- Room-Temperature Amination of Chloroheteroarenes in Water by a Recyclable Copper(II)-Phosphaadamantanium Sulfonate System
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Buchwald-Hartwig amination of chloroheteroarenes has been a challenging synthetic process, with very few protocols promoting this important transformation at ambient temperature. The current report discusses about an efficient copper-based catalytic system (Cu/PTABS) for the amination of chloroheteroarenes at ambient temperature in water as the sole reaction solvent, a combination that is first to be reported. A wide variety of chloroheteroarenes could be coupled efficiently with primary and secondary amines as well as selected amino acid esters under mild reaction conditions. Catalytic efficiency of the developed protocol also promotes late-stage functionalization of active pharmaceutical ingredients (APIs) such as antibiotics (floxacins) and anticancer drugs. The catalytic system also performs efficiently at a very low concentration of 0.0001 mol % (TON = 980,000) and can be recycled 12 times without any appreciable loss in activity. Theoretical calculations reveal that the π-acceptor ability of the ligand PTABS is the main reason for the appreciably high reactivity of the catalytic system. Preliminary characterization of the catalytic species in the reaction was carried out using UV-VIS and ESR spectroscopy, providing evidence for the Cu(II) oxidation state.
- Dandela, Rambabu,Desai, Aman A.,Kapdi, Anant R.,Kori, Santosh,Maity, Dilip K.,Parmar, Udaysinh,Somvanshi, Dipesh
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p. 8900 - 8925
(2021/07/20)
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- Cu-Catalyzed Direct Amination of Cyclic Amides via C-OH Bond Activation Using DMF
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Herein, we describe a Cu-catalyzed approach to directly accessing aromatic heterocyclic amines from cyclic amides. The most-reported methods for cyclic amide conversions to aromatic heterocyclic amines use an activating group, such as a halogen atom or a
- Chen, Peng,Luo, Kaixiu,Yu, Xianglin,Yuan, Xu,Liu, Xiaoyu,Lin, Jun,Jin, Yi
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supporting information
p. 6547 - 6551
(2020/09/02)
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- N-heteroarylsulfonamide derivative, and preparation and application of same
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The invention provides an N-heteroarylsulfonamide derivative, and preparation and an application of same. The derivative includes pharmaceutically acceptable salts and solvates thereof; a test provesthat the N-heteroarylsulfonamide derivative allows specific combination and inhibit or reduce the activity of potassium pathway Kv1.3, so that the derivative can be used for treating autoimmune diseases, caused by abnormal activation of the potassium pathway Kv1.3, of human or animal. An inhibitor in the invention also includes a medicinal composition of the compound. The invention also provides amethod for preparing the compound. The derivative has the general formula as the specification.
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Paragraph 0119; 0120-0122
(2019/05/15)
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- HFIP Promoted Low-Temperature SNAr of Chloroheteroarenes Using Thiols and Amines
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A highly efficient and an unprecedented hexafluoro-2-propanol, promoting low-temperature aromatic nucleophilic substitutions of chloroheteroarenes, has been performed using thiols and (secondary) amines under base-free and metal-free conditions. The developed protocol also provides excellent regio-control for the selective functionalization of dichloroheteroarenes, while the utility of the protocol was demonstrated by the modification of a commercially available drug ceritinib.
- Bhujabal, Yuvraj B.,Vadagaonkar, Kamlesh S.,Gholap, Aniket,Sanghvi, Yogesh S.,Dandela, Rambabu,Kapdi, Anant R.
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p. 15343 - 15354
(2019/12/04)
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- First-in-class DAPK1/CSF1R dual inhibitors: Discovery of 3,5-dimethoxy-N-(4-(4-methoxyphenoxy)-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-5-yl)benzamide as a potential anti-tauopathies agent
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Kinase irregularity has been correlated with several complex neurodegenerative tauopathies. Development of selective inhibitors of these kinases might afford promising anti-tauopathy therapies. While DAPK1 inhibitors halt the formation of tau aggregates and counteract neuronal death, CSF1R inhibitors could alleviate the tauopathies-associated neuroinflammation. Herein, we report the design, synthesis, biological evaluation, mechanistic study, and molecular docking study of novel CSF1R/DAPK1 dual inhibitors as multifunctional molecules inhibiting the formation of tau aggregates and neuroinflammation. Compound 3l, the most potent DAPK1 inhibitor in the in vitro kinase assay (IC50 = 1.25 μM) was the most effective tau aggregates formation inhibitor in the cellular assay (IC50 = 5.0 μM). Also, compound 3l elicited potent inhibition of CSF1R in the in vitro kinase assay (IC50 = 0.15 μM) and promising inhibition of nitric oxide production in LPS-induced BV-2 cells (55% inhibition at 10 μM concentration). Kinase profiling and hERG binding assay anticipated the absence of off-target toxicities while the PAMPA-BBB assay predicted potentially high BBB permeability. The mechanistic study and selectivity profile suggest compound 3l as a non-ATP-competitive DAPK1 inhibitor and an ATP-competitive CSF1R inhibitor while the in silico calculations illustrated binding of compound 3l to the substrate-binding site of DAPK1. Hence, compound 3l might act as a protein-protein interaction inhibitor by hindering DAPK1 kinase reaction through preventing the binding of DAPK1 substrates.
- Farag, Ahmed Karam,Hassan, Ahmed H.E.,Jeong, Hyeanjeong,Kwon, Youngji,Choi, Jin Gyu,Oh, Myung Sook,Park, Ki Duk,Kim, Yun Kyung,Roh, Eun Joo
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p. 161 - 175
(2018/11/23)
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- Design, synthesis and biological evaluation N2-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives bearing acylamino or DBTD ‘head’ as potential ALK inhibitors
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Aiming to develop promising ALK inhibitors, two series of N2-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives (22a-x and 23a-d) were designed according to scaffold hopping and bioisosterism principles. All compounds were efficiently synthesized by concise reactions and anti-proliferative activities on ALK-addicted H2228, Karpas299 cells and EGFR-expressive A549 cell were evaluated by MTT assay. Several compounds exhibited potential cytotoxic activities with IC50 values below 0.10 μM. Five compounds (22g, 22h, 22l, 22s and 23a) were selected for further enzymatic determination, resulting in the discovery of 22l against ALK and ALKL1196M with IC50 values of 2.1 nM and 3.8 nM. Particularly, western blot and cell apoptosis assays identified 22l as a promising ALK inhibitor, which was capable of obviously inhibiting cellular ALK activity and inducing cell apoptosis. Eventually, molecular docking modes of 22l with ALK confirmed structural basis in accordance with the SARs analysis.
- Xing, Lingyun,Jing, Tongfei,Zhang, Junlong,Guo, Ming,Miao, Xiuqi,Jiang, Feng,Zhai, Xin
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p. 689 - 699
(2018/10/02)
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- Synthesis and antiproliferative activity of novel 4-substituted-phenoxy-benzamide derivatives
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A series of novel 4-substituted-phenoxy-benzamide derivatives bearing an aryl cycloaliphatic amine moiety were synthesized and evaluated for antiproliferative activity against SW620, HT29 and MGC803 cancer cell lines in vitro. The pharmacological data demonstrated that the majority of target compounds exhibited moderate efficacy in HT29 and MGC803 cell lines. Compound 10c showed promising inhibition of hedgehog (Hh) signaling pathway in an Hh-related assay. In addition, the superposition pattern of 10c showed a good fit for a pharmacophoric model generated by Hh inhibitors and provided a basis for further structural optimization.
- Sun, Chi-Yu,Li, Yang-Sheng,Shi, Ai-Long,Li, Ya-Fei,Cao, Rui-Fang,Ding, Huai-Wei,Yin, Qing-Qing,Zhang, Li-Juan,Zheng, Hua-Chuan,Song, Hong-Rui
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supporting information
p. 1307 - 1310
(2015/12/31)
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- Nucleophilic heteroaromatic substitution: Kinetics of the reactions of nitropyridines with aliphatic amines in dipolar aprotic solvents
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Rate data are reported for the reactions of 2-chloro-5-nitropyridine 2a, 2-chloro-3-nitropyridine 2b, and the corresponding 2-phenoxy derivatives 2c with n-butylamine, pyrrolidine and piperidine and 2d with n-butylamine and pyrrolidine in dimethyl sulfoxi
- Isanbor, Chukwuemeka,Emokpae, Thomas A.
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p. 125 - 135
(2008/09/18)
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- The effects of ring substituents and leaving groups on the kinetics of SNAr reactions of 1-halogeno- and 1-phenoxy-nitrobenzenes with aliphatic amines in acetonitrile
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Rate constants are reported for the reactions of a series of 1-chloro-, 1-fluoro- and 1-phenoxy-nitrobenzenes activated by CF3 or CN groups or by ring-nitrogen with n-butylamine, pyrrolidine or piperidine in acetonitrile. The results are compar
- Crampton, Michael R.,Emokpae, Thomas A.,Isanbor, Chukwuemeka
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p. 1378 - 1383
(2008/09/18)
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- C-N bond formation by the oxidative alkylamination of azines: Comparison of AgPy2MnO4 versus KMnO4 as oxidant
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Reports on the successful oxidative alkylamination of azines by the S NH-reaction, with the use of alkylamines other than methylamine, are very scarce. Hitherto, the experimental limitation to extend oxidative animation of azines wit
- Gulevskaya, Anna V.,Maes, Bert U. W.,Meyers, Caroline,Herrebout, Wouter A.,Van Der Veken, Benjamin J.
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p. 5305 - 5314
(2007/10/03)
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- 1,1,1-TRIFLUORO-4-PHENYL-4-METHYL-2-(1H-PYRROLO
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Compounds of Formula (IA), IB), IC), and (ID) wherein R1, R2, R3, R4, R5, and R6 are as respectively defined herein for Formula (IA), (IB), (IC), and (ID), or a tautomer, prodrug, solvate, or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.
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Page/Page column 172
(2010/02/11)
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- Neuropeptide Y antagonists
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The compound is a neuropeptide Y antagonist and is effective in treating feeding disorders, cardiovascular diseases and other physiological disorders.
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Page column 34
(2010/02/05)
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- Nucleophilic substitutions at the pyridine ring: Kinetics of the reaction of 2-chloro-3-nitro and 2-chloro-5-nitropyridines with piperidine and morpholine in methanol and benzene
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The kinetics of the reactions of 2-chloro-3-nitropyridine (ortho-like) and 5-nitro (para-like) isomer with morpholine and piperidine were studied in methanol and benzene at several amine concentrations and temperatures in the range 25-45°C. The data show that k3-NO2/k5-NO2ratios are less than unity in methanol. The steric hindrance in the transition state of the 3-nitro (ortho-like) isomer retards o-substitution while the stability of p-quinonoid structure of the 5-nitro (para-like) isomer favors p-substitution. In benzene, the k3-NO2/k5-NO2 ratios are greater than unity. The hydrogen bonding formation between the ammonium hydrogen and the ortho-nitro group in the transition state of 3-nitro isomer favors the o-substitution.
- Hamed, Ezzat A.
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p. 599 - 605
(2007/10/03)
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- Novel potassium channel openers: Synthesis and pharmacological evaluation of new N-(substituted-3-pyridyl)-N'-alkylthioureas and related compounds
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This report describes the synthesis and pharmacological evaluation of a series of novel potassium channel openers related to the pinacidil-type compounds. Thioureas, cyanoguanidines, and pyridine N-oxides were systematically evaluated for their effects on both the inhibition of spontaneous mechanical activity in rat portal vein (in vitro) and their antihypertensive activity (in vivo), and the structure-activity relationship for this series of compounds was discussed. Good correlation between in vitro and iv antihypertensive activity was observed for these compounds. Among them, cyanoguanidines bearing a conformationally rigid unit such as a norbornyl group generally possessed potent activity in both in vitro and in vivo studies. Especially, N-(6-amino-3-pyridyl)-N'-cyano-N''-(1-methyl-2- norbornyl)guanidine (23d) was identified as a more potent potassium channel opener in vitro (EC100 = 3 x 10-8 M) than pinacidil (EC100 = 10-7 M).
- Takemoto,Eda,Okada,Sakashita,Matzno,Gohda,Ebisu,Nakamura,Fukaya,Hihara,Eiraku,Yamanouchi,Yokoyama
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- The Chemistry of 5-Oxodihydroisoxazoles. IV. Reactions of Some N-Arylisoxazol-5-ones with Nucleophiles
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The reactions of ethyl 2-aryl-5-oxo-2,5-dihydroisoxazole-4-carboxylate (aryl = phenyl, isoquinolin-1-yl, 2-phenylquinazolin-4-yl and 5-nitropyridin-2-yl) with azide and primary, secondary and tertiary amines, and a number of other nucleophiles are describ
- Ang, Kiah H.,Donati, Cosimo,Donkor, Augustine,Prager, Rolf H.
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p. 2037 - 2048
(2007/10/02)
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- INVERSE ELECTRON DEMAND DIELS-ALDER REACTIONS OF 5-NITROPYRIMIDINE WITH ENAMINES. SYNTHESIS OF 3-NITROPYRIDINE DERIVATIVES
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The reaction of cyclic and non-cyclic enamines with 5-nitropyrimidine has been studied.Many enamines react in an inverse electron-demand Diels-Alder reaction, leading to the formation of 3-nitropyridines.N,S-ketene acetals were also found to react with 5-nitropyrimidines.The mechanism of the reaction will be discussed.
- Marcelis, Antonius T. M.,Plas, Henk C. van der
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p. 2693 - 2702
(2007/10/02)
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- 1H and 13C NMR Studies of Substituted Nitropyridines and Nitrobenzenes
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The 1H and 13C NMR spectra of 3-nitro-, 5-nitro- and 3,5-dinitro-2-methoxypyridines have been determined.The results show the preferred cis conformation for the 2-methoxy group, and the importance of steric repulsion between the oxygen atom of this group
- Nudelman, N. S.,Cerdeira, S. B.
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p. 507 - 511
(2007/10/02)
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- RING TRANSFORMATIONS OF 5-NITROPYRIMIDINE VIA INVERSE DIELS-ALDER REACTIONS
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5-Nitropyrimidine undergoes inverse Diels-Alder cycloadditions with ketene-N,N-, -O,O- acetals and enamines resulting in pyridine derivatives.The 1H NMR evidence for the 1-N,N-diethylaminopropyne cycloadduct formation is presented.
- Charushin, Valery N.,van der Plas, Henk C.
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p. 3965 - 3968
(2007/10/02)
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- 9-(P-phenylazoanilino)-7-methyl-1H-imidazo[4,5-f]quinolines
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A series of 9-(substituted amino)imidazo[4,5-f]quinolines are effective anthelmintic agents; particularly in respect to the tapeworm Hymenolepis nana.
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