- HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF EPILEPSY
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The present invention provides a novel heterocyclic compound represented by Formula [I] and a salt thereof: wherein the symbols are as defined in the specification, which is useful for treating, preventing and/or diagnosing seizure and the like in disease involving epileptic seizure or convulsive seizure (including multiple drug resistant seizure, refractory seizure, acute symptomatic seizure, febrile seizure and status epilepticus), as well as a medical use therefor.
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Paragraph 0134; 0143; 0144
(2020/06/19)
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- Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide
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Topoisomerase II (TOP2) poisons as anticancer drugs work by trapping TOP2 cleavage complexes (TOP2cc) to generate DNA damage. Repair of such damage by tyrosyl DNA phosphodiesterase 2 (TDP2) could render cancer cells resistant to TOP2 poisons. Inhibiting TDP2, thus, represents an attractive mechanism-based chemosensitization approach. Currently known TDP2 inhibitors lack cellular potency and/or permeability. We report herein two novel subtypes of the deazaflavin TDP2 inhibitor core. By introducing an additional phenyl ring to the N-10 phenyl ring (subtype 11) or to the N-3 site of the deazaflavin scaffold (subtype 12), we have generated novel analogues with considerably improved biochemical potency and/or permeability. Importantly, many analogues of both subtypes, particularly compounds 11a, 11e, 12a, 12b, and 12h, exhibited much stronger cancer cell sensitizing effect than the best previous analogue 4a toward the treatment with etoposide, suggesting that these analogues could serve as effective cellular probes.
- Kankanala, Jayakanth,Ribeiro, Carlos J. A.,Kiselev, Evgeny,Ravji, Azhar,Williams, Jessica,Xie, Jiashu,Aihara, Hideki,Pommier, Yves,Wang, Zhengqiang
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p. 4669 - 4682
(2019/05/17)
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- Synthesis and evaluation of aminobenzothiazoles as blockers of N- and T-type calcium channels
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Both N- and T-type calcium ion channels have been implicated in pain transmission and the N-type channel is a well-validated target for the treatment of neuropathic pain. An SAR investigation of a series of substituted aminobenzothiazoles identified a subset of five compounds with comparable activity to the positive control Z160 in a FLIPR-based intracellular calcium response assay measuring potency at both CaV2.2 and CaV3.2 channels. These compounds may form the basis for the development of drug leads and tool compounds for assessing in vivo effects of variable modulation of CaV2.2 and CaV3.2 channels.
- Sairaman, Anjali,Cardoso, Fernanda Caldas,Bispat, Anjie,Lewis, Richard J.,Duggan, Peter J.,Tuck, Kellie L.
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supporting information
p. 3046 - 3059
(2018/04/06)
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- Microwave assisted synthesis of selected diaryl ethers under Cu(I)-catalysis
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A practical synthesis of diaryl ethers has been achieved from cross coupling reaction between aryl halides and phenols under Cu(I)-catalysis and using ACHN as a ligand. The presence of catalysis and microwave-assistance benefitted the synthesis by increasing the yield of diaryl ethers with a reduction of reaction time.
- Navarro, Lorena,Pujol, M. Dolors
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supporting information
p. 1812 - 1815
(2015/03/30)
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- CsF/clinoptilolite: An efficient solid base in SNAr and copper-catalyzed Ullmann reactions
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CsF/clinoptilolite was found to be an efficient solid base catalyst for both SNAr and Ullmann ether reactions. A general and efficient one-step procedure was developed for the synthesis of biaryl ethers via direct coupling of electron-deficient aryl halides to phenols using CsF/clinoptilolite. The protocol was also applied to electron-rich aryl halides by addition of a catalytic amount of copper oxide nanoparticles. Both SNAr and Ullmann reactions were rapid and provided good to excellent yields.
- Keipour, Hoda,Hosseini, Abolfazl,Afsari, Amir,Oladee, Razieh,Khalilzadeh, Mohammad A.,Ollevier, Thierry
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- Synthesis and biological evaluation of pentanedioic acid derivatives as farnesyltransferase inhibitors
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Structure-based virtual screening of a commercial library identified pentanedioic acid derivatives (6 and 13b) as a kind of novel scaffold farnesyltransferase inhibitors (FTIs). Chemical modifications of the lead compounds, biological assays and analysis of the structure-activity relationships (SAR) were conducted to discover more potent FTIs. Some of them displayed excellent inhibition against FTase, and among them, the most active compound 13n with an IC50 value of 0.0029 μM and SAR analysis might be helpful to the discovery of more potent FTIs. This journal is
- Yang, Liuqing,Liu, Wei,Mei, Hanbing,Zhang, Yuan,Yu, Xiaojuan,Xu, Yufang,Li, Honglin,Huang, Jin,Zhao, Zhenjiang
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supporting information
p. 671 - 676
(2015/04/27)
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- BENZIMIDAZOLE DERIVATIVES AND USE THEREOF
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The invention provides compounds that are useful as sodium channel blockers. In one aspect, the invention provides compounds of Formula I: and pharmaceutically acceptable salts, solvates, hydrates, or diastereomers thereof, wherein W1, W2, W3, W4, U, G, m, R1, and R2 are defined in the disclosure. In certain embodiments, the invention provides compounds of Formulae II to V as set forth supra. The invention also provides the use of compounds of any of the above discussed formulae to treat a disorder responsive to blockade of sodium channels. In one embodiment, Compounds of the Invention are useful for treating pain.
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Paragraph 0411
(2015/06/08)
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- On the frontier between nucleophilic aromatic substitution and catalysis
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A study on the arylation of heteroatom nucleophiles by using activated haloarenes, with or without metal catalysts, is reported. A discussion concerning the involvement of traces of metals is presented, supported by an unexpected ''ligand'' effect in the absence of added metal catalysts. We believe that the frontier between nucleophilic aromatic substitution and catalysis will likely prove to be much harder to delimit than is generally thought. S NAr or catalysis? A study on the arylation of heteroatom nucleophiles by using activated haloarenes, with or without added metal catalysts, is reported. A discussion concerning the involvement of traces of metals is presented, supported by an unexpected "ligand" effect in the absence of added metal catalysts (see scheme, EWG=electron-withdrawing group).
- Pichette Drapeau, Martin,Ollevier, Thierry,Taillefer, Marc
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supporting information
p. 5231 - 5236
(2014/05/20)
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- ARGININE METHYLTRANSFERASE INHIBITORS AND USES THEREOF
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Described herein are compounds of Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds described herein are useful for inhibiting arginine methyltransferase activity. Methods of using the compounds for treating arginine methyltransferase-mediated disorders are also described.
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Paragraph 0259
(2014/11/11)
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- HETEROARYL COMPOUNDS AS SODIUM CHANNEL BLOCKERS
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The invention relates to aryl substituted compounds of Formula (I) : and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein Het, G, A, R, and n are defined as set forth in the specification. The invention is also directed to the use
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Paragraph 0333; 0334; 0335
(2013/05/22)
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- PYRIDINE COMPOUNDS AS SODIUM CHANNEL BLOCKERS
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The invention relates to substituted pyridine compounds of Formula I: (I) or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein A1, X, A2, R1a, R1b, R1c, G, and z are defined as
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Page/Page column 80-81
(2012/02/02)
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- PYRIDINE COMPOUNDS AND THE USES THEREOF
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The invention relates to substituted pyridine compounds of Formula (I) and the pharmaceutically acceptable salts, prodrugs, and solvates thereof, wherein R1a, A1, A2, E, G, Z1, and Z2 are defined as set forth in the specification. The invention is also directed to the use of compounds of Formula I to treat a disorder responsive to the blockade of sodium channels. Compounds of the present invention are especially useful for treating pain.
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Page/Page column 178
(2012/04/04)
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- Discovery of novel and potent aryl diamines as leukotriene A4 hydrolase inhibitors
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The synthesis and biological evaluation of a series of aryl diamines as inhibitors of LTA4-h inhibitors are described. The optimization which led to the identification of the optimal para-substitution on the diphenyl ether moiety and diamine spacer is discussed. The resulting compounds such as 3l have excellent enzyme and cellular potency as well as desirable pharmacokinetic properties.
- Khim, Seock-Kyu,Bauman, John,Evans, Jarred,Freeman, Beverly,King, Beverly,Kirkland, Thomas,Kochanny, Monica,Lentz, Dao,Liang, Amy,Mendoza, Lisa,Phillips, Gary,Tseng, Jih-Lie,Wei, Robert G.,Ye, Hong,Yu, Limei,Parkinson, John,Guilford, William J.
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scheme or table
p. 3895 - 3898
(2009/04/07)
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- GLYT2 MODULATORS
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α-, β-, and γ-amino acid derivatives of formula I are disclosed as selective GlyT2 inhibitors for the treatment of central nervous system (CNS) conditions such as muscle spasticity, tinnitus, epilepsy and neuropathic pain. Formula I
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Page/Page column 44
(2010/02/11)
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- Novel glycine transporter type-2 reuptake inhibitors. Part 1: α-amino acid derivatives
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A variety of α-amino acid derivatives were prepared as glycine transport inhibitors and their ability to block the uptake of [ 14C]-glycine in COS7 cells transfected with human glycine transporter-2 (hGlyT-2) was evaluated. An array of substituents at the chiral center was studied and overall, L-phenylalanine was identified as the preferred amino acid residue. Compounds prepared from L-amino acids were more potent GlyT-2 inhibitors than analogs derived from the corresponding D-amino acids. Introducing an achiral amino acid such as glycine, or incorporating geminal substitution in the α-position, led to a significant reduction in GlyT-2 inhibitory properties.
- Wolin, Ronald L.,Venkatesan, Hariharan,Tang, Liu,Santillán Jr., Alejandro,Barclay, Tristin,Wilson, Sandy,Lee, Doo Hyun,Lovenberg, Timothy W.
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p. 4477 - 4492
(2007/10/03)
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- Synthesis and structure-activity relationships of trisubstituted phenyl urea derivatives as neuropeptide Y5 receptor antagonists
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1-((1R,2R)-2-Hydroxy-1-methyl-2-phenylethyl)-1-methyl-3-(4-phenoxyphenyl)urea (1) was identified as a hit from the screening of the neuropeptide Y5 (NPY5) receptor. This lead was optimized for in vitro potency by changing the stereochemistry, the phenylethyl segment, the urea portion, and the 4-phenoxyphenyl group on the molecule. Over 40 analogues of 1 were prepared to study the structure-activity relationship for this series. The most potent compounds in this class have IC50S less than 0.1 nM at the NPY5 receptor (e.g., 40f, 44a, and 47). To determine the functional activity for this series of compounds, selected analogues were tested in a cellular assay measuring forskolin-induced cyclic AMP accumulation in 293 cells transfected with the human NPY5 receptor. All urea analogues tested in the functional assay acted as antagonists (e.g., 1, 32, 40a, and 44e).
- Fotsch,Sonnenberg,Chen,Hale,Karbon,Norman
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p. 2344 - 2356
(2007/10/03)
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- Preparation process of fluorine substituted aromatic compound
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A preparation process of a fluorine substituted aromatic compound comprising reacting an alkali metal or alkali earth metal salt of an aromatic compound having a hydroxy group with an organic fluorinating agent is disclosed. As a representative fluorinating agent, a bis-dialkylamino-difluoromethane compound, for example, 2,2′-difluoro-1,3-dimethylimidazolidine, is exemplified. According to the process, an industrially useful fluorinated aromatic compound, for example, a fluorobenzene, a fluorine substituted benzophenone, a fluorine substituted diarylsulfone can be prepared with ease in economy without specific equipment.
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