- Double Carbonylation Using Glyoxal (HCOCOH): A Practical Copper-Promoted Synthesis of Isatins from Primary and Secondary Anilines
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A novel double carbonylation process has been demonstrated with easily available HCOCOH (glyoxal) as the double carbonylation reagent. Simple CuCl2?2H2O (copper(II) chloride dihydrate) was used as the oxidant for this transformation. Under optimized reaction conditions, various primary and secondary anilines were double-carbonylated to afford their corresponding isatins (26 examples, up to 80% yields). (Figure presented.).
- Kuan, Suzie Hui Chin,Sun, Wei,Wang, Lu,Xia, Chungu,Tay, Meng Guan,Liu, Chao
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- Combretastatin A-4 analogues with benzoxazolone scaffold: Synthesis, structure and biological activity
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In order to design and synthesize a new class of heterocyclic analogues of natural combretastatin A-4 and its synthetic derivative AVE8062, the benzoxazolone ring was selected as a scaffold for a bioisosteric replacement of the ring B of both molecules. A library of 28 cis- and trans-styrylbenzoxazolones was obtained by a modified Wittig reaction under Boden's conditions. Structures of the newly synthesized compounds bearing the 3,4,5-trimethoxy-, 3,4-dimethoxy-, 3,5-dimethoxy-, and 4-methoxystyryl fragment at position 4, 5, 6 or 7 of benzoxazolone core were determined on the basis of spectral and X ray data. The in vitro cytotoxicity of styrylbenzoxazolones against different cell lines was examined. Stilbene derivative 16Z, (Z)-3-methyl-6-(3,4,5-trimethoxystyryl)-2(3H)-benzoxazolone, showed highest antiproliferative potential of the series, with IC50 of 0.25 μM against combretastatin resistant cell line HT-29, 0.19 μM against HepG2, 0.28 μM against EA.hy926 and 0.73 μM against K562 cells. Furthermore, the results of flow cytometric analysis confirmed that 16Z induced cell cycle arrest in G2/M phase in the cell lines like combretastatin A-4. This arrest is followed by an abnormal exit of cells from mitosis without cytokinesis into a pseudo G1-like multinucleate state leading to late apoptosis and cell death. Accordingly, synthetic analogue 16Z was identified as the most promising potential anticancer agent in present study, and was selected as lead compound for further detailed investigations.
- Gerova, Mariana S.,Stateva, Silviya R.,Radonova, Elena M.,Kalenderska, Rositsa B.,Rusew, Rusi I.,Nikolova, Rositsa P.,Chanev, Christo D.,Shivachev, Boris L.,Apostolova, Margarita D.,Petrov, Ognyan I.
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- Ylide mediated carbonyl homologations for the preparation of isatin derivatives
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An exceptionally mild method for the preparation of isatin derivatives has been developed using a sulfur ylide mediated carbonyl homologation sequence starting from anthranilic acid precursors. This method proceeds at ambient temperature via a sulfur ylide intermediate without the need for protection of the amine or chromatographic isolation of the intermediate ylide. Gentle oxidation of the sulfur ylides provides isatin derivatives with N-H, N-alkyl, N-aryl substitution, electron-rich and electron-poor aromatic rings, and heterocyclic aromatic systems. We anticipate that this method will greatly expand the accessibility of complex isatin derivatives.
- Lollar, Christina T.,Krenek, Katherine M.,Bruemmer, Kevin J.,Lippert, Alexander R.
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- Isatin N,N′-Cyclic Azomethine Imine 1,3-Dipole and Abnormal [3 + 2]-Cycloaddition with Maleimide in the Presence of 1,4-Diazabicyclo[2.2.2]octane
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A new isatin N,N′-cyclic azomethine imine synthon was devised, and an unexpected abnormal [3 + 2]-cycloaddition with maleimide catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) has been disclosed. A variety of tricyclic spiropyrrolidine oxindoles bearing a dinitrogen heterocycle and succinimide scaffold were obtained in excellent yields (up to 96%) and diastereoselectivities (up to 97:3) under mild conditions.
- Wang, Xiao,Yang, Peng,Zhang, Yong,Tang, Chao-Zhe,Tian, Fang,Peng, Lin,Wang, Li-Xin
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- Entry into the bi-aryl moiety of the TMC-95 proteasome inhibitors via the Stille protocol
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The synthesis of the bi-aryl moiety of the TMC-95 natural products has been achieved via a palladium-catalyzed Stille cross-coupling reaction of an aryl stannane tyrosine derivative and 7-iodoisatin.
- Albrecht, Brian K.,Williams, Robert M.
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Read Online
- AN EFFICIENT NEW PROCESS FOR SYNTHESIS OF 2-AMINO-5-CHLORO-N-,3-DIMETHYLBENZAMIDE
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Described herein are novel methods of synthesizing 2-amino-5-chloro-N,3- dimethylbenzamide. Compounds prepared by the methods disclosed herein are useful for preparation of certain anthranilamide compounds that are of interest as insecticides, such as, for example, the insecticides chlorantraniliprole and cyantraniliprole.
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- Study on synthesis of some substituted N-propargyl isatins by propargylation reaction of corresponding isatins using potassium carbonate as base under ultrasound- and microwave-assisted conditions
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Substituted N-propargyl isatins were synthesized by SN2 reaction of corresponding substituted isatins with propargyl bromide in the presence of anhydrous K2CO3 as base. We reported about study on systematically synthesis of these compounds using heating procedures under different reaction conditions, including microwave-assisted heating conditions at power of 100?W (Procedure A), conventional heating conditions in water bath at 50?°C in acetonitrile (Procedure B), and conventional heating conditions in water bath at 50?°C in DMF (procedure C). The best procedure A was deduced based on the investigations on the reaction conditions. Almost all substituted N-propargyl isatins were new, except compounds with R of H, 5-Me, 5-Cl and 5-Br substituents. The structures of the obtained compounds were confirmed by the modern spectroscopic methods.
- Tri, Nguyen Minh,Thanh, Nguyen Dinh,Ha, Luong Ngoc,Anh, Dang Thi Tuyet,Toan, Vu Ngoc,Giang, Nguyen Thi Kim
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p. 4793 - 4801
(2021/05/31)
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- Single step regioselective cyclization and chlorination of hydroxyamino-N-(2-methylphenyl)acetamide to 5-chloro-7-methylindoline-2,3-dione
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A one-pot process for the manufacture of 5-chloro-7-methylindoline-2,3-dione starting from 2-hydroxyimino-N-(2-methylphenyl)acetamide via tandem cyclization in sulfuric acid and acetic acid, followed by in-situ chlorination with sulfur dioxide and chlorine gas in high regioselectivity and yield.
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Page/Page column 5; 6
(2021/04/21)
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- A PROCESS FOR PREPARING ANTHRANILIC DIAMIDES AND INTERMEDIATES THEREOF
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The present invention relates a novel process for preparing a compound of Formula I, wherein, R1, R2, R3a, R3b, R3c, R4, R5, R6, R7 and Z are as defined in the description. The process comprises a novel and inventive step of converting a dione of Formula II into an isatoic anhydride of Formula V in a single step, wherein, R2 is F, Cl, Br or I; R1, R3a, R3b, R3c, R4, R5, R6, R7 and Z are as defined in the description.
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- Visible-Light-Mediated Dearomatisation of Indoles and Pyrroles to Pharmaceuticals and Pesticides
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Dearomatisation of indole derivatives to the corresponding isatin derivatives has been achieved with the aid of visible light and oxygen. It should be noted that isatin derivatives are highly important for the synthesis of pharmaceuticals and bioactive compounds. Notably, this chemistry works excellently with N-protected and protection-free indoles. Additionally, this methodology can also be applied to dearomatise pyrrole derivatives to generate cyclic imides in a single step. Later this methodology was applied for the synthesis of four pharmaceuticals and a pesticide called dianthalexin B. Detailed mechanistic studies revealed the actual role of oxygen and photocatalyst.
- Schilling, Waldemar,Zhang, Yu,Riemer, Daniel,Das, Shoubhik
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supporting information
p. 390 - 395
(2019/12/15)
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- Design and development of Isatin-triazole hydrazones as potential inhibitors of microtubule affinity-regulating kinase 4 for the therapeutic management of cell proliferation and metastasis
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Microtubule affinity-regulating kinase 4 (MARK4) is a potential drug target as the same is found to be over expressed in several types of cancers. In search of effective MARK4 inhibitors, we have synthesized and characterized Isatin-triazole hydrazones (9a-i) and evaluated their inhibitory potential. Of all the compounds, 9g showed better binding affinity and enzyme inhibition potential in sub micromolar range. Human serum albumin (HSA) binding assay suggested an easy transportation of 9g in blood stream due to its binding affinity. In vitro anticancer studies performed on MCF-7, MDA-MB-435s and HepG2 cells using 9g showed inhibition of cell proliferation and cell migration. Further, 9g induces apoptosis in these cancerous cells, with IC50 values of 6.22, 9.94 and 8.14 μM, respectively. Putatively, 9g seems to cause oxidative stress resulting in apoptosis. Functional assay of 9g with a panel of 26 kinases showed MARK4 specific profile. In conclusion, 9g seems to possess an effective inhibitory potential towards MARK4 adding an additional repertoire to anticancer therapeutics.
- Aneja, Babita,Khan, Nashrah Sharif,Khan, Parvez,Queen, Aarfa,Hussain, Afzal,Rehman, Md. Tabish,Alajmi, Mohamed F.,El-Seedi, Hesham R.,Ali, Sher,Hassan, Md. Imtaiyaz,Abid, Mohammad
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p. 840 - 852
(2019/01/04)
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- Enantioselective synthesis of tunable chiral pyridine-aminophosphine ligands and their applications in asymmetric hydrogenation
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A small library of tunable chiral pyridine-aminophosphine ligands were enantioselectively synthesized based on chiral 2-(pyridin-2-yl)-substituted 1,2,3,4-tetrahydroquinoline scaffolds, which were obtained in high yields and with excellent enantioselectivities via ruthenium-catalyzed asymmetric hydrogenation of 2-(pyridin-2-yl)quinolines. The protocol features a wide substrate scope and mild reaction conditions, enabling scalable synthesis. These chiral P,N ligands were successfully applied in the Ir-catalyzed asymmetric hydrogenation of benchmark olefins and challenging seven-membered cyclic imines including benzazepines and benzodiazepines. Excellent enantio- and diastereoselectivity (up to 99% ee and >20:1 dr), and/or unprecedented chemoselectivity were obtained in the asymmetric hydrogenation of 2,4-diaryl-3H-benzo[b]azepines and 2,4-diaryl-3H-benzo[b][1,4]diazepines.
- Liu, Youran,Chen, Fei,He, Yan-Mei,Li, Chenghao,Fan, Qing-Hua
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p. 5099 - 5105
(2019/05/29)
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- Palladium(II)/N-Heterocyclic Carbene Catalyzed One-Pot Sequential α-Arylation/Alkylation: Access to 3,3-Disubstituted Oxindoles
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Rationally designed fluorene-based mono- and bimetallic Pd-PEPPSI complexes were synthesized and demonstrated to be effective for the one-pot sequential α-arylation/alkylation of oxindoles. This streamlined approach offers efficient access to functionalized 3,3-disubstituted oxindoles in excellent yields (up to 89%) under mild reaction conditions.
- Reddy Panyam, Pradeep Kumar,Ugale, Bharat,Gandhi, Thirumanavelan
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p. 7622 - 7632
(2018/06/22)
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- Method for preparing indole-2,3-dione derivatives by catalytic oxidation of microwave copper/peroxyacetic acid
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The invention discloses a method for preparing indole-2,3-dione derivatives by catalytic oxidation of microwave copper/peroxyacetic acid. The method comprises the following steps: a catalytic amount of catalyst copper iodide, indole, a derivative of the indole and peroxyacetic acid are added into a reaction vessel, wherein the indole, the derivative of the indole and the peroxyacetic acid are usedas raw materials, ethanol is used as a solvent, the reaction vessel is placed into a microwave reaction instrument, a reaction is performed at certain temperature and power, after a certain time, reduced-pressure concentration is performed, and a product is purified by column chromatography. The method provided by the invention is a method having novel raw materials, simple operation and high efficiency used for preparing a benzimidazole derivative; and compared with the prior art, the method provided by the invention has an obviously-accelerated reaction speed than that under conventional heating, mild reaction conditions, simple operation, a high yield, safety, low costs and environmental protection.
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Paragraph 0024; 0056
(2018/09/08)
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- NaI-mediated divergent synthesis of isatins and isoindigoes: A new protocol enabled by an oxidation relay strategy
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A new approach for the synthesis of isatins and isoindigoes by an inexpensive and environmentally friendly NaI-mediated transformation is disclosed. The selectivity could be switched by simply varying the solvent, and isatins (using THF) and isoindigoes (using DMSO) could be obtained in moderate to excellent yields.
- Zhang, Hong-Hua,Wang, Yong-Qiang,Huang, Long-Tao,Zhu, Long-Qing,Feng, Yi-Yue,Lu, Ying-Mei,Zhao, Quan-Yi,Wang, Xue-Qiang,Wang, Zhen
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supporting information
p. 8265 - 8268
(2018/07/29)
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- Synthesis, Crystal Structure, and Biological Activity of Novel Anthranilic Diamide Insecticide Containing Propargyl Ether Group
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In search of environmentally benign insecticides with high activity, low toxicity, and low residue, a series of novel anthranilic diamide containing propargyl ether were designed and synthesized. All compounds were characterized by1H NMR spectroscopy, high-resolution mass spectrometry, or elemental analysis. The single crystal structure of 18g was determined by X-ray diffraction. The insecticidal activities against Lepidoptera pests of the new compounds were evaluated. Their insecticidal activities against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella) indicated that most of the compounds showed moderate to high activities at the tested concentration.
- Huang, Zhiqiang,Tong, Jun,Zhou, Sha,Xiong, Lixia,Wang, Hongxue,Zhao, Yu
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p. 1036 - 1045
(2016/07/28)
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- A Benzisoelenazolone modified pyrrole methyl ester substituted indole ketone compound and use thereof
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The invention discloses a benzisoselenazolone-modified pyrrolyl formate-substituted indolone compound and a use thereof. The invention depends on and claims the priority of a Chinese patent application 201110105248.0 submitted on April 26, 2011. Through reference, all contents of the Chinese patent application 201110105248.0 are incorporated into the invention. The benzisoselenazolone-modified pyrrolyl formate-substituted indolone compound is shown in the general formula I. The 2-indolone compound provided by the invention has excellent antitumor activity and can be widely used for preparation of antitumor drugs.
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Paragraph 0113-0114; 0211-0213
(2016/10/08)
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- Synthesis of diverse isatins: Via ring contraction of 3-diazoquinoline-2,4-diones
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An efficient synthesis of diverse isatin derivatives was accomplished by a copper-mediated reaction of 3-diazoquinoline-2,4-diones via ring contraction through domino Wolff rearrangement, decarboxylation, bromination, substitution, and dehydration. This protocol has several advantages as a one-pot procedure, with functional group tolerance, and high yield.
- Shrestha, Rajeev,Lee, Gun Joon,Lee, Yong Rok
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p. 63782 - 63787
(2016/07/19)
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- Synthesis and pharmacological evaluation of N-benzyl substituted 4-bromo-2,5-dimethoxyphenethylamines as 5-HT2A/2C partial agonists
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N-Benzyl substitution of phenethylamine 5-HT2A receptor agonists has dramatic effects on binding affinity, receptor selectivity and agonist activity. In this paper we examine how affinity for the 5-HT2A/2C receptors are influenced by N-benzyl substitution of 4-bromo-2,5-dimethoxyphenethylamine derivatives. Special attention is given to the 2′ and 3′-position of the N-benzyl as such compounds are known to be very potent. We found that substitutions in these positions are generally well tolerated. The 2′-position was further examined using a range of substituents to probe the hydrogen bonding requirements for optimal affinity and selectivity, and it was found that small changes in the ligands in this area had a profound effect on their affinities. Furthermore, two ligands that lack a 2′-benzyl substituent were also found to have high affinity contradicting previous held notions. Several high-affinity ligands were identified and assayed for functional activity at the 5-HT2A and 5-HT2C receptor, and they were generally found to be less efficacious agonists than previously reported N-benzyl phenethylamines.
- Hansen, Martin,Jacobsen, Stine Engesgaard,Plunkett, Shane,Liebscher, Gudrun Eckhard,McCorvy, John D.,Br?uner-Osborne, Hans,Kristensen, Jesper Langgaard
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p. 3933 - 3937
(2015/01/30)
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- Structure-based design, synthesis, andanticonvulsant activity of isatin-1-N-phenylacetamide derivatives
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In an effort to develop the potent anticonvulsant agents, a series of novel isatin-1-N-phenylacetamide derivatives was synthesized and screened for their in vivo anticonvulsant activity against maximal electroshock test and evaluated for their neurotoxicity by the rotarod test at the same dose levels. Ten compounds exhibited the anticonvulsant activity. 2-(5-Methyl-2,3-dioxoindolin-1- yl)-N-phenylacetamide (4b) was found to be the most potent compound of the series with an ED50 of 91.3 mg/kg, TD50 of >1,000 mg/kg, a higher protective index (PI = TD50/ED50, >11) was gained than the reference drug phenobarbital and carbamazepine. The essential structural features responsible for interaction with receptor site are established within a suggested pharmacophore. Springer Science+Business Media 2013.
- Xie, Chao,Tang, Li-Ming,Li, Fu-Nan,Guan, Li-Ping,Pan, Cheng-Yan,Wang, Si-Hong
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p. 2161 - 2168
(2014/05/06)
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- Design, synthesis and antiproliferative activity evaluation of new 5-azaisoindigo derivatives
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New 5-azaisoindigo derivatives were synthesized with two key intermediates 5-azaoxindole (7) and substituted indole-2,3-dione (10) in this paper. Intermediate 7 was prepared from 3-methylpyridine (1) through 6 steps containing oxidation reaction and so on. Intermediate 10 was obtained by a convenient Sandmeyer's method. The target compounds 5-azaisoindigo derivatives 11a-f were obtained by condensation of these two intermediates 7 and 10 in acidic condition. All target compounds were evaluated for their antiproliferative activity against seven cell lines by SRB assay. Compounds 11e and 11f showed significant antiproliferative activity against K562 cells (IC50: 8.9 μM and 13.6 μM, respectively).
- Zhao, Ping,Yan, Yun,Li, Yanzhong,Zhang, Aiying,Zhan, Xiaoping,Liu, Zenglu,Mao, Zhenmin,Chen, Shaoxiong,Wang, Liqun
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p. 1923 - 1932
(2014/08/18)
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- QUINAZOLINES AND AZAQUINAZOLINES AS DUAL INHIBITORS OF RAS/RAF/MEK/ERK AND PI3K/AKT/PTEN/MTOR PATHWAYS
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The present application provides novel quinazolines and azaquinazolines and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in for co-regulating RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways by administering a therapeutically effective amount of one or more of the compounds of formula (I), wherein X, Y, T and R4, and R6 to R8' are defined herein, to a patient. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment/ the disease is cancer.
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- Synthesis of isatins by I2/TBHP mediated oxidation of indoles
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An I2/TBHP mediated oxidation of commercially available indoles has been developed, which affords isatins in moderate to good yields.
- Zi, You,Cai, Zhong-Jian,Wang, Shun-Yi,Ji, Shun-Jun
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supporting information
p. 3094 - 3097
(2014/06/23)
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- Synthesis, crystal structure and biological activity of a novel anthranilic diamide insecticide containing allyl ether
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In search of environmentally benign insecticides with high activity, low toxicity and low residue, a series of novel anthranilic diamides containing allyl ether were designed and synthesized. All the compounds were characterized by 1H NMR spectroscopy, HRMS or elemental analysis. The single crystal structure of 18e was determined by X-ray diffraction. The insecticidal activities of the new compounds were evaluated. The results showed that some compounds exhibited excellent insecticidal activities against Lepidoptera pests. Among this series compounds, 18l showed 100 % larvicidal activity against Mythimna separate Walker and Plutella xylostella Linnaeus at the test concentration.
- Zhao, Yu,Xiong, Li-Xia,Xu, Li-Ping,Wang, Hongxue,Xu, Han,Li, Hua-Bin,Tong, Jun,Li, Zheng-Ming
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p. 3071 - 3088
(2013/09/23)
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- Design, synthesis and biological activities of novel anthranilic diamide insecticide containing trifluoroethyl ether
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Two series of novel anthranilic diamide insecticide containing trifluoroethyl ether were designed and synthesized, and their structures were characterized by 1H NMR spectroscopy, elemental analysis and single crystal X-ray diffraction analysis. The insecticidal activities of the new compounds were evaluated. The results of bioassays indicated that some of these title compounds exhibited excellent insecticidal activities. The insecticidal activities of compounds 19a, 19b, 19d, 19g, 19k and 19m against oriental armyworm at 2.5 mg·kg-1 were 100%. The larvicidal activities of 19a, 19b, 19c, 19d, 19e, 19g and 19n against diamond-back moth were 100% at 0.1 mg·kg-1. Surprisingly, most of them still exhibited perfect insecticidal activity against diamond-back moth when the concentration was reduced to 0.05 mg·kg-1, which was higher than the commercialized Chlorantraniliprole.
- Zhao, Yu,Li, Yongqiang,Xiong, Lixia,Wang, Hongxue,Li, Zhengming
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p. 1748 - 1758
(2012/11/13)
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- A palladium-catalyzed synthesis of isatins (1H-Indole-2,3-diones) from 1-(2-haloethynyl)-2-nitrobenzenes
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An inherently regiospecific synthesis of isatins (1H-indole-2,3-diones) starting from 1-halo-2-nitrobenzenes is described. The isatins are formed by an intramolecular palladium-catalyzed annulation of 2-(2-haloethynyl)-1-nitrobenzenes via the formation of 2-haloisatogens.
- S?derberg, Bj?rn C.G.,Gorugantula, Sobha P.,Howerton, Chet R.,Petersen, Jeffrey L.,Dantale, Shubhada W.
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experimental part
p. 7357 - 7363
(2009/12/04)
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- Methods and Compositions for Selectin Inhibition
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The present teachings relate to novel compounds of formula I: wherein the constituent variables are as defined herein. Compounds of the present teachings can act as antagonists of the mammalian adhesion proteins known as selecting. Methods for treating or preventing selectin-mediated disorders are provided, which include administration of these compounds in a therapeutically effective amount.
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Page/Page column 23-24
(2008/12/04)
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- Use of pyridinium chlorochromate and reusable polyaniline salt catalyst combination for the oxidation of indoles
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A novel method is described herein for the simple, convenient and efficient oxidation of indoles to isatins using pyridinium chlorochromate with the aid of polyaniline salt catalyst at room temperature or at reflux in dichloroethane. Interestingly, oxidation of 3-alkyl indoles by this procedure gave 3-hydroxy 3-alkyl oxindoles. On the other hand, indol-3-alkanols gave mixtures of isatins and 3-formyl indoles. This is the first example of use of polyaniline as a catalyst in oxidation reaction.
- Kumar, Chebolu Naga Sesha Sai Pavan,Devi, Chebrolu Lavanya,Rao, Vaidya Jayathirtha,Palaniappan, Srinivasan
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scheme or table
p. 2023 - 2027
(2009/04/07)
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- Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists
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Leukocyte recruitment of sites of inflammation and tissue injury involves leukocyte rolling along the endothelial wall, followed by firm adherence of the leukocyte, and finally transmigration of the leukocyte across cell junctions into the underlying tissue. The initial rolling step is mediated by the interaction of leukocyte glycoproteins containing active moieties such as sialyl Lewisx (sLex) with P-selectin expressed on endothelial cells. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of inflammatory diseases such as arthritis. High-throughput screening of the Wyeth chemical library identified the quinoline salicylic acid class of compounds (1) as antagonists of P-selectin, with potency in in vitro and cell-based assays far superior to that of sLex. Through iterative medicinal chemistry, we identified analogues with improved P-selectin activity, decreased inhibition of dihydrooratate dehydrogenase, and acceptable CYP profiles. Lead compound 36 was efficacious in the rat AIA model of rheumatoid arthritis.
- Kaila, Neelu,Janz, Kristin,DeBernardo, Silvano,Bedard, Patricia W.,Camphausen, Raymond T.,Tam, Steve,Tsao, Desirée H.H.,Keith Jr., James C.,Nickerson-Nutter, Cheryl,Shilling, Adam,Young-Sciame, Ruth,Wang, Qin
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- 2-(4-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[H] quinoline-4-carboxylic acid (PSI-697): Identification of a clinical candidate from the quinoline salicylic acid series of P-selectin antagonists
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P-selectin-PSGL-1 interaction causes rolling of leukocytes on the endothelial cell surface, which subsequently leads to firm adherence and leukocyte transmigration through the vessel wall into the surrounding tissues. P-selectin is upregulated on the surface of both platelets and endothelium in a variety of atherosclerosis-associated conditions. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of atherosclerosis. High-throughput screening and subsequent analoging had led to the identification of compound 1 as the lead candidate. Herein, we report the continuation of this work and the discovery of a second-generation series, the tetrahydrobenzoquinoline salicylic acids. These compounds have improved pharmacokinetic properties, and a number of them have shown oral efficacy in mouse and rat models of atherogenesis and vascular injury. The lead 31 (PSI-697), is currently in clinical development for the treatment of atherothrombotic vascular events.
- Kaila, Neelu,Janz, Kristin,Huang, Adrian,Moretto, Alessandro,DeBernardo, Silvano,Bedard, Patricia W.,Tam, Steve,Clerin, Valerie,Keith Jr., James C.,Tsao, Desirée H.H.,Sushkova, Natalia,Shaw, Gray D.,Camphausen, Raymond T.,Schaub, Robert G.,Wang, Qin
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- The synthesis and resolution of 2,2′-, 4,4′-, and 6,6′-substituted chiral biphenyl derivatives for application in the preparation of chiral materials
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Various routes were examined for the synthesis of chiral biphenyl species that are substituted at the 2,2′, 4,4′ and 6,6′ positions. Because the biaryl bond is tetrasubstituted, many coupling reactions were not suitable. The most reliable coupling reaction proved to be the Ullmann, which gave the desired product in 82% yield. The products were required as the starting point for the preparation of chiral materials using these as the monomer. For this reason, a route was required that produced large quantities of both enantiomers. The two enantiomers were resolved at the penultimate step by the use of chiral HPLC. A complicating feature proved to be the necessity to have a reactive group at the 4,4′ positions, which would permit polymerization though this point. Ultimately, we employed an Ullmann coupling on a dibrominated arene, which occurred selectively at the more hindered bromine by virtue of the directing effect of an ortho ester substituent.
- Montoya-Pelaez, Pedro J.,Uh, Yoon-Seo,Lata, Christopher,Thompson, Matthew P.,Lemieux, Robert P.,Crudden, Cathleen M.
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p. 5921 - 5929
(2007/10/03)
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- Synthesis of brequinar analogue inhibitors of malaria parasite dihydroorotate dehydrogenase
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A series of 2-phenyl quinoline-4-carboxylic acid derivatives related to brequinar, an inhibitor of human dihydroorotate dehydrogenase (DHODH), has been prepared and evaluated as inhibitors of DHODH from the malaria parasite Plasmodium falciparum. Brequinar was essentially inactive against PfDHODH (IC50 880 μM) whereas several members of the series inhibited PfDHODH. Unexpectedly, replacement of the carboxylic acid required for brequinar to inhibit hDHODH was not essential in the diisopropylamides that inhibited PfDHODH.
- Boa, Andrew N.,Canavan, Shane P.,Hirst, Paul R.,Ramsey, Christopher,Stead, Andrew M.W.,McConkey, Glenn A.
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p. 1945 - 1967
(2007/10/03)
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- Biphenyl-substituted quinoline derivatives
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Compounds of the formula wherein X, R1, R2, R3, R4, R5, R6, A, B, D and E are as defined herein. These compounds inhibit the action of angiotensin II and are useful, therefore, for example, as antihypertensive agents.
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- Process for producing quinolin-2-yl benzoic acid compounds
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A quinolin-2-yl benzoic acid compound useful as intermediates of angiotensin II antagonists which are effective for treating hypertension can be produced by decarboxylating a 2-carboxyphenyl-4-quinolinecarboxylic acid compound in which two carboxyl groups are not substituted and a benzene ring and a quinoline ring may have substituents inert to said decarboxylation reaction.
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- Syntheses, Enrichment of Enantiomers, and Barriers to Racemization of Twisted 9,10-Phenanthrenquinones
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The known syntheses of the 9,10-phenanthrenequinones 10a-c were improved by the chlorotrimethylsilane modification of the acyloin condensation of biaryl diesters.The novel quinones 4a, 4b, and 12 were prepared.For the first time, enantiomers (M and P) of this class of compounds were enriched semipreparatively by liquid chromatography on optically active sorbents.The barriers to thermal racemization amount to 90-130 kJ mol-1 (Table 2) and are thus higher than the barriers for the corresponding phenanthrene hydrocarbons by roughly 20 kJ mol -1.The reasons for this increase are discussed in terms of repulsive interactions in the trans ition state of helix inversion.
- Fritsch, Rainer,Hartmann, Erwin,Andert, Doris,Mannschreck, Albrecht
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p. 849 - 856
(2007/10/02)
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- Benzo-Fused Bicyclic Imides
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The benzo-fused bicyclic imides, 2 and 3, were synthesized via acetic anhydride promoted ring closure of lactam acids 10 and 15.Attempts to carry out the analogous reaction with lactam acid 21 failed to afford the desired 5,5-benzo-fused bicyclic imide 4.Possible reasons for the failure of this reaction are discussed.
- Pavia, Michael R.,Moos, Walter H.,Hershenson, Fred M.
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p. 560 - 564
(2007/10/02)
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- Benzobicyclic lactam acids and derivatives as cognition activators
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Benzobicyclic lactam acids having a fused aromatic carbocyclic and a saturated lactam ring of five- or six-members, their salts, esters, and amides, are useful for reversing amnesia. Pharmaceutical compositions including these compounds, a method of preparing the compounds, and a method of treating senility and reversing amnesia are also disclosed.
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- Benzotricyclic nitrogen-containing diones and their use in reversing electroconvulsive shock-induced amnesia
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A class of novel fused-ring, benzotricyclic, nitrogen-containing diones useful as agents in reversing electroconvulsive shock-induced amnesia. A method of preparing the compounds, pharmaceutical compositions including the compounds, and a method of reversing electroconvulsive shock-induced amnesia are disclosed.
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- A VERSATILE AND EFFICIENT PROCESS TO 3-SUBSTITUTED INDOLES FROM ANILINES
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Borane-mediated reductive elimination of α-thiomethyl-, α-hydroxy-, or α-alkoxy-, α'-substituted oxindoles affords 3-substituted indoles in high yield.Isatins, available via several routes from oxindoles, also afford indoles.
- Wierenga, Wendell,Griffin, John,Warpehoski, Martha A.
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p. 2437 - 2440
(2007/10/02)
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- Heterocyclic Systems Containing Bridgehead Nitrogen Atom: Part XLIII - Reactions of 6-Methyl-5H-2,3-dihydrotriazinoindole-3-thione with Bifunctional Compounds
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6-Methyl-5H-2,3-dihydrotriazinoindole-3-thione (III) on condensation with α-halogenoketones gives 6-methyl-3-aroylmethylthio-5H-triazinoindole hydrobromides (IV) which on PPA-catalyzed cyclization furnish 9-methyl-3-arylthiazolotriazinoindoles (V) and not the angular isomeric 9-methyl-1-arylthiazolotriazinoindoles (VII).The unequivocal synthesis of the angular isomer (VII) has been accomplished by the reaction of 7-methylisatin-3-thiosemicarbazone (II) with α-halogenoketones and subsequent cyclization of the intermediate (VI) using POCl3.Condensation of III with 1,2-dibromoethane, on the other hand, yields the angular isomer 9-methyl-1,2-dihydrothiazolotriazinoindole (VIII), identical with a sample obtained unambiguously by the reaction of II with 1,2-dibromoethane.
- Gupta, G. D.,Pujari, H. K.
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p. 311 - 314
(2007/10/02)
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- Air oxidation of oxindoles to isatins
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An aniline is converted to a 3-lower hydrocarbonthiooxindole by processes already known in the art and then air oxidized in an inert liquid vehicle in the presence of a base. The inert liquid vehicle advantageously is aprotic and the base is non-nucleophilic. Also, the aprotic liquid vehicle is desirably solvent for the starting 3-lower hydrocarbonthiooxindole and the non-nucleophilic base.
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- Derivatives of 3,3-bis-(4-hydroxyphenyl)-2-indolinone and process for the preparation thereof
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This invention relates to a group of compounds derived from 3,3-bis-(4-hydroxyphenyl)-2-indolinone having an effective laxative activity. The process for their preparation comprises reacting a substituted 3,3-bis-(4-hydroxyphenyl)-2-indolinone with a compound of the group comprising ethyl chloroformiate, chloracetyl chloride, acetyl chloride, acetyl anhydride, propionyl chloride, propionyl anhydride and chlorosulphonic acid (in pyridine).
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