- INDOLE DERIVATIVES AND USES THEREOF FOR TREATING A CANCER
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The present invention relates to indole derivatives of formula (I') as CK2 inhibitor and pharmaceutical compositions comprising the same. The present invention further relates to the use of such compounds of formula (I) for use for preventing and/or treating a cancer.
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Page/Page column 72; 82; 88; 151-153
(2022/02/06)
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- Scaffold Hopping of Natural Product Evodiamine: Discovery of a Novel Antitumor Scaffold with Excellent Potency against Colon Cancer
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Inspired by the natural product evodiamine, a novel antitumor indolopyrazinoquinazolinone scaffold was designed by scaffold hopping. Structure-activity relationship studies led to the discovery of compound 15j, which shows low nanomolar inhibitory activity against the HCT116 cell line. Further antitumor mechanism studies indicated that compound 15j acted by the dual inhibition of topoisomerase 1 and tubulin and induced apoptosis with G2 cell-cycle arrest. The quaternary ammonium salt of compound 15j (compound 15js) exhibited excellent in vivo antitumor activity (TGI = 66.6%) in the HCT116 xenograft model with low toxicity. Indolopyrazinoquinazolinone derivatives represent promising multitargeting antitumor leads for the development of novel antitumor agents.
- Wang, Lei,Fang, Kun,Cheng, Junfei,Li, Yu,Huang, Yahui,Chen, Shuqiang,Dong, Guoqiang,Wu, Shanchao,Sheng, Chunquan
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p. 696 - 713
(2020/02/04)
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- Synthesis method for preparing 2-substituted indole derivative
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The invention relates to a synthesis method for preparing a 2-substituted indole derivative. The method includes the following steps: mixing aromatic amine compounds (I), ketone compounds (II) and a drying agent in an organic solvent; adding a palladium catalyst; and reacting in an aerobic weak acid environment to prepare the indole compounds (III). (I), (II) and (III) are as shown in the specification, wherein R1 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted phenyl, pyridyl and heterocyclic aryl; (I) can be pyridylamine, pyrimidylamine, pyridazinam or pyrazinamide which may further be substituted or unsubstituted; and the substituents are selected fromone or more C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, hydroxyl, amino; and R2 is selected from C1-C6 alkyl, formate groups or C1-C6 alkylamide groups.
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Paragraph 0183-0186
(2019/05/28)
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- ANTIBACTERIAL COMPOUNDS
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The present application provides compounds of formula: Methods of using these compounds for killing bacterial growth and treating bacterial infections are also provided.
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Page/Page column 86-89; 100
(2019/11/04)
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- Carboxylic Acid-Promoted Single-Step Indole Construction from Simple Anilines and Ketones via Aerobic Cross-Dehydrogenative Coupling
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The cross-dehydrogenative coupling (CDC) reaction is an efficient strategy for indole synthesis. However, most CDC methods require special substrates, and the presence of inherent groups limits the versatility for further transformation. A carboxylic acid-promoted aerobic catalytic system is developed herein for a single-step synthesis of indoles from simple anilines and ketones. This versatile system is featured by the broad substrate scope and the use of ambient oxygen as an oxidant and is convenient and economical for both laboratory and industry applications. The existence of the labile hydrogen at C-3 and the highly transformable carbonyl at C-2 makes the indoles versatile building blocks for organic synthesis in different contexts. Computational studies based on the density functional theory (DFT) suggest that the rate-determining step is carboxylic acid-assisted condensation of the substrates, rather than the functionalization of aryl C-H. Accordingly, a pathway via imine intermediates is deemed to be the preferred mechanism. In contrast to the general deduction, the in situ formed imine, instead of its enamine isomer, is believed to be involved in the first ligand exchange and later carbopalladation of the α-Me, which shed new light on this indolization mechanism.
- Ren, Long,Nan, Guanglei,Wang, Yongcheng,Xiao, Zhiyan
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p. 14472 - 14488
(2018/11/23)
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- NOVEL COMPOUND, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention relates to a novel compound controlling the phosphorylation of PPARandgamma; by CDK5, a process for the preparation thereof, and a pharmaceutical composition comprising the same. The novel compound of the present invention combines t
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Paragraph 0112; 0117-0119
(2017/09/26)
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- Cu nanoparticles immobilized on montmorillonite by biquaternary ammonium salts: a highly active and stable heterogeneous catalyst for cascade sequence to indole-2-carboxylic esters
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Copper nanoparticles immobilized on montmorillonite (MMT) by biquaternary ammonium salts (N1,N6-dibenzyl-N1,N1,N6,N6-tetramethylheptane-1,6-diaminium bromide, Q) were prepared by cation-exchange and impregnation-reduction and designated Cu-Q-MMT. The material was extensively characterized by various characterization techniques such as FTIR, XRD, XPS, SEM, TEM, and N2 adsorption-desorption. The Cu-Q-MMT could be used as a highly active heterogeneous catalyst for cascade sequence to indole-2-carboxylic esters from ortho-bromobenzaldehydes with ethyl acetamidoacetate. Even for inactive chlorobenzaldehydes, a good yield could be obtained. In addition, the catalyst can be reused six times without any significant loss of activity. The high activity and stability of the Cu-Q-MMT catalyst is mainly attributed to the excellent synergistic effects of biquaternary ammonium salts, Cu nanoparticles and the nanospace structure of MMT.
- Lang, Wencheng,Yang, Qin,Song, Xueping,Yin, Mengyun,Zhou, Limei
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p. 13754 - 13759
(2017/03/11)
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- Synthesis of Indole-2-carboxylate Derivatives via Palladium-Catalyzed Aerobic Amination of Aryl C-H Bonds
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A direct oxidative C-H amination affording 1-acetyl indolecarboxylates starting from 2-acetamido-3-arylacrylates has been achieved. Indole-2-carboxylates can be targeted with a straightforward deacetylation of the initial reaction products. The C-H amination reaction is carried out using a catalytic Pd(II) source with oxygen as the terminal oxidant. The scope and application of this chemistry is demonstrated with good to high yields for numerous electron-rich and electron-poor substrates. Further reaction of selected products via Suzuki arylation and deacetylation provides access to highly functionalized indole structures.
- Clagg, Kyle,Hou, Haiyun,Weinstein, Adam B.,Russell, David,Stahl, Shannon S.,Koenig, Stefan G.
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p. 3586 - 3589
(2016/08/16)
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- Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators
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Existing CB1 negative allosteric modulators (NAMs) fall into a limited range of structural classes. In spite of the theoretical potential of CB1 NAMs, published in vivo studies have generally not been able to demonstrate the expected therapeutically-relevant CB1-mediated effects. Thus, a greater range of molecular tools are required to allow definitive elucidation of the effects of CB1 allosteric modulation. In this study, we show a novel series of indole sulfonamides. Compounds 5e and 6c (ABD1075) had potencies of 4 and 3?nM respectively, and showed good oral exposure and CNS penetration, making them highly versatile tools for investigating the therapeutic potential of allosteric modulation of the cannabinoid system.
- Greig, Iain R.,Baillie, Gemma L.,Abdelrahman, Mostafa,Trembleau, Laurent,Ross, Ruth A.
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p. 4403 - 4407
(2016/08/25)
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- Synthesis and in vitro characterization of novel fluorinated derivatives of the TSPO 18 kDa ligand SSR180575
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Abstract SSR180575 (1) is a high-affinity (0.83 nM) TSPO 18 kDa ligand belonging to the pyridazino[4,5-b]indole-1-acetamides family. Herein we describe the synthesis and in vitro characterization of two series of new fluorinated analogues. Eleven compounds (out of fifteen) displayed nanomolar to subnamolar affinities (0.30-8.1 nM) and high selectivities (Ki(CBR)/Ki(TSPO) > 103). Two derivatives stand out as promising candidates for drug development or use as PET probes for in vivo neuroinflammation imaging, once fluorine-18-labelled.
- Damont, Annelaure,Marguet, Frank,Puech, Frédéric,Dollé, Frédéric
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p. 736 - 745
(2015/08/04)
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- ZrCl4-promoted facile synthesis of indole derivatives
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Zirconium(iv) chloride effectively activates nitrogen (N2) extrusion from aryl azidoacrylates followed by annulation to provide the desired indole products in moderate to good yields. The reaction proceeds at low temperature and in short reaction time and is applicable to a variety of substrates.
- Tummatorn,Gleeson,Krajangsri,Thongsornkleeb,Ruchirawat
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p. 20048 - 20052
(2014/05/20)
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- 5-Oxo-ETE receptor antagonists
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5-Oxo-ETE is the most powerful eosinophil chemoattractant among lipid mediators. Eosinophil infiltration into the lungs of asthmatics may be responsible for the late phase of inflammatory asthma. We have designed and synthesized a 5-oxo-ETE receptor antagonist, the purpose of which is to prevent eosinophil migration to the lung during an asthma attack and thereby reduce asthma symptoms.
- Gore, Vivek,Patel, Pranav,Chang, Chih-Tsung,Sivendran, Sashikala,Kang, Namin,Ouedraogo, Yannick P.,Gravel, Sylvie,Powell, William S.,Rokach, Joshua
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p. 3725 - 3732
(2013/06/27)
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- Design, synthesis and aromatase inhibitory activities of novel indole-imidazole derivatives
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A series of novel indole-imidazole derivatives have been prepared and evaluated in vitro on the aromatase inhibitory activities. The results suggested that proton or a small electron-withdrawing group at para-position of the phenyl ring would enhance the inhibitory activities and any bulky group should be avoided in order to keep a relative small volume for this kind of molecules.
- Wang, Rui,Shi, Hong-Fan,Zhao, Jing-Feng,He, Yan-Ping,Zhang, Hong-Bin,Liu, Jian-Ping
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p. 1760 - 1762
(2013/04/10)
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- AUTOTAXIN INHIBITORS AND USES THEREOF
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Described herein are compounds that are inhibitors of autotaxin. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such inhibitors, alone and in combination with other compounds, for treating autotaxin-dependent or autotaxin-mediated conditions or diseases.
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Page/Page column 169
(2012/03/11)
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- NOVEL P53-MDM2/P53-MDM4 ANTAGONISTS TO TREAT PROLIFERATIVE DISEASE
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High-resolution structural information delineates key interactions between MDM2 or MDM4 and heterocyclic compounds that bind to these proteins. These compounds are potent agonists of the p53-MDM2/p53-MDM4 complex.
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- Substituted Heterocycles as Therapeutic agents for treating cancer
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MDM2 and MDM4 proteins prevent apoptosis of cancer cells by negatively regulating the transcription factor p53. Compounds according to Formula I are selective antagonists of MDM2 and MDM4 proteins, disrupting the p53/MDM2 and p53/MDM4 complex. These compo
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- A tandem "on-palladium" Heck-Jeffery amination route toward the synthesis of functionalized indole-2-carboxylates
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A direct synthesis of functionalized indole-2-carboxylates involving a PdII-catalyzed annulation of ortho-iodoanilines onto a vinyl ether is described. The reaction mechanism is shown to be distinct from a stepwise Heck, intramolecular amination pathway, likely involving a tandem "on-palladium" Heck-Jeffery amination process incorporating a novel intramolecular amination step.
- McNulty, James,Keskar, Kunal
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experimental part
p. 6902 - 6908
(2012/01/02)
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- Efficient synthesis of 2-ethoxycarbonyl indoles
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An efficient one-pot procedure for the synthesis of 2-ethoxycarbonyl indoles from commercially available materials has been developed. The one-step procedure involves in situ formation of the hydrazones from phenylhydrazine hydrochloride and ethyl pyruvate in the presence of bismuth nitrate followed by Fischer cyclization in polyphosphoric acid and ethanol. This method is efficient and simple.
- Sudhakara,Jayadevappa,Mahadevan,Hulikal, Vijaykumar
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experimental part
p. 2506 - 2515
(2009/12/06)
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- Methods for the use of inhibitors of cytosolic phospholipase A2 in the treatment of thrombosis
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This invention provides methods for the use of substituted indole compounds of the general formula: and pharmaceutically acceptable salt forms thereof. The invention provides methods for the use of the compounds in the treating or preventing thrombosis in a mammal, or preventing progression of symptoms of thrombosis.
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Page/Page column 30
(2010/11/29)
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- Discovery of ecopladib, an indole inhibitor of cytosolic phospholipase A2α
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The synthesis and structure-activity relationship of a series of indole inhibitors of cytosolic phospholipase A2α (cPLA 2α, type IVA phospholipase) are described. Inhibitors of cPLA2α are predicted to be efficacious in treating asthma as well as the signs and symptoms of osteoarthritis, rheumatoid arthritis, and pain. The introduction of a benzyl sulfonamide substituent at C2 was found to impart improved potency of these inhibitors, and the SAR of these sulfonamide analogues is disclosed. Compound 123 (Ecopladib) is a submicromolar inhibitor of cPLA2α in the GLU micelle and rat whole blood assays. Compound 123 displayed oral efficacy in the rat carrageenan air pouch and rat carrageenan-induced paw edema models.
- Lee, Katherine L.,Foley, Megan A.,Chen, Lihren,Behnke, Mark L.,Lovering, Frank E.,Kirincich, Steven J.,Wang, Weiheng,Shim, Jaechul,Tam, Steve,Shen, Marina W. H.,Khor, SooPeang,Xu, Xin,Goodwin, Debra G.,Ramarao, Manjunath K.,Nickerson-Nutter, Cheryl,Donahue, Frances,Ku, M. Sherry,Clark, James D.,McKew, John C.
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p. 1380 - 1400
(2008/02/01)
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- Dioxomolybdenum(VI)-catalyzed reductive cyclization of nitroaromatics. Synthesis of carbazoles and indoles
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Reductive cyclization of nitrobiphenyls and nitrostyrenes to carbazoles and indoles, respectively, is carried out by triphenylphosphine under mild conditions catalyzed by a dichlorodioxomolybdenum(VI) complex. A one-pot procedure for the synthesis of regioselectively functionalized indoles has been developed from commercially available onitrobenzaldehydes and phosphoranes.
- Sanz, Roberto,Escribano, Jaime,Pedrosa, Maria R.,Aguado, Rafael,Arnaiz, Francisco J.
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p. 713 - 718
(2008/02/09)
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- Targeted, NIR imaging agents for therapy efficacy monitoring, deep tissue disease demarcation and deep tissue imaging
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Compounds and methods related to NIR molecular imaging, in-vitro and in-vivo functional imaging, therapy/efficacy monitoring, and cancer and metastatic activity imaging. Compounds and methods demonstrated pertain to the field of peripheral benzodiazepine
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Page/Page column 16-17
(2008/06/13)
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- Inhibitors of cytosolic phospholipase A2
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This invention provides substituted indole compounds of the general formula: and pharmaceutically acceptable salt forms thereof, and methods for using the compounds as inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A2 enzymes, and for the medical treatment, prevention and inhibition of pain and inflammation.
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- Novel Indole-2-carboxylates as Ligands for the Strychnine-Insensitive N-Methyl-D-aspartate-Linked Glycine Receptor
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A series of indole-2-carboxylates were prepared and evaluated for their ability to inhibit the binding at the strychnine-insensitive glycine receptor that is associated with the NMDA-PCP-glycine receptor complex.All of the compounds were selective for the glycine site relative to other sites on the receptor macrocomplex and several of the compounds in this series were found to have submicromolar affinity for this receptor.The lead compound, 2-carboxy-6-chloro-3-indoleacetic acid (Ki = 1.6 μM vsglycine), was also found to noncompetitively inhibit the binding of MK-801, a ligand for the phencyclidine site on the receptor macrocomplex.These latter data suggest that the compound functions as an antagonist at the strychnine-insensitive glycine receptor.The structural activity relationships within this series of indole-2-carboxylates is discussed and several key pharmacophores are identified for this series of glycine ligands.In general, the most potent compounds were the C-3 acetamides, with N-propyl-2-carboxy-6-chloro-3-indoleacetamide having the highest receptor affinity.
- Gray, Nancy M.,Dappen, Michael S.,Cheng, Brian K.,Cordi, Alexis A.,Biesterfeldt, John P.,et al.
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p. 1283 - 1292
(2007/10/02)
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- Indoline Analogues of Idazoxan: Potent α2-Antagonists and α1-Agonists
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The synthesis and α-adrenergic activity of a series of substituted 2-imidazolinylindolines are described.Substitution in the indoline ring generated compounds with a spectrum of adrenoceptor antagonist/agonist profiles that proved sensitive to both the nature and position of the substituent.Many of the derivatives possess greater presynaptic antagonist potency that the corresponding benzodioxan 1, dihydrobenzofuran 2, and indan 3 analogues; however, this α2-antagonism is often accompanied by α1-agonist activity.It was not possible to separate α2-antagonist from α1-agonist properties in this series.Compounds of most interest proved to be the N-ethyl 6, 5-chloro-N-methyl 18 and 5-chloro-N-ethyl 23 derivatives, all being potent α2-antagonists and α1-agonists.Substitution at the 4- and 7-position of the indoline ring generally gave compounds with nonselective agonist properties.
- Fagan, Gay P.,Chapleo, Christopher B.,Lane, Anthony C.,Myers, Malcolm,Roach, Alan G.,et al
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p. 944 - 948
(2007/10/02)
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