cas 4760-34-3, N-Methylbenzene-1,2-diamine

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Regioselective Radical Arene Amination for the Concise Synthesis ofortho-Phenylenediamines
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.
p. 9355 - 9360
(2021/07/19)

N-substituted benzimidazole acrylonitriles as in vitro tubulin polymerization inhibitors: Synthesis, biological activity and computational analysis
We present the design, synthesis and biological activity of novel N-substituted benzimidazole based acrylonitriles as potential tubulin polymerization inhibitors. Their synthesis was achieved using classical linear organic and microwave assisted techniques, starting from aromatic aldehydes and N-substituted-2-cyanomethylbenzimidazoles. All newly prepared compounds were tested for their antiproliferative activity in vitro on eight human cancer cell lines and one reference non-cancerous assay. N,N-dimethylamino substituted acrylonitriles 30 and 41, bearing N-isobutyl and cyano substituents placed on the benzimidazole nuclei, showed strong and selective antiproliferative activity in the submicromolar range of inhibitory concentrations (IC50 0.2–0.6 μM), while being significantly less toxic than reference systems docetaxel and staurosporine, thus promoting them as lead compounds. Mechanism of action studies demonstrated that two most active compounds inhibited tubulin polymerization. Computational analysis confirmed the suitability of the employed benzimidazole-acrylonitrile skeleton for the binding within the colchicine binding site in tubulin, thus rationalizing the observed antitumor activities, and demonstrated that E-isomers are active substances. It also provided structural determinants affecting both the binding position and the matching affinities, identifying the attached NMe2 group as the most dominant in promoting the binding, which allows ligands to optimize favourable cation???π and hydrogen bonding interactions with Lys352.
Perin,Hok,Be?,Persoons,Vanstreels,Daelemans,Vianello,Hranjec
(2020/12/02)

2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling
Leishmaniasis is a major infectious disease with hundreds of thousands of new cases and over 20,000 deaths each year. The current drugs to treat this life-threatening infection have several drawbacks such as toxicity and long treatment regimens. A library of 1.8 million compounds, from which the hits reported here are publicly available, was screened against Leishmania infantum as part of an optimization program; a compound was found with a 2-aminobenzimidazole functionality presenting moderate potency, low metabolic stability and high lipophilicity. Several rounds of synthesis were performed to incorporate chemical groups capable of reducing lipophilicity and clearance, leading to the identification of compounds that are active against different parasite strains and have improved in vitro proper-ties. As a result of this optimization program, a group of compounds was further tested in anticipation of in vivo evaluation. In vivo tests were carried out with compounds 29 (L. infantum IC50: 4.1 μM) and 39 (L. infantum IC50: 0.5 μM) in an acute L. infantum VL mouse model, which showed problems of poor exposure and lack of efficacy, despite the good in vitro potency.
Ferreira, Rafael Augusto Alves,Junior, Celso de Oliveira Rezende,Martinez, Pablo David Grigol,Koovits, Paul John,Soares, Bruna Miranda,Ferreira, Leonardo L. G.,Michelan-Duarte, Simone,Chelucci, Rafael Consolin,Andricopulo, Adriano D.,Galuppo, Mariana K.,Uliana, Silvia R. B.,Matheeussen, An,Caljon, Guy,Maes, Louis,Campbell, Simon,Kratz, Jadel M.,Mowbray, Charles E.,Dias, Luiz Carlos
(2021/03/24)

Method for synthesizing heteroatom- substituted aromatic compound from styrene compound
The invention discloses a method for synthesizing a heteroatom-substituted aromatic compound from a styrene compound, which comprises the following steps of: mixing a styrene compound with a general formula (I) and a heteroatom-containing compound with a general formula (II), and reacting in the presence of an acid additive and an organic solvent to obtain a heteroatom-substituted compound with ageneral formula (III). According to the synthesis method disclosed by the invention, a large amount of styrene compounds are used as raw materials and react to generate aromatic amine or phenol compounds under the action of no metal catalysis; and compared with the traditional aromatic amine and phenol synthesis method, the method has the advantages of high yield, simple conditions, low waste discharge amount, no metal participation, simple reaction equipment, easiness in industrial production and the like.
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Paragraph 0177-0180

(2021/02/06)

Ru-Catalyzed Selective Catalytic Methylation and Methylenation Reaction Employing Methanol as the C1 Source
Methanol can be employed as a green and sustainable methylating agent to form C-C and C-N bonds via borrowing hydrogen (BH) methodology. Herein we explored the activity of the acridine-derived SNS-Ru pincer for the activation of methanol to apply it as a C1 building block in different reactions. Our catalytic system shows great success toward the β-C(sp3)-methylation reaction of 2-phenylethanols to provide good to excellent yields of the methylated products. We investigated the mechanistic details, kinetic progress, and temperature-dependent product distribution, which revealed the slow and steady generation of in situ formed aldehyde, is the key factor to get the higher yield of the β-methylated product. To establish the environmental benefit of this reaction, green chemistry metrics are calculated. Furthermore, dimerization of 2-naphthol via methylene linkage and formation of N-methylation of amine are also described in this study, which offers a wide range of substrate scope with a good to excellent yield.
Biswas, Nandita,Srimani, Dipankar
p. 10544 - 10554
(2021/07/31)

HMOX1 inducers
The present invention is related to compounds of structure (I) as heme oxygenase 1 (HMOX 1) inducers. The present invention is also related a method of controlling the activity or the amount, or both the activity and the amount, of heme-oxygenase 1 in a mammalian subject. The definitions of the variables are provided herein.
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Page/Page column 21; 159

(2020/09/18)

Benzimidazole derivatives as potent and isoform selective tumor-associated carbonic anhydrase IX/XII inhibitors
We describe the synthesis of a series of 2-arylbenzimidazole derivatives bearing sulfonamide functionality (4a–d, 7a–c and 10) as well as hydroxamic acid (15a–b), carboxylic acid (16a–b), carboxamide (17a–b) and boronic acid (22a–b and 26) functionalities, which act as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors. The newly synthesized benzimidazole derivatives were evaluated against 4 physiologically relevant CA isoforms (hCA I, II, IX, and XII), and especially the sulfonamide-containing benzimidazoles demonstrated intriguing inhibitory activity against tumor associated CA IX and XII with KI values in the range of 5.2–29.3 nM and 9.9–41.7 nM, respectively. Notably, compound 4c was the most potent and selective CA IX (KI = 6.6 nM) and XII (KI = 9.9 nM) inhibitor with a significant selectivity ratio over cytosolic CA I and II isoforms in the range of 3.4–25.2. In addition, compounds having hydroxamic acid (15a-b) or carboxylic acid (16a-b) functionalities resulted in greater selectivity ratios for CA IX/XII over CAI/II in the range of 4.1–121.5 although with KI values in lower micromolar potency (KIs = 0.36–0.85 μM for CA IX/XII).
?al??kan, Burcu,Banoglu, Erden,Gür Maz, Tu??e,Nocentini, Alessio,Supuran, Claudiu T.,Uslu, Azize Gizem
supporting information

(2020/01/08)

Discovery of a Highly Selective Sigma-2 Receptor Ligand, 1-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (CM398), with Drug-Like Properties and Antinociceptive Effects In Vivo
The sigma-2 receptor has been cloned and identified as Tmem97, which is a transmembrane protein involved in intracellular Ca2+ regulation and cholesterol homeostasis. Since its discovery, the sigma-2 receptor has been an extremely controversial target, and many efforts have been made to elucidate the functional role of this receptor during physiological and pathological conditions. Recently, this receptor has been proposed as a potential target to treat neuropathic pain due to the ability of sigma-2 receptor agonists to relieve mechanical hyperalgesia in mice model of chronic pain. In the present work, we developed a highly selective sigma-2 receptor ligand (sigma-1/sigma-2 selectivity ratio > 1000), 1-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H- benzo[d]imidazol-2(3H)-one (CM398), with an encouraging in vitro and in vivo pharmacological profile in rodents. In particular, radioligand binding studies demonstrated that CM398 had preferential affinity for sigma-2 receptor compared with sigma-1 receptor and at least four other neurotransmitter receptors sites, including the norepinephrine transporter. Following oral administration, CM398 showed rapid absorption and peak plasma concentration (Cmax) occurred within 10?min of dosing. Moreover, the compound showed adequate, absolute oral bioavailability of 29.0%. Finally, CM398 showed promising anti-inflammatory analgesic effects in the formalin model of inflammatory pain in mice. The results collected in this study provide more evidence that selective sigma-2 receptor ligands can be useful tools in the development of novel pain therapeutics and altogether, these data suggest that CM398 is a suitable lead candidate for further evaluation.
Avery, Bonnie A.,Chin, Frederick T.,Intagliata, Sebastiano,King, Tamara I.,Matsumoto, Rae R.,McCurdy, Christopher R.,McLaughlin, Jay P.,Mesangeau, Christophe,Seminerio, Michael,Sharma, Abhisheak,Wilson, Lisa L.
(2020/07/25)

Endogenous X-C=O species enable catalyst-free formylation prerequisite for CO2reductive upgrading
CO2, the main component of greenhouse gas, is currently developed as a promising surrogate of carbon feedstock. Among various conversion routes, CO2undergoing catalytic reduction can furnish hydrogen/energy carriers and value-added chemicals, while specific metal-containing catalysts or organocatalysts are often prerequisite for smooth proceeding of the involved reaction processes. In this work, both formic acid and N-containing benzoheterocyclic compounds (including various benzimidazoles, benzothiazole, and benzoxazole) along with silanols could be synthesized with high yields (>90%) from catalyst-free reductive upgrading of CO2under mild conditions (50 °C). The endogenous X-CO species, derived from the N-methyl-substituted amide-based solvent [Me2N-C(O)-R], especially PolarClean, and O-formyl group [O-C(O)-H] of in situ formed silyl formate, were found to play a prominent promotional role in the activation of the used hydrosilane for reductive CO2insertion, as demonstrated by density functional theory (DFT) calculations and isotopic labeling experiments. Moreover, reaction mechanisms and condition-based sensitivity assessment were also delineated.
Dai, Wenshuai,Li, Hu,Saravanamurugan, Shunmugavel,Wu, Hongguo,Yang, Song
p. 5822 - 5832
(2020/10/21)

Catalytic trifluoromethylation of iodoarenes by use of 2-trifluoromethylated benzimidazoline as trifluoromethylating reagent
The trifluoromethylation of iodoarenes was accomplished by use of a 2-trifluoromethylbenzimidazoline derivative as the trifluoromethylating reagent and a catalytic amount of Cu(I) in the presence of 2,2'-bipyridyl as the ligand. Through a mechanistic study, we found that the oxidative addition of the iodoarene to the Cu(I)–CF3 species is the rate-determining step.
Akiyama, Takahiko,Ishikawa, Taisuke,Kamiyama, Nanami,Uchikura, Tatsuhiro
supporting information
p. 2442 - 2447
(2020/11/07)

Total Syntheses of Pyocyanin, Lavanducyanin, and Marinocyanins A and B
Total syntheses of pyocyanin, lavanducyanin, and marinocyanins A and B have been accomplished. The N-substituted phenazin-1-one skeleton, a common framework of these natural products, was constructed through the oxidative condensation of pyrogallol with N-substituted benzene-1,2-diamine under an oxygen atmosphere in a single step. Regioselective bromination with N-bromosuccinimide at the C-2 position of N-alkylated phenazin-1-ones afforded brominated natural products.
Kohatsu, Haruki,Kamo, Shogo,Tomoshige, Shusuke,Kuramochi, Kouji
supporting information
p. 7311 - 7314
(2019/10/02)

Hydrogenation of nitroaromatics to anilines catalyzed by air-stable arene ruthenium (II)–NNN pincer complexes
A series of air-stable, phosphine-free arene ruthenium (II)–NNN pincer complexes (RuL, RuL1, RuL2 and RuL3) have been synthesized and characterized by spectroscopic and single-crystal X-ray analysis. Further, arene ruthenium (II)–NNN pincer complexes have been used as catalyst for hydrogenation of nitroaromatics into aniline in the presence of NaBH4 at room temperature. The catalytic process suggested highly chemo-selective nitroreduction with wide functional group tolerance.
Pitchaimani, Jayaraman,Gunasekaran, Nanjappan,Anthony, Savarimuthu Philip,Moon, Dohyun,Madhu, Vedichi
(2019/04/14)

Ligand-free trifluoromethylation of iodoarenes by use of 2-Aryl-2-trifluoromethylbenzimidazoline as new trifluoromethylating reagent
N-Methyl 2-aryl-2-trifluoromethylbenzimidazolines were synthesized and utilized in the trifluoromethylation reaction of iodoarenes in the presence of copper(I) salt and base. Iodoarenes bearing electron-donating and electron-withdrawing groups were tolerant to this reaction in the absence of a ligand and gave trifluorotoluene derivatives in good to high yields.
Miyagawa, Masamichi,Ishikawa, Taisuke,Shinkai, Kota,Akiyama, Takahiko
supporting information
p. 29 - 31
(2019/01/04)

Iridium complex and organic light-emitting device (OLED)
The invention discloses an iridium complex and an organic light-emitting device (OLED), and relates to the technical field of organic photoelectric materials. On the one hand, a guanidine group with acarbene-like structure is introduced into a metal complex molecule as an ancillary ligand, and a four-membered ring coordination structure is constructed, so that a series of green phosphorescence complex material systems with brand-new molecular structures and photoelectric properties are obtained. The iridium complex has more stable central positive trivalent ruthenium atoms, thus having betterchemical stability and thermal stability; furthermore, the iridium complex can reduce unnecessary vibration energy loss, so that the non-radiative transition of the molecules is reduced, and the luminous efficiency of the complex is accordingly increased. On the other hand, an alkyl structure is introduced into the structure, so that the solubility of the ruthenium complex is improved. A device is prepared by carrying out diffraction on the iridium complex, especially using the iridium complex as a doping material; the device shows the advantages of being low in driving voltage, high in luminous efficiency and better in color purity, and is superior to the existing common OLED devices.
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Paragraph 0070; 0071; 0074

(2018/12/02)

PYRIMIDINE OR PYRIDINE COMPOUNDS, PREPARATION METHOD THEREFOR AND PHARMACEUTICAL USES THEREOF
The present invention disclosed a class of pyrimidine or pyridine compounds, pharmaceutically acceptable salts, stereoisomers, prodrugs and solvates thereof, preparation method therefor and pharmaceutical compositions and pharmaceutical uses thereof. The compounds can inhibit the variants of EGFR (Epidermis Growth Factor Receptor) proteinases, and therefore can inhibit the growth of a variety of tumor cells effectively. The compounds can be used to prepare antitumor drugs, used for the treatment, combined therapy or prevention of various different cancers. The compounds can overcome the drug resistance induced by the existing first-generation EGFR inhibitors such as gefitinib, erlotinib and so on. Particularly, the compounds can be used to prepare drugs for treating or preventing diseases, disturbances, disorders or conditions mediated by epidermis growth factor receptor variants (such as L858R activated mutants, Exon19 deletion activated mutants and T790M resistant mutants).
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Paragraph 0571-0572

(2017/09/19)

Non-noble metal catalysts for hydrogenation: A facile method for preparing Co nanoparticles covered with thin layered carbon
Metallic cobalt nanoparticles with surface CoOx patches covered by thin layered carbon (named Co@C) have been directly synthesized by thermal decomposition of Co-EDTA complex. Raman spectra and HRTEM images suggest that discontinuities can be found in the disordered layered carbon. XPS shows that the CoOx patches in the Co@C nanoparticles can reduced to metallic Co by H2 under reaction conditions (7 bar at 120 °C), and H2-D2 exchange experiments show that the reduced metallic Co nanoparticles covered by carbon layers can dissociate H2. The Co@C nanoparticles show excellent activity and selectivity during chemoselective hydrogenation of nitroarenes for a wide scope of substrates under mild reaction conditions. Based on the results from DRIFTS adsorption experiments, we propose that metallic Co in the Co@C nanoparticles is the active phase. The role of the carbon layers is to protect the Co from overoxidation by air, leading to the chemoselective hydrogenation of nitroarenes.
Liu, Lichen,Concepción, Patricia,Corma, Avelino
p. 1 - 9
(2016/06/09)

Synthetic, structural, and computational investigations of N-alkyl benzo-2,1,3-selenadiazolium iodides and their supramolecular aggregates
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
p. 3285 - 3293
(2016/03/05)

Amino Azaxylylenes Photogenerated from o-Amido Imines: Photoassisted Access to Complex Spiro-Poly-Heterocycles
Upon irradiation, cyclic imines containing o-amido groups are shown to produce reactive intermediates, amino azaxylylenes, which undergo intramolecular cycloadditions to tethered unsaturated pendants to yield complex N,O-heterocycles having an additional spiro-connected nitrogen heterocyclic moiety. Modular assembly of the photoprecursors allows expeditious increase of the complexity of the target poly-heterocyclic scaffolds with a minimal number of experimentally simple reaction steps. The photocyclization and subsequent postphotochemical transformations are accompanied by an increase of Lovering's fsp3 factor, thus producing unprecedented three-dimensional molecular architectures, and offering extended sampling of chemical space. Rings in three dimensions: Cyclic imines containing an o-amido group undergo excited-state intramolecular proton transfer to generate amino azaxylylenes. The amino azaxylylenes undergo intramolecular cycloadditions to tethered unsaturated pendants to yield complex heterocyclic three-dimensional molecular architectures.
Mukhina, Olga A.,Kuznetsov, Dmitry M.,Cowger, Teresa M.,Kutateladze, Andrei G.
supporting information
p. 11516 - 11520
(2015/11/03)

Supercritical methanol as solvent and carbon source in the catalytic conversion of 1,2-diaminobenzenes and 2-nitroanilines to benzimidazoles
Benzimidazoles and N-methylbenzimidazoles were synthesized by simply heating 1,2-diaminobenzenes in supercritical methanol over copper-doped porous metal oxides. These catalysts were derived from synthetic hydrotalcites that only contain earth-abundant starting materials. The carbon equivalents needed for the construction of the benzimidazole core originated from the solvent itself, which is known to undergo reforming to hydrogen and carbon monoxide through the formation of a formaldehyde intermediate. A variety of 1,2-diaminobenzenes were converted to the corresponding mixtures of benzimidazoles and N-methylated analogues in good yields. Interestingly, the more challenging, but readily available 2-nitroanilines, which require an additional reduction step prior to cyclization, could also be successfully converted to benzimidazoles in high selectivity. Furthermore, various other alcohols were applied besides methanol, to obtain 2-alkyl- and 1,2-dialkylbenzimidazoles. Preliminary mechanistic insights into the origins of N-alkylation as well as the reactivity of the nitro derivatives are discussed.
Sun, Zhuohua,Bottari, Giovanni,Barta, Katalin
p. 5172 - 5181
(2015/12/08)

Methanol dehydrogenation by iridium N-heterocyclic carbene complexes
A series of homogeneous iridium bis(N-heterocyclic carbene) catalysts are active for three transformations involving dehydrogenative methanol activation: acceptorless dehydrogenation, transfer hydrogenation, and amine monoalkylation. The acceptorless dehydrogenation reaction requires base, yielding formate and carbonate, as well as 2-3 equivalents of H2. Of the few homogeneous systems known for this reaction, our catalysts tolerate air and employ simple ligands. Transfer hydrogenation of ketones and imines from methanol is also possible. Finally, N-monomethylation of anilines occurs through a borrowing hydrogen reaction. Notably, this reaction is highly selective for the monomethylated product.
Campos, Jesús,Sharninghausen, Liam S.,Manas, Michael G.,Crabtree, Robert H.
p. 5079 - 5084
(2015/06/16)

USE OF THERMALLY-TREATED SUPPORTED COBALT CATALYSTS COMPRISING A POLYCYCLIC AROMATIC STRUCTURE CONSISTING OF NITROGEN LIGANDS FOR HYROGENATING AROMATIC NITRO COMPOUNDS
The invention relates to the use of thermally-treated supported cobalt catalysts for hydrogenating aromatic nitro compounds, the cobalt catalysts having been prepared by in situ immobilization of a cobalt-amine complex on an inorganic porous support and subsequent pyrolysis, and, in the cobalt-amine complex used, cobalt being present bonded to an aromatic or heterocyclic nitrogen ligand L, the nitrogen ligand being selected so as to form a polyaromatic structure with the cobalt atom.
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Paragraph 0031; 0032

(2015/11/16)

Discovery of 2-iminobenzimidazoles as potent hepatitis C virus inhibitors with a novel mechanism of action
In this report we describe 2-iminobenzimidazole (IBI) analogs, identified during the course of a phenotypic high-throughput screening campaign, as novel hepatitis C virus (HCV) inhibitors. A series of IBI derivatives was synthesized and evaluated for their inhibitory activity against infectious HCV. Among the IBIs derivatives studied in this work, we identified promising compounds with high antiviral efficacy, high selectivity index and good microsomal stability. Noteworthy, the IBI series exhibited inhibitory activity on early and late steps of the viral cycle, but not in the HCV replicon system demonstrating a mechanism of action distinct from clinical-stage and approved anti-HCV drugs. Overall, our results suggest that IBIs are predestinated for further exploration as lead compounds for novel HCV interventions.
Windisch, Marc Peter,Jo, Suyeon,Kim, Hee-Young,Kim, Soo-Hyun,Kim, Keumhyun,Kong, Sunju,Jeong, Hyangsuk,Ahn, Sujin,No, Zaesung,Hwang, Jong Yeon
p. 35 - 42
(2014/04/17)

Synthesis and in vitro antifungal evaluation of benzoimidazolyl-piperazinyl-phenylmethanone derivatives
Benzimidazole and piperazines are the important pharmacophores in the structures of many antifungal compounds. Further, the phenylmethanone are also a unique class of compounds whose antifungal profile is not much exploited. So to exploit their antifungal potential we have selected these three combinations and framed the novel parent structure for our research work. In this study a novel series of benzimidazoles derivatives was synthesized by microwave irradiation and characterized by 1H NMR, 13C NMR, Infra Red (IR), and Mass Spectroscopy (MS), and by elemental analysis. The screening of compound for in vitro (turbidimetric method) antifungal activity against C.albicans revealed activity in many of the compounds as comparable to that of ketoconazole.
Kankate, Rani S.,Gide, Parag S.,Belsare, Deepak P.
p. 1855 - 1863
(2015/04/22)

Identification of novel HDAC inhibitors through cell based screening and their evaluation as potential anticancer agents
A series of benzimidazole based HDAC inhibitors have been rationally designed, synthesized and screened. The SAR of this new chemotype is described. The lead compound, 11e, showed strong activity in several cellular assays and demonstrated in vivo efficacy in mouse xenograft pancreatic cancer models.
Wang, Tong,Sepulveda, Mario,Gonzales, Paul,Gately, Stephen
p. 4790 - 4793
(2013/09/02)

Indole RSK inhibitors. Part 2: Optimization of cell potency and kinase selectivity
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.
scheme or table
p. 738 - 742
(2012/03/11)

Systematic evaluation of structure-activity relationships of the riminophenazine class and discovery of a C2 pyridylamino series for the treatment of multidrug-resistant tuberculosis
Clofazimine, a member of the riminophenazine class of drugs, is the cornerstone agent for the treatment of leprosy. This agent is currently being studied in clinical trials for the treatment of multidrug-resistant tuberculosis to address the urgent need for new drugs that can overcome existing and emerging drug resistance. However, the use of clofazimine in tuberculosis treatment is hampered by its high lipophilicity and skin pigmentation side effects. To identify a new generation of riminophenazines that is less lipophilic and skin staining, while maintaining efficacy, we have performed a systematic structure-activity relationship (SAR) investigation by synthesizing a variety of analogs of clofazimine and evaluating their anti-tuberculosis activity. The study reveals that the central tricyclic phenazine system and the pendant aromatic rings are important for anti-tuberculosis activity. However, the phenyl groups attached to the C2 and N5 position of clofazimine can be replaced by a pyridyl group to provide analogs with improved physicochemical properties and pharmacokinetic characteristics. Replacement of the phenyl group attached to the C2 position by a pyridyl group has led to a promising new series of compounds with improved physicochemical properties, improved anti-tuberculosis potency, and reduced pigmentation potential.
Liu, Binna,Liu, Kai,Lu, Yu,Zhang, Dongfeng,Yang, Tianming,Li, Xuan,Ma, Chen,Zheng, Meiqin,Wang, Bin,Zhang, Gang,Wang, Fei,Ma, Zhenkun,Li, Chun,Huang, Haihong,Yin, Dali
experimental part
p. 4545 - 4559
(2012/07/01)

Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity
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.
scheme or table
p. 3138 - 3141
(2010/09/03)

Metal organic frameworks as heterogeneous catalysts for the selective N-methylation of aromatic primary amines with dimethyl carbonate
Metal organic frameworks (MOFs) with aluminium, copper and iron as central metal atoms with 1,4-benzenedicarboxylic acid (aluminium) and 1,3,5-benzenetricarboxylic acid (copper and iron) as ligands are selective and active catalysts in promoting the polymethylation of aromatic amines with dimethyl carbonate (DMC). N-methylation prevails over carbamoylation even though they are competing parallel processes. The present N-methylation protocol using DMC enjoys advantages such as convenient reaction conditions, benign, reusable, cost-effective catalyst, avoids the use of additional solvent and uses a safe, green methylating agent that only produces CO2 and methanol as by-products.
Dhakshinamoorthy, Amarajothi,Alvaro, Mercedes,Garcia, Hermenegildo
experimental part
p. 19 - 25
(2010/08/20)

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
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.
experimental part
p. 5703 - 5711
(2010/02/28)

4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: Potent and selective p70S6 kinase inhibitors
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
scheme or table
p. 5191 - 5194
(2010/03/24)

Concise synthesis of telmisartan via decarboxylative cross-coupling
(Chemical Equation Presented) An efficient synthesis of the angiotensin II receptor antagonist telmisartan is presented involving a decarboxylative cross-coupling of isopropyl phthalate (1) with 2-(4-chlorophenyl)-1,3-dioxolane (2c) as the key step (85% yield). The benzimidazole moiety is constructed regioselectively via a reductive animation-condensation sequence, replacing the previously published route via alkylation of the preformed benzimidazole. The product is obtained in an overall yield of 35% in a convergent synthesis with the longest sequence consisting of eight steps.
Goossen, Lukas J.,Knauber, Thomas
supporting information; experimental part
p. 8631 - 8634
(2009/04/11)

Lead identification of 2-iminobenzimidazole antagonists of the chemokine receptor CXCR3
Modification of a 2-iminobenzimidazole series derived from an HTS hit resulted in compounds with improved in-vitro species selectivity. Incorporation of an 8-quinoline amide and conformational rigidification of an aliphatic tether furnished potent compounds suitable for further lead optimization.
Hayes, Martin E.,Breinlinger, Eric C.,Wallace, Grier A.,Grongsaard, Pintipa,Miao, Wenyan,McPherson, Michael J.,Stoffel, Robert H.,Green, David W.,Roth, Gregory P.
p. 2414 - 2419
(2008/09/20)

Discovery of small molecule benzimidazole antagonists of the chemokine receptor CXCR3
High-throughput screening identified a low molecular weight antagonist of CXCR3 displaying micromolar activity in a membrane filtration-binding assay. Systematic modification of the benzimidazole core and tethered acetophenone moiety established tractable SAR of analogs with improved physicochemical properties and sub-micromolar activity across both human and murine receptors.
Hayes, Martin E.,Wallace, Grier A.,Grongsaard, Pintipa,Bischoff, Agnieszka,George, Dawn M.,Miao, Wenyan,McPherson, Michael J.,Stoffel, Robert H.,Green, David W.,Roth, Gregory P.
p. 1573 - 1576
(2008/09/21)

HETEROCYCLYC SULFONAMIDES HAVING EDG-I ANTAGONISTIC ACTIVITY
The invention relates to chemical compounds of formula (I), (Ia) and (Ib) or pharmaceutically acceptable salts thereof, which possess Edg-1 antagonistic activity and are accordingly useful for their anti-cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an anti-cancer effect in a warm-blooded animal, such as man.
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Page/Page column 128-129

(2008/12/05)

An efficient and impurity-free process for telmisartan: An antihypertensive drug
Telmisartan (1), a substituted dibenzimidazole derivative, is an antihypertensive drug, essentially used to control blood pressure. An improved, cost-effective, and impurity-free process for telmisartan (1) suitable for large-scale production is described here by addressing various process development issues. The overall yield obtained from this newly developed process is around 50% (over five steps) compared to the literature reported process (21%, over eight steps).
Reddy, Kikkuru Srirami,Srinivasan, Neti,Reddy, Chinta Raveendra,Kolla, Naveenkumar,Anjaneyulu, Yerremilli,Venkatraman, Sundaram,Bhattacharya, Apurba,Mathad, Vijayavitthal T.
p. 81 - 85
(2012/12/26)

Highly selective zeolite-catalysed mono-N-alkylation of arylenediamines by dialkyl carbonates
Arylenediamines are mono-N-alkylated by dialkyl carbonates in the presence of NaY zeolite catalyst in a regioselective and nontoxic process.
Ebenezer, Warren J.,Hutchings, Michael G.,Jones, Ken,Lambert, David A.,Watt, Ian
p. 1641 - 1643
(2008/02/03)

METHOD FOR THE PRODUCTION OF MONOALKYLATED DIAMINES
The invention relates to a method for production of a compound of general formula (I) by reaction of a compound of general formula (II) with a compound of general formula (III) (RO)2CO, or a compound of formula (IV) in the presence of a zeolite of the NaY- Faujasite type, where Ar, X, R and n are as defined in claim 1.
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Page/Page column 4

(2008/06/13)

Benzimidazolones and indoles as non-thiol farnesyltransferase inhibitors based on tipifarnib scaffold: Synthesis and activity
A series of analogs of tipifarnib (1) has been synthesized as inhibitors of FTase by substituting the benzimidazolones and indoles for the 2-quinolone of tipifarnib. The novel benzimidazolones are potent and selective FTase inhibitors (FTIs) with IC50 values of the best compounds close to that of tipifarnib. The current series demonstrate good cellular activity as measured in their inhibiting the Ras processing in NIH-3T3 cells, with compounds 2c and 2f displaying EC50 values of 18 and 22 nM, respectively.
Li, Qun,Li, Tongmei,Woods, Keith W.,Gu, Wen-Zhen,Cohen, Jerry,Stoll, Vincent S.,Galicia, Tomas,Hutchins, Charles,Frost, David,Rosenberg, Saul H.,Sham, Hing L.
p. 2918 - 2922
(2007/10/03)

1, 3, 4-BENZOTRIAZEPIN-2-ONE SALTS AND THEIR USE AS CCK RECEPTOR LIGANDS
This invention relates to pharmaceutically acceptable salts of compounds of formula (I) wherein: W is N or N+-O-; R2 is an optionally substituted C1 to C18 hydrocarbyl group wherein up to three C atoms may optionally be replaced by N, O and/or S atoms. R3 is -(CR11R12)m-X-(CR13R14)p-R9; m is 0, 1, 2, 3 or 4; p is 0, 1 or 2; X is a bond, -CR15=CR16-, -C≡C-, C(O)NH, NHC(O), C(O)NMe, NMeC(O), C(O)O, NHC(O)NH, NHC(O)O, OC(O)NH, NH, O, CO, SO2, SO2NH, C(O)NHNH, R9 is H ; C1 to C6 alkyl ; or phenyl, naphthyl, pyridyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolinyl, isoindolinyl, indolyl, isoindolyl or 2-pyridonyl substituted with -L-Q. R4 is an optionally substituted C1 to C18 hydrocarbyl group wherein up to three C atoms may optionally be replaced by N, O and/or S atoms ; and Such salts are useful, for example, for the treatment of gastrin related disorders.
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Page 77

(2008/06/13)

Carbonylation of o-phenylenediamine and o-aminophenol with dimethyl carbonate using lead compounds as catalysts
Lead compounds are active catalysts for carbonylation and carbonylation/methylation of o-phenylenediamine and o-aminophenol with dimethyl carbonate (DMC). 2-Benzimidazolone was obtained in 84% yield by the reaction of o-phenylenediamine with DMC for 1 h at 443 K in the presence of Pb(NO3)2. In the presence of Pb(OAc)2, the reaction quantitatively gave 1,3-dimethyl-2-benzimidazolone, which was formed by methylation of the primary product, 2-benzimidazolone, at 473 K. The effects of reaction variables on the yields of 2-benzimidazolone and 1,3-dimethyl-2-benzimidazolone were examined. The reaction of o-aminophenol with DMC selectively gave a carbonylation product, 2-benzoxazolone, or a carbonylation/methylation product, 3-methyl-2-benzoxazolone, depending on the reaction conditions in the presence of Pb(OAc)2.
Fu, Yue,Baba, Toshihide,Ono, Yoshio
p. 91 - 97
(2007/10/03)

Synthesis and antiparasitic activity of 2-(Trifluoromethyl)benzimidazole derivatives
2-(Trifluoromethyl)benzimidazole derivatives substituted at the 1-, 5-, and 6-positions have been synthesized and in vitro tested against the protozoa Giardia lamblia, Entamoeba histolytica, and the helminth Trichinella spiralis. Results indicate that all the compounds tested are more active as antiprotozoal agents than Albendazole and Metronidazole. One compound (20) was as active as Albendazole against T. spiralis. These compounds were also tested for their effect on tubulin polymerization and none inhibited tubulin polymerization.
Navarrete-Vazquez, Gabriel,Cedillo, Roberto,Hernandez-Campos, Alicia,Yepez, Lilian,Hernandez-Luis, Francisco,Valdez, Juan,Morales, Raul,Cortes, Rafael,Hernandez, Manuel,Castillo, Rafael
p. 187 - 190
(2007/10/03)

Phosphoric acid salts of an aromatic diamine
The present invention relates to a phosphoric acid salt of N-methyl-o-phenylenediamine and processes for making the same. In preferred embodiments of the invention, the phosphoric acid salt of N-methyl-o-phenylenediamine has the general Formula I wherein n is a number between 0.5 and 1.0, between 0.7 and 0.8, or between 0.75 and 0.78. The process for making the phosphoric acid salt of N-methyl-o-phenylenediamine comprises (a) dissolving the N-methyl-o-phenylenediamine in a first solvent, and (b) reacting the dissolved N-methyl-o-phenylenediamine with crystalline phosphoric acid or phosphoric acid dissolved in a second solvent.
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(2008/06/13)

Linear free energy substitutent effect on flavin redox chemistry
A systematic study on the effect of various substituents at the 7- and/or 8-position on the redox properties of isoalloxazines (flavins) is reported. The redox properties of these flavin derivatives were studied by cyclic voltammetry in 100 mM, pH 7.4 HEPES and 200 mM, pH 10 borate buffers. The magnitude and direction of the effect was dependent on the nature and location of the substituent. The redox potentials of the substituted flavins were correlated with the Hammett σ value of the substituents.
Hasford, Justin J.,Rizzo, Carmelo J.
p. 2251 - 2255
(2007/10/03)

Diheteroarylmethanes. IV. Oxidations and Metal-promoted Coupling Reactions of Bis(benzoheteroaryl)methanes
Bis(2-benzothiazolyl)methane, 1, bis(benzoxazolyl)methane, 2, and bis(N-methyl-2-benzimidazolyl)methane, 3, undergo easy oxidation by common oxidizing agents (air, KMnO4, K2Cr2O7, CrO3, H2O2) and give rise to a variety of products showing different levels of oxidation.They range from hydroxylation of the bridge methylene, e.g. in 25, to formation of the corresponding ketone, e. g. in 19, to dimerization to ethane and/or ethene derivatives as 23-24 and 20-22, respectively.The output of the oxidations is strongly dependent upon the nature of the second heteroatom in the azole ring (sulfur, oxygen or nitrogen), the oxidant, and the reaction conditions.Also the treatment of compounds 1 and 2 with the acetates of poorly azaphilic transition-metal ions promotes the dimerization couplings to the ethane or ethene products instead of leading to the formation of neutral chelates MetL2.Hydroxylation at the bridge methine in derivetives of 1 substituted at this position with a functionalized benzylic residue may result particularly easy, being simply accomplished by exposure to air.Although no mechanistic studies have been carried out on these reactions, it appears likely that a carbanionic or an enaminic intermediate is responsible for the air- and metal-promoted oxidations and oxidative couplings.
Bradamante, Silvia,Facchetti, Antonio,Pagani, Giorgio A.
p. 329 - 338
(2007/10/03)

Glycine receptor antagonists and the use thereof
Methods of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, treating or preventing the adverse consequences of the hyperactivity of the excitatory amino acids, as well as treating anxiety, chronic pain, convulsions, inducing anesthesia and treating psychosis are disclosed by administering to an animal in need of such treatment a compound having high affinity for the glycine binding site, lacking PCP side effects and which crosses the blood brain barrier of the animal. Also disclosed are novel 1,4-dihydroquinoxaline-2,3-diones, and pharmaceutical compositions thereof. Also disclosed are highly soluble ammonium salts of 1,4-dihydroquinoxaline-2,3-diones.
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(2008/06/13)

Synthesis of Some Novel 1,3-Dihydro-2H-benzamidazol-2-ylidenes
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Mack, Robert A.,Georgiev, Vassil St.,Wu, Edwin S. C.,Matz, James R.
p. 6158 - 6162
(2007/10/02)

PERI-NAPHTHYLENEDIAMINES XI. 1,8- DIAMINONAPHTHALENE ANION - AN EFFECTIVE NUCLEOPHILE FOR ELIMINATION OF THE μ-CH GROUP IN 1-SUBSTITUTED PERIMIDINES. A CONVENIENT METHOD FOR THE SYNTHESIS OF MONO-N-SUBSTITUTED 1,8-DIAMINONAPHTHALENES
The 1,8-diaminonaphthalene N-anion, generated by the action of sodium hydride, sodium amide, or metallic sodium on the diamine, is a strong nucleophile capable of removing the μ-CH group from the heterocycle of 1-R-perimidines.The reaction is of synthetic importance since it makes it possible to obtain good yields of extremely difficultly obtainable mono-N-substituted 1,8-diaminonaphthalenes.
Konstantinchenko, A. A.,Pozharskii, A. F.
p. 1191 - 1194
(2007/10/02)

Synthesis of Bi- and Tri-cyclic Tetrazepinones
Diazotization of N,N'-dialkyl-N-(o-aminophenyl) ureas 7, 13 and 17 gave 3,5-dimethyl-3H-1,2,3,5-benzotetrazepin-4(5H)-one 8, 3-methyl-6,7-dihydro-1,2,3,5-tetrazepinoquinolin-4(3H)-one 14 and 3-methyl-6,7-dihydrooxazino-1,2,3,5-benzotetrazepin-4-one 19.The structures of these bi- and tri-cyclic systems were confirmed by 1H, 13C and 15N NMR data.X-Ray diffraction of compound 14 shows that the tetrazepinone ring is nonplanar.
Bertrand, J. Jean-Claude,Just, George
p. 2525 - 2529
(2007/10/02)

Photochemical Dehydrogenation, Ring Contraction, and Ring Expansion of Hydrogenated Derivatives of Benzoxazino-benzoxazine, Quinoxalino-quinoxaline, and Bibenzothiazole
The photochemical properties of the title compounds have been investigated and compared.The benzoxazino-benzoxazine derivatives 1 are photochemically converted into hydrogenated oxazolo derivatives.In some cases this ring contraction is accompanied by a dehydrogenation reaction whereby the heterocyclic ring system becomes aromatic.Hydrogenated quinoxalino-quinoxalines also undergo a photodehydrogenation reaction and become aromatic.However, a ring contraction yielding the the imidazolyl system does not take place.The only investigated sulfur-containing analog has different properties.The stable form is the bibenzothiazole 23 which contains a five-membered heterocyclic ring system.Photochemically 23 rearranges under ring expansion to give the benzothiazino-benzothiazine 24.
Tauer, Erich,Grellmann, Karl-Heinz
p. 1149 - 1154
(2007/10/02)

A NEW ROUTE TO N-ALKYL-o-PHENYLENEDIAMINES UTILISING N-ALKYL-2,1,3-BENZOTHIADIAZOLIUM SALTS AND THEIR SELENIUM ANALOGUES
The alkyl quaternary salts of 2,1,3-benzothiadiazole and 2,1,3-benzoselenadiazole undergo facile ring-opening to produce the corresponding N-alkyl-o-phenylenediamines.
Ralph, J. T.
p. 1381 - 1388
(2007/10/02)