Lida,Swinamer, Alan,Zhang, Yunlong,Madwed, Jeffery B.,Kashem, Mohammed,Kugler, Stanley,O'Neill, Margaret M.
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p. 738 - 742
(2012/03/11)
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- HETEROCYCLIC COMPOUNDS CONTAINING A PYRROLOPYRIDINE OR BENZIMIDAZOLE CORE
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The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5 and n are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
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- Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity
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A series of N-hydroxy-3-[3-(1-substituted-1H-benzoimidazol-2-yl)-phenyl]-acrylamides (5a-5ab) and N-hydroxy-3-[3-(1,4,5-trisubstituted-1H-imidazol-2-yl)-phenyl]-acrylamides (12a-s) were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases. Multiple compounds bearing an N1-piperidine demonstrate EC50s of 20-100 nM in human A549, HL60, and PC3 cells, in vitro and in vivo hyperacetylation of histones H3 and H4, and induction of p21waf. Compound 5x displays efficacy in human tumor xenograft models.
- Bressi, Jerome C.,Jong, Ron de,Wu, Yiqin,Jennings, Andy J.,Brown, Jason W.,O'Connell, Shawn,Tari, Leslie W.,Skene, Robert J.,Vu, Phong,Navre, Marc,Cao, Xiaodong,Gangloff, Anthony R.
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scheme or table
p. 3138 - 3141
(2010/09/03)
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- BENZAMIDE DERIVATIVES
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Disclosed are benzamide derivatives useful in slowing the expansion of cancer cells.
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Page/Page column 26
(2011/01/12)
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- Bicyclic Benzimidazole Compounds and Their Use as Metabotropic Glutamate Receptor Potentiators
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Compounds of Formula I: wherein A, B, D, L, R1, R2, R3, R4, m, and n are as defined for Formula I in the description. The invention also relates to processes for the preparation of the compounds and to new intermediates employed in the preparation, pharmaceutical compositions containing the compounds, and to the use of the compounds in therapy.
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Page/Page column 56
(2009/08/14)
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- 1- Or 3-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2- ones: Potent, selective, and orally efficacious norepinephrine reuptake inhibitors
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Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC 50 values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg.
- Zhang, Puwen,Terefenko, Eugene A.,Bray, Jenifer,Deecher, Darlene,Fensome, Andrew,Harrison, Jim,Kim, Callain,Koury, Elizabeth,Mark, Lilly,McComas, Casey C.,Mugford, Cheryl A.,Trybulski, Eugene J.,Vu, An T.,Whiteside, Garth T.,Mahaney, Paige E.
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experimental part
p. 5703 - 5711
(2010/02/28)
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- 4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: Potent and selective p70S6 kinase inhibitors
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We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (Ki 100-fold selectivity against PKA, ROCK and GSK3.
- Bandarage, Upul,Hare, Brian,Parsons, Jonathan,Pham, Ly,Marhefka, Craig,Bemis, Guy,Tang, Qing,Moody, Cameron Stuver,Rodems, Steve,Shah, Sundeep,Adams, Chris,Bravo, Jose,Charonnet, Emmanuelle,Savic, Vladimir,Come, Jon H.,Green, Jeremy
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scheme or table
p. 5191 - 5194
(2010/03/24)
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- A mild and expedient one-pot synthesis of substituted benzimidazoles in water using a phase-transfer catalyst
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1-Alkyl/phenyl-2-arylbenzimidazoles have been synthesized in very good to excellent yields by a one-pot condensation of N-alkyl/phenyl-o-phenylenediamines with aryl aldehydes in water at room temperature using cetylpyridinium bromide as a cheap and eco-friendly catalyst.
- Chakrabarty, Manas,Karmakar, Sulakshana,Mukherjee, Ratna,Arima, Shiho,Harigaya, Yoshihiro
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body text
p. 375 - 380
(2010/05/01)
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- Benzothiadiazolylphenylalkylamine derivatives and methods of their use
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The present invention is directed to benzothiadiazolylphenylalkylamine derivatives of formula I: or a pharmaceutically acceptable salt thereof, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditi
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Page/Page column 19
(2008/06/13)
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- CARBAMATE COMPOUNDS AS 5-HT4 RECEPTOR AGONISTS
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The invention provides novel benzoimidazolone-carboxamide-derived carbamate 5-HT4 receptor agonist compounds of formula (I): wherein R1, R2, R3, R4, a, and b are defined in the disclosure. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
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Page/Page column 15
(2008/06/13)
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- THIENOPYRIMIDINES FOR PHARMACEUTICAL COMPOSITIONS
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The present invention relates to novel pharmaceutical compositions of general formula (I) comprising thienopyrimidine compounds. Moreover, the present invention relates to the use of the thienopyrimidine compounds of the invention for the production of pharmaceutical compositions for the prophylaxis and/or treatment of diseases which can be influenced by the inhibition of the kinase activity of Mnk1 and/or Mnk2 (Mnk2a or Mnk2b) and/or variants thereof.
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- USE OF TRANSITION METAL CARBENE COMPLEXES IN ORGANIC LIGHT-EMITTING DIODES (OLEDS)
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The invention relates to the use of transition metal carbene complexes in organic light-emitting diodes (OLEDS), to a light-emitting layer, a blocking layer for electrons or excitrons or a blocking layer for holes containing these transition metal carbene
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Page/Page column 73
(2008/06/13)
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- Benzoimidazolone-carboxamide compounds as 5-HT4 receptors agonists
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The invention provides novel benzoimidazolone-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
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Page/Page column 19
(2010/11/25)
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- Synthesis and evaluation of 3-anilino-quinoxalinones as glycogen phosphorylase inhibitors
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A series of 3-anilino-quinoxalinones has been identified as a new class of glycogen phosphorylase inhibitors. The lead compound 1 was identified through high throughput screening as well as through pharmacophore-based electronic screening. Modifications were made to the scaffold of 1 to produce novel analogues, some of which are 25 times more potent than the lead compound.
- Dudash Jr., Joseph,Zhang, Yongzheng,Moore, John B.,Look, Richard,Liang, Yin,Beavers, Mary Pat,Conway, Bruce R.,Rybczynski, Philip J.,Demarest, Keith T.
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p. 4790 - 4793
(2007/10/03)
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- Synthesis and resolution of 2-(2-diphenylphosphinyl-naphthalen-1-yl)-1-isopropyl-1H-benzoimidazole; a new atropisomeric P,N-chelating ligand for asymmetric catalysis
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A multistep synthesis resulting in a good yield of the title compound 13 (BIMNAP) has been developed based on N,N-acetal-formation and oxidation with MnO2. The product 11 is converted into the corresponding trifluoromethane sulfonate 12 by trea
- Figge, Axel,Altenbach, Hans J.,Brauer, David J.,Tielmann, Patrick
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p. 137 - 144
(2007/10/03)
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- 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxamides with selective affinity for the 5-HT4 receptor: Synthesis and structure-affinity and structure-activity relationships of a new series of partial agonist and antagonist derivatives
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A series of 2,3-dihydro-2-oxo-1H-benzimidazole-l-carboxamide derivatives bearing a piperazine moiety was synthesized. Their in vitro 5-HT4, 5-HT3, and D2 receptors affinities were evaluated by radioligand binding assay. For selected compounds functional studies at the 5-HT4 receptor were made by using precontracted (by carbachol) preparations of rat esophageal tunica muscularis mucosae (TMM). The influence of the 3-substituent of the benzimidazole ring, the 4-substituent of the piperazine moiety, and the alkylene spacer was studied. Compounds with an ethyl or a cyclopropyl substituent in the 3-position of the benzimidazole ring showed moderate to high affinity (K(i) = 6.7-75.4 nM) for the 5-HT4 receptor with selectivity over 5-HT3 and D2 receptors and moderate antagonist activity (pK(b) = 6.19- 7.73). Compounds with an isopropyl substituent in the 3-benzimidazole position exhibited moderate and selective 5-HT4 affinity (K(i) ≥ 38.9 nM) and a partial agonist activity (5a, i.a. = 0.94) higher than that of the reference compound BIMU 8 (i.a. = 0.70). This reversal of the pharmacological activity due only to a small structural difference might confirm the existence of two binding sites on the 5-HT4 receptor. In the alkylene spacer, a two-methylene chain is favorable to optimize the affinity and the antagonist or the partial agonist activity. In the ethyl and cyclopropyl series, 5-HT4 antagonist activity seems to be unrelated to the size of the 4-substituent of the piperazine moiety, whereas a methyl group is optimal for high partial agonist activity in the isopropyl series; however, the presence of a butyl substituent is a favorable pattern for 5-HT4 antagonism and even causes a reversal of the pharmacological profile in the isopropyl series (5h, pK(b) = 7.94). N-Butyl quaternization of 5a led to an improvement in affinity for the 5-HT4 receptor and maintained the high partial agonist activity (5r, K(i) = 66.3 nM, i.a. = 0.93).
- Tapia, Inés,Alonso-Cires, Luisa,López-Tudanca, Pedro Luis,Mosquera, Ramón,Labeaga, Luis,Innerárity, Ana,Orjales, Aurelio
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p. 2870 - 2880
(2007/10/03)
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- 3-Phenyl-substituted imidazo[1,5-a]quinoxalin-4-ones and imidazo[1,5- a]quinoxaline ureas that have high affinity at the GABA(A)/benzodiazepine receptor complex
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A series of imidazo[1,5-a]quinoxalin-4-ones and imidazo[1,5- a]quinoxaline ureas containing substituted phenyl groups at the 3-position was developed. Compounds within the imidazo-[1,5-a]quinoxaline urea series had high affinity for the GABA(A)/benzodiaze
- Jacobsen, E. Jon,Stelzer, Lindsay S.,Belonga, Kenneth L.,Carter, Donald B.,Im, Wha Bin,Sethy, Vimala H.,Tang, Andrew H.,Von Voigtlander, Philip F.,Petke, James D.
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p. 3820 - 3836
(2007/10/03)
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- BORANE-TETRAHYDROFURAN AS A USEFUL REAGENT IN THE N-MONOALKYLATION OF AMINES AND AMINOALCOHOLS BY CARBONYL COMPOUNDS.
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A new procedure for the high-yield N-monoalkylation of primary aromatic and aliphatic amines is described.
- Morales, Hilda R.,Perez-Juarez, Martin,Cuellar, Laura,Mendoza, Lourdes,Fernandez, Hector,Contreras, Rosalinda
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p. 1213 - 1220
(2007/10/02)
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- Pyrimidobenzodiazepinones, their use and medicaments containing them
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11-Acyl-2-phenyl- and 11-acyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-ones, their acid-addition salts and their N-oxides provide protective action for the stomach and intestines of warm-blooded animals and inhibit the formation of gastric and intestinal ulcers.
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- Competitive Cyclisations of Singlet and Triplet Nitrenes. Part 9. 2-(2-Nitrophenyl)-benzothiazoles and -benzimidazoles
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2-(2-Nitrophenyl)benzothiazole, produced by deoxygenation of the corresponding nitro-compound or by thermolysis or photolysis of the related azide, gives indazolobenzothiazole by attack on the benzothiazole nitrogen.Similar attack of the nitrene in 2-(2-nitrophenyl)benzimidazoles gives benzimidazoindazoles in good yield.However, with an appropriate 1-substituent in the benzimidazole (e.g.Me or CHMe2) the nitrene in its triplet state (generated by acetophenone-sensitised photolysis or by thermolysis of the azide bearing a 4-dimethylamino-group) preferentially attacks this substituent giving benzimidazoquinazolines.
- Hawkins, David,Lindley, John M.,McRobbie, Ian M.,Meth-Cohn, Otto
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p. 2387 - 2391
(2007/10/02)
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