- The Nucleophilic Ring-opening of N-Benzylquinuclidinium Bromide
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N-Benzylquinuclidinium bromide was ring opened by a series of heteronucleophiles, in the presence of cesium carbonate, to yield the corresponding N-benzyl-4-(2-hetero-ethyl)piperidines. The best yields were found with thiophenol (56%), phenol (55%), and benzimidazole (38%) as nucleophiles.
- Axelsson, Oskar,Peters, Dan
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- 2-Aminobenzothiazole derivatives: Search for new antifungal agents
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A new series of 6-substituted 2-aminobenzothiazole derivatives were synthesized and screened in vitro as potential antimicrobials. Almost all the compounds showed antifungal activity. In particular, compounds 1n,o, designed on the basis of molecular modeling studies, were the best of the series, showing MIC values of 4-8 μg/mL against Candida albicans, Candida parapsilosis and Candida tropicalis. None of the two compounds did show any cytotoxicity effect on human THP-1 cells.
- Catalano, Alessia,Carocci, Alessia,Defrenza, Ivana,Muraglia, Marilena,Carrieri, Antonio,Van Bambeke, Fran?oise,Rosato, Antonio,Corbo, Filomena,Franchini, Carlo
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- Ionic liquid as an efficient promoting medium for two-phase nucleophilic displacement reactions
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The use of the room temperature ionic liquid (RTIL) 1-n-butyl-3-methylimidazolium hexafluorophosphate as an efficient catalyst and solvent for several representative nucleophilic substitution reactions under aqueous-RTIL phase transfer conditions was explored. Recycling and reuse of the reaction medium was demonstrated for the azide formation.
- Louren?o, Nuno M.T.,Afonso, Carlos A.M.
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- Discovery of anilino-furo[2,3-d]pyrimidine derivatives as dual inhibitors of EGFR/HER2 tyrosine kinase and their anticancer activity
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Being responsible for the development of many cancer types, EGFR (Epidermal Growth Factor Receptor) and HER2 (Human Epidermal growth factor Receptor 2) were the focus of this study where a series of novel 4-anilino-furo[2,3-d]pyrimidine derivatives was designed, synthesized and biologically evaluated. Modification of the solvent accessible 5-position side chain greatly affected the in-vitro EGFR/HER2 inhibitory activity. Three derivatives bearing 5-carboxylic acid side chain, namely the 3-chloroanilino derivative (8c), the 3-bromoaniline (8d) and the lapatinib analogue (10) demonstrated the most significant submicromolar EGFR inhibition. Surprisingly, the in-vitro assay of the ester 7h and its acid analogue 10 showed a significant variation of results between the antiproliferative activity against A549 cell line (IC50 0.5 and 21.4 μM) respectively and EGFR inhibitory activity (18% and 100%) respectively, suggesting that 7h might be a prodrug for 10. This assumption was also affirmed by the in-vivo results, where the in-vivo antitumor assessment against EAC (Ehrlich Ascites Carcinoma) solid tumor model revealed that 7h and 8d (10 mg/kg dose) exhibited antitumor activity comparable to that of gefitinib at the same dose, exhibiting TGI% of 67%, 71% and 70%, respectively. This effect could be explained, at least partly, via activation of apoptosis, where 7h and 8d caused more than 2-fold increase of caspase 3 and cytochrome c expression than the control group which is comparable to that of gefitinib-treated group. Finally, 7h was the most effective apoptotic inducer, resulting in a significant elevation in annexin V–FITC-positive apoptotic cells (both early and late apoptosis) by 25 and 79-folds, respectively, compared to control, which is higher than that of gefitinib (22 and 61-folds, respectively).
- Hossam, Monia,Lasheen, Deena S.,Ismail, Nasser S.M.,Esmat, Ahmed,Mansour, Ahmed M.,Singab, Abdel Nasser B.,Abouzid, Khaled A.M.
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- Design, synthesis, and evaluation of salicyladimine derivatives as multitarget-directed ligands against Alzheimer's disease
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A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-β (Aβ) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aβ1–42 aggregation (91.3 ± 2.1%, 25 μM), inhibition of hMAO-B (IC50, 1.73 ± 0.39 μM), antioxidant effects (43.4 ± 2.6 μM of IC50 by DPPH method, 0.67 ± 0.06 trolox equivalent by ABTS method), metal chelation and BBB penetration. Furthermore, compound 5 had neuroprotective effects against ROS generation, H2O2-induced apoptosis, 6-OHDA-induced cell injury, and a significant in vitro anti-inflammatory activity. Collectively, these findings highlighted that compound 5 was a potential balanced multifunctional neuroprotective agent for the development of anti-AD drugs.
- Yang, Hua-Li,Cai, Pei,Liu, Qiao-Hong,Yang, Xue-Lian,Fang, Si-Qiang,Tang, Yan-Wei,Wang, Cheng,Wang, Xiao-Bing,Kong, Ling-Yi
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- Ultrasound assisted arylation of benzyl alcohol with 4-nitrochlorobenzene under a new multi-site phase-transfer catalyst in solid-liquid condition
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The ultrasound assisted preparation of 1-(benzyloxy)-4-nitrobenzene from the reaction of 4-chloronitrobenzene (CNB) and benzyl alcohol was carried out successfully using potassium hydroxide and catalyzed by a new multi-site phase-transfer catalyst (MPTC) viz., 1,3,5-triethyl-1,3,5-trihexyl-1,3,5- triazinane-1,3,5-triium trichloride in a solid-liquid reaction condition (SL-MPTC). The advantage of using SL-MPTC is to avoid a serious hydration of potassium salt of benzyl alcohol in the reaction between 4-chloronitrobenzene (CNB) and benzyl alcohol. The reaction is greatly enhanced in the solid-liquid system, catalyzed by multi-site quaternary ammonium salt (MPTC) and ultrasound irradiation (40 kHz, 300 W) in a batch reactor, it shows that the overall reaction greatly enhanced with ultrasound irradiation than without ultrasound. The reaction mechanism is proposed and verified by examining the experimental evidence. A kinetic model is proposed in which a pseudo first-order rate law is sufficient to describe the results, such as the effects of agitation speed, ultrasound, different phase transfer catalysts and the effect of organic solvents, the amount of newly prepared MPTC, the effect of temperature, the amount of water, the concentration of 4-chloronitrobenzene (CNB) and potassium hydroxide concentrations. The apparent rate constant (kapp) were investigated in detail. Rational explanations to account for the phenomena on the results were made.
- Selvaraj, Varathan,Abimannan, Pachaiyappan,Rajendran, Venugopal
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- Structure based design, synthesis, and biological evaluation of imidazole derivatives targeting dihydropteroate synthase enzyme
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In this study, we have designed and synthesized 2-((5-acetyl-1-(phenyl)-4-methyl-1H-imidazol-2-yl)thio)-N-(4-((benzyl)oxy)phenyl) acetamide derivatives. Antimicrobial activities of all the imidazole derivatives have been examined against Gram-positive and Gram-negative bacteria and results showed that the conjugates have appreciable antibacterial activity. Besides, several analogous were evaluated for their in vitro antiresistant bacterial strains such as Extended-spectrum beta-lactamases (ESBL), Vancomycin-resistant Enterococcus (VRE), and Methicillin-resistant Staphylococcus aureus (MRSA). The SAR revealed that the 12l compound resulted in potency against all bacterial strains as well as ESBL, VRE, and MRSA strains. Lipinski's rule of five, and ADME studies were preformed for all the synthesized compounds with Staphylococcus aureus dihydropteroate synthase (saDHPS) protein (PDB ID: 6CLV) and were found standard drug-likeness properties of conjugates. Moreover, the binding mode of the ligands with the protein study has been examined by molecular docking and results are quite promising. Besides, all the analogous were tested for their in vitro antituberculosis, antimalarial, and antioxidant activity.
- Daraji, Drashti G.,Rajani, Dhanji P.,Rajani, Smita D.,Pithawala, Edwin A.,Jayanthi, Sivaraman,Patel, Hitesh D.
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supporting information
(2021/02/16)
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- Chemoselective Hydrogenation of Nitroarenes Using an Air-Stable Base-Metal Catalyst
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The reduction of nitroarenes to anilines as well as azobenzenes to hydrazobenzenes using a single base-metal catalyst is reported. The hydrogenation reactions are performed with an air-and moisture-stable manganese catalyst and proceed under relatively mild reaction conditions. The transformation tolerates a broad range of functional groups, affording aniline derivatives and hydrazobenzenes in high yields. Mechanistic studies suggest that the reaction proceeds via a bifunctional activation involving metal-ligand cooperative catalysis.
- Zubar, Viktoriia,Dewanji, Abhishek,Rueping, Magnus
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supporting information
p. 2742 - 2747
(2021/05/05)
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- Design, synthesis and evaluation of tetrahydrocarbazole derivatives as potential hypoglycemic agents
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Two series of tetrahydrocarbazole derivatives have been designed and synthesized based on ZG02, a promising candidate developed in our previous studies. The newly prepared compounds were screened for glucose consumption activity in HepG2 cell lines. Aza-tetrahydrocarbazole compound 12b showed the most potent hypoglycemic activity with a 45% increase in glucose consumption when compared to the solvent control, which had approximately 1.2-fold higher activity than the positive control compounds (metformin and ZG02). An investigation of the potential mechanism indicated that 12b may exhibit hypoglycemic activity via activation of the AMPK pathway. Metabolic stability assays revealed that 12b showed good stability profiles in both artificial gastrointestinal fluids and blood plasma from SD rats. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 12b was a potent hypoglycemic agent.
- Chen, Rui,Cheng, Fei,Cui, Xing,Du, Yao,Fan, Ling-Ling,Guo, Bing,Li, Shu-Min,Tang, Lei,Wang, Jian-Ta,Wang, Li-Li,Wu, Hao-Shu,Yang, Sheng-Gang,Zhang, Ji-Quan,Zhang, Na-Na
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- Method for synthesizing aryl benzyl ether compound
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The invention discloses a method for synthesizing aryl benzyl ether compounds, which comprises the following steps: by using an iron (III) complex containing 1, 3-di-tert-butyl imidazole cations and having a molecular formula of [(tBuNCH = CHNtBu) CH] [FeBr4] as a catalyst and di-tert-butyl peroxide as an oxidant, carrying out oxidative coupling reaction on phenolic compounds and toluene compounds to synthesize the corresponding aryl benzyl ether compounds. The method is the first example for preparing the aryl benzyl ether compound through the oxidative coupling reaction of the phenolic compound and the toluene compound, which is realized by an iron-based catalyst, and has the advantages of atom economy, environmental friendliness and good substrate applicability.
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Paragraph 0020-0022; 0041
(2021/04/14)
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- Application of iron (III) complex containing 1,3-di-tert-butyl imidazole cations in synthesis of aryl benzyl ether compounds
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The invention discloses an application of an iron (III) complex containing 1,3-di-tert-butyl imidazole cations in synthesis of aryl benzyl ether compounds, and particularly relates to a method for synthesizing corresponding aryl benzyl ether compounds by taking di-tert-butyl peroxide as an oxidizing agent and carrying out oxidative coupling reaction on phenolic compounds and toluene compounds. According to the method, the iron (III) complex is used as the catalyst for the first time, and oxidative coupling of the phenolic compound and the toluene compound is realized. The method is the first oxidative coupling reaction of phenolic compounds and benzyl C(sp3)-H bonds, and a new method is provided for synthesizing aryl benzyl ether compounds. Compared with an existing synthesis method, the method provided by the invention avoids using toxic and polluting halogenated hydrocarbon and strong base, has better atom economy, and conforms to the development concept of green synthetic chemistry.
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Paragraph 0020-0022
(2021/04/26)
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- Applicability of aluminum amalgam to the reduction of arylnitro groups
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An array of arylnitro compounds with various functionality were treated with freshly-prepared aluminum amalgam in THF/water solution and resulted in the corresponding arylamines. The Al(Hg)-mediated reductions are relatively rapid with consumption of the amalgam and disappearance of starting material occurring over 20–30 min. The workup of the reductions involves only removal of the insoluble by-products by filtration followed by concentration. Only in some cases is chromatography required to secure the pure product. The desired arylamines are furnished in quantities of 25–100 mg, which in some cases, could be taken on to the next reaction without further purification. Reductions of 4-nitrobenzyl derivatives of carbohydrates or nucleosides were selective in affording the corresponding 4-aminobenzyl products. To show applicability in click chemistry, selected aminobenzyl products are directly azidated to yield products that were then used in click reactions to afford the corresponding 1,2,3-triazoles.
- Luzzio, Frederick A.,Monsen, Paige J.
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supporting information
(2020/11/02)
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- PHENAZINES AS INHIBITORS OF DISCOIDIN DOMAIN RECEPTORS 2 (DDR2)
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The invention concerns a compound of Formula (I) or a pharmaceutically acceptable salt or derivative thereof, wherein R1 and R2 are independently H or a group -O(CHR5)nR6, where n is an integer value from 1 to 3, R5 is independently H or CH3 for each integer value of n, R6 is H, an optionally substituted saturated heterocyclic ring or NR7R8, where R7 and R8 are independently H or (C1-C3)alkyl, R4 is H or CH3, R3 is a group selected from the group consisting of an optionally substituted aryl, (C3-C6)alkyl, benzyl, an optionally substituted saturated (C3-C6)cycloalkyl and an optionally substituted unsaturated heterocyclic ring for use as a medicament. The compounds as medicament are used in the treatment (DDR2)-mediated diseases and disorders such as a cancer, acute and chronic pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, atherosclerosis, various fibrotic disorders, fibrosis or kidney injury.
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Page/Page column 23
(2020/10/21)
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- Aryl Ether Syntheses via Aromatic Substitution Proceeding under Mild Conditions
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In this study, mild conditions for aromatic substitutions during the syntheses of aryl ethers were developed. In the reaction conditions, the choices of solvent, base, and the sequence for the addition of the reagents proved important. A wide variety of alcohols were used directly as nucleophiles and smoothly reacted with aryl chlorides that possessed either a nitro or a cyano group at either the ortho- or para-position. Controlled experiments we performed suggested that the reaction underwent a charge-transfer process mediated by a combination of DMF and tert-BuOK.
- Ando, Shin,Tsuzaki, Marina,Ishizuka, Tadao
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p. 11181 - 11189
(2020/10/12)
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- Catalytic Transfer Hydrodebenzylation with Low Palladium Loading
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A highly-efficient catalytic system for hydrodebenzylation reaction is described. The cleavage of O-benzyl and N-benzyl protecting groups was performed using an uncommonly low palladium loading (0.02–0.3 mol%; TON up to 5000) in a relatively short reaction time. The approach was used for a variety of substrates including pharmaceutically important precursors, and gram-scale deprotection reaction was shown. Transfer conditions together with easy-to-make Pd/C catalyst are the key features of this debenzylation scheme. (Figure presented.).
- Yakukhnov, Sergey A.,Ananikov, Valentine P.
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supporting information
p. 4781 - 4789
(2019/09/16)
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- Structural optimization and structure–activity relationship of 4-thiazolidinone derivatives as novel inhibitors of human dihydroorotate dehydrogenase
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Human dihydroorotate dehydrogenase (hDHODH), one of the attractive targets for the development of immunosuppressive drugs, is also a potential target of anticancer drugs and anti-leukemic drugs. The development of promising hDHODH inhibitors is in high demand. Based on the unique binding mode of our previous reported 4-thiazolidinone derivatives, via molecular docking method, three new series 4-thiazolidinone derivatives were designed and synthesized as hDHODH inhibitors. The preliminary structure–activity relationship was investigated. Compound 9 of biphenyl series and compound 37 of amide series displayed IC50 values of 1.32 μM and 1.45 μM, respectively. This research will provide valuable reference for the research of new structures of hDHODH inhibitors.
- Zeng, Fanxun,Quan, Lina,Yang, Guantian,Qi, Tiantian,Zhang, Letian,Li, Shiliang,Li, Honglin,Zhu, Lili,Xu, Xiaoyong
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- Natural Product Neopeltolide as a Cytochrome bc1 Complex Inhibitor: Mechanism of Action and Structural Modification
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The marine natural product neopeltolide was isolated from a deep-water sponge specimen of the family Neopeltidae. Neopeltolide has been proven to be a new type of inhibitor of the cytochrome bc1 complex in the mitochondrial respiration chain. However, its detailed inhibition mechanism has remained unknown. In addition, neopeltolide is difficult to synthesize because of its very complex chemical structure. In the present work, the binding mode of neopeltolide was determined for the first time by integrating molecular docking, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, which showed that neopeltolide is a Qo site inhibitor of the bc1 complex. Then, according to guidance via inhibitor-protein interaction analysis, structural modification was carried out with the aim to simplify the chemical structure of neopeltolide, leading to the synthesis of a series of new neopeltolide derivatives with much simpler chemical structures. The calculated binding energies (ΔGcal) of the newly synthesized analogues correlated very well (R2 = 0.90) with their experimental binding free energies (ΔGexp), which confirmed that the computational protocol was reliable. Compound 45, bearing a diphenyl ether fragment, was successfully designed and synthesized as the most potent candidate (IC50 = 12 nM) against porcine succinate cytochrome c reductase. The molecular modeling results indicate that compound 45 formed a π-π interaction with Phe274 and two hydrogen bonds with Glu271 and His161. The present work provides a new starting point for future fungicide discovery to overcome the resistance that the existing bc1 complex inhibitors are facing.
- Zhu, Xiao-Lei,Zhang, Rui,Wu, Qiong-You,Song, Yong-Jun,Wang, Yu-Xia,Yang, Jing-Fang,Yang, Guang-Fu
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- Ambident Reactivity of Phenolate Anions Revisited: A Quantitative Approach to Phenolate Reactivities
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Prompted by the observation that the regioselectivities of phenolate reactions (C versus O attack) are opposite to the predictions by the principle of hard and soft acids and bases, we performed a comprehensive experimental and computational investigation of phenolate reactivities. Rate and equilibrium constants for the reactions of various phenolate ions with benzhydrylium ions (Aryl2CH+) and structurally related quinone methides have been determined photometrically in polar aprotic solvents. Quantum chemical calculations at the SMD(MeCN)/M06-2X/6-31+G(d,p) level confirmed that O attack is generally favored under kinetically controlled conditions, whereas C attack is favored under thermodynamically controlled conditions. Exceptions are diffusion-limited reactions with strong electrophiles, which give mixtures of products arising from O and C attack, as well as reactions with metal alkoxides in nonpolar solvents, where oxygen attack is blocked by strong ion pairing. The Lewis basicity (LB) and nucleophilicity (N, sN) parameters of phenolates determined in this work can be used to predict whether their reactions with electrophiles are kinetically or thermodynamically controlled and whether the rates are activation- or diffusion-limited. Comparison of the measured rate constants for the reactions of phenolates with carbocations with the Gibbs energies for single-electron transfer manifests that these reactions proceed via polar mechanisms.
- Mayer, Robert J.,Breugst, Martin,Hampel, Nathalie,Ofial, Armin R.,Mayr, Herbert
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p. 8837 - 8858
(2019/07/08)
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- AGRICULTURAL CHEMICALS
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The present invention relates to picolinic acid derivatives that are useful in treating fungal diseases ofplants.
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Page/Page column 55
(2019/08/08)
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- Novel substituted sulfamide compound, preparation method and application thereof as PTP1B inhibitor
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The invention relates to a novel substituted sulfamide compound of a structure of a formula I as shown in the description, a pharmaceutically acceptable salt of the novel substituted sulfamide compound, a preparation method, and relates to a medicinal composition comprising the compound of the formula I or a pharmaceutically acceptable salt of the compound. The compound of the formula I or the pharmaceutically acceptable salt of the compound has activity of inhibiting protein tyrosine phosphatase 1B (PTP1B), so that the compound or the pharmaceutically acceptable salt of the compound has an application of preparing a medicine for preventing/treating symptoms or diseases such as hyperglycemia and type-2 diabetes.
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Paragraph 0019; 0022
(2017/06/28)
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- Synthesis and application of a novel asymmetric azo reagent: 1-(tert-butyl)-2-(4-chlorobenzyl) azodicarboxylate (tBCAD)
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A series of novel asymmetric azo reagents, 1-(tert-butyl)-2-(4-substituted benzyl) azodicarboxylate, were prepared. The synthetic process has the advantage of simpleness, easy operation, mild reaction condition and high yield. The 1-(tert-butyl)-2-(4-chlorobenzyl) azodicarboxylate (tBCAD) was selected for its stability and convenience to handle, and its precursor can be recycled by recrystallization with toluene. The tBCAD and DIAD were applied to a wide variety of Mitsunobu reactions. The experimental results showed that the performance of tBCAD in Mitsunobu reaction was comparable to that of DIAD, while the stability of tBCAD was much better than DIAD. Thus, tBCAD can be a novel, stable, effective azo-reagent for the Mitsunobu reaction.
- Xie, Jian,Xu, Cai,Dai, Qianjin,Wang, Xiaozhong,Xu, Gang,Chen, Yingqi,Dai, Liyan
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p. 5321 - 5326
(2017/08/04)
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- Discovery of 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-phenylacetamide derivatives as new potent and selective human sirtuin 2 inhibitors
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Human sirtuin 2 (SIRT2) plays pivotal roles in multiple biological processes such as cell cycle regulation, autophagy, immune and inflammatory responses. Dysregulation of SIRT2 was considered as a main aspect contributing to several human diseases, including cancer. Development of new potent and selective SIRT2 inhibitors is currently desirable, which may provide a new strategy for treatment of related diseases. Herein, a structure-based optimization approach led to new 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-phenylacetamide derivatives as SIRT2 inhibitors. SAR analyses with new synthesized derivatives revealed a number of new potent SIRT2 inhibitors, among which 28e is the most potent inhibitor with an IC50 value of 42?nM. The selectivity analyses found that 28e has a very good selectivity to SIRT2 over SIRT1 and SIRT3. In cellular assays, 28e showed a potent ability to inhibit human breast cancer cell line MCF-7 and increase the acetylation of α-tubulin in a dose-dependent manner. This study will aid further efforts to develop highly potent and selective SIRT2 inhibitors for the treatment of cancer and other related diseases.
- Yang, Lingling,Ma, Xiaobo,Yuan, Chen,He, Yanying,Li, Ling,Fang, Sha,Xia, Wei,He, Tao,Qian, Shan,Xu, Zhihong,Li, Guobo,Wang, Zhouyu
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p. 230 - 241
(2017/04/19)
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- N-(4-substituted phenyl)-2-substituted acetamide compound and is use as SIRT2 protein inhibitor
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The invention discloses a compound shown in the formula I or its pharmaceutically acceptable salt, crystalline form and solvate. X represents a group shown in the description, Y represents a group shown in the description, R1, R2 and R3 independently represent H, hydroxyl, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl or phenyl, and R4 represents aryl, heteroaryl, substituted aryl or substituted heteroaryl. The novel compound shown in the formula I has good inhibition activity to SIRT2 and tumors, has a good medicinal value and provides a novel potential choice for clinical medication.
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Paragraph 0152; 0153
(2017/08/02)
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- Method for preparing a SUO draw non-Buddhist nun (by machine translation)
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This invention involves a kind of SUO draw non-Buddhist nun (structural formula as follows) and its toluene sulfonate preparation method, this method, in order to P-nitro-phenol as raw materials, by the benzyl protection, reduction, condensation, debenzylation, coupling and salt forming the several step to synthesize SUO draw non-Buddhist nun. The preparation method of fewer steps, high yield, low cost, environmental pollution is small, is suitable for industrial production. (by machine translation)
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Paragraph 0011; 0012
(2016/12/22)
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- Piperazinone compounds and application thereof
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The invention belongs to the technical field of medicine and relates to 1-ethyl-4-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole-1-yl]butyl]piperazine-2,3-dione as well as a medical application, a stereoisomer and pharmaceutically acceptable salt thereof. The structural formula of 1-ethyl-4-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole-1-yl] butyl]piperazine-2,3-dione is represented in the specification; 1-ethyl-4-[4-[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole-1-yl]butyl]piperazine-2,3-dione and pharmaceutically acceptable acid addition salt of the compound can be combined with existing drugs or can be independently used as an estrogen receptor modulator for treating or preventing various estrogen function related diseases such as bone loss, fracture, osteoporosis, hectic fever, LDL cholesterol level rise, cardiovascular disease, cognitive impairment, brain degeneration disease and anxiety, as well as depression, sexual dysfunction, hypertension, retinal degeneration and cancer caused by estrogen deficiency, especially osteoporosis.
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Paragraph 0026; 0030; 0031; 0032
(2016/10/09)
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- Chromogenic nitrophenolate-based substrates for light-driven hybrid P450 BM3 enzyme assay
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The incorporation of a p-nitrophenoxy moiety in substrates has enabled the development of colorimetric assays to rapidly screen for O-demethylation activity of P450 enzymes. For the light-driven hybrid P450 BM3 enzymes, where a Ru(II) photosensitizer powers the enzyme upon visible light irradiation, we have investigated a family of p-nitrophenoxy derivatives as useful chromogenic substrates compatible with the light-driven approach. The validation of this assay and its adaptability to a 96-well plate format will enable the screening of the next generation of hybrid P450 BM3 enzymes towards C-H bond functionalization of non-natural substrates.
- Lam, Quan,Cortez, Alejandro,Nguyen, Thanh Truc,Kato, Mallory,Cheruzel, Lionel
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- Design and Synthesis of 4-Anilinothieno[2,3-d]pyrimidine-Based Compounds as Dual EGFR/HER-2 Inhibitors
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Dual inhibition of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER-2) is an attractive cancer therapeutic approach. In this study, new series of 4-anilinothieno[2,3-d]pyrimidines were designed, synthesized, and tested as dual EGFR/HER-2 kinase inhibitors. Five compounds (8a, 8b, 8e–g) demonstrated low to submicromolar inhibition of both kinases with IC50 values of 1.2, 0.6, 0.3, 0.2, 0.4 μM and 8.2, 3.4, 1.3, 0.5, 2.7 μM for the EGFR and HER-2, respectively. Introduction of a 5,6-tetramethylene moiety into the thienopyrimidine core bearing a 4-(3-fluorobenzyloxy)-3-chloroaniline tail resulted in a favorable increase in both the EGFR and HER-2 inhibitory activities. Compound 8f (IC50 EGFR/HER-2: 0.2/0.5 μM) also exhibited significant cell growth inhibition on some specific NCI cell lines, especially ovarian, breast, non-small-cell lung cancer, and renal cancer cell lines.
- Abd El Hadi, Soha R.,Lasheen, Deena S.,Hassan, Mahmoud A.,Abouzid, Khaled A. M.
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p. 827 - 847
(2016/11/09)
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- Room temperature, metal-free arylation of aliphatic alcohols
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Diaryliodonium salts are demonstrated as efficient arylating agents of aliphatic alcohols under metal-free conditions. The reaction proceeds at room temperature within 90 min to give alkyl aryl ethers in good to excellent yields. Aryl groups with electron
- Ghosh, Raju,Lindstedt, Erik,Jalalian, Nazli,Olofsson, Berit
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- Choline chloride based deep eutectic solvent as an efficient solvent for the benzylation of phenols
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Deep eutectic solvents (such as the combination of urea and choline chloride) are found to be promising solvent and phase-transfer-media for benzylation of phenol. These methods avoided the complexity of multiple alkylations giving selectively O-alkylated aromatic products. Good to excellent yields of the corresponding benzyl phenyl ether were obtained. The non-toxic, biodegradable, inexpensive, and recyclable nature of DES make this protocol green and cost-effective.
- Singh, Abhilash S.,Shendage, Suresh S.,Nagarkar, Jayashree M.
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p. 7243 - 7246
(2015/02/02)
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- PROCESS FOR THE PREPARATION AND PURIFICATION OF APIXABAN
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The present invention provides a process for the preparation and purification of apixaban.
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Paragraph 0152
(2014/08/06)
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- Metal-free synthesis of aryl ethers in water
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The first arylation of allylic and benzylic alcohols with diaryliodonium salts is reported. The reaction yields alkyl aryl ethers under mild and metal-free conditions. Phenols are arylated to diaryl ethers in good to excellent yields. The reaction employs diaryliodonium salts and sodium hydroxide in water at low temperature, and excess amounts of the coupling partners are avoided.
- Lindstedt, Erik,Ghosh, Raju,Olofsson, Berit
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supporting information
p. 6070 - 6073
(2014/01/06)
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- Copper-catalyzed N- and O-alkylation of amines and phenols using alkylborane reagents
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By the reaction of amines with alkylborane reagents in the presence of a catalytic amount of copper(II) acetate Cu(OAc)2 and di-tert-butyl peroxide, a cross-coupling reaction proceeded and alkylated amines were obtained in good to excellent yields. Phenols are also applicable for this reaction, and the corresponding alkyl aryl ethers were produced.
- Sueki, Shunsuke,Kuninobu, Yoichiro
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supporting information
p. 1544 - 1547
(2013/06/26)
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- C,N-chelated organotin(IV) compounds as catalysts for transesterification and derivatization of dialkyl carbonates
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The potential catalytic activity of selected C,N-chelated organotin(IV) compounds (e.g. halides and trifluoroacetates) for derivatization of both dimethyl carbonate (DMC) and diethyl carbonate (DEC) was investigated. Some tri-, di- and monoorganotin(IV) species (LCN(n-Bu)2SnCl (1), LCN(n-Bu)2SnCl.HCl (1a), LCN(n-Bu) 2SnI (2), LCNPh2SnCl (3), LCNPh 2SnI (4), LCN(n-Bu)SnCl2 (5), L CNSnBr3 (6) and [LCNSn(OC(O)CF 3)]2(μ-O)(μ-OC(O)CF3)2 (7)) bearing the LCN moiety (LCN = 2-(N,N-dimethylaminomethyl) phenyl-) were assessed as catalysts for reactions of both DMC and DEC with various substituted anilines. The catalytic activities of 4 and 7 for derivatization of DMC with p-substituted phenols were studied for comparison with the standard base K2CO3/Silcarbon K835 catalyst (catalyst 8). The composition of resulting reaction mixtures was monitored by multinuclear NMR spectroscopy, GC and GC-MS techniques. In general, catalysts 1, 3 and 7 exhibited the highest catalytic activity for all reactions studied, while some of them yielded selectively carbonates, carbamates, lactam or substituted urea. Copyright
- Weidlich, Tomas,Dusek, Libor,Vystrcilova, Barbora,Eisner, Ales,Svec, Petr,Ruzicka, Ales
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experimental part
p. 293 - 300
(2012/10/07)
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- Synthesis and reactivity of dimethoxy-functionalised Troeger's base analogues
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Troeger's base analogues were prepared bearing methoxy groups in the 1,7-, 2,8-, 3,9- or 4,10-positions. These compounds were converted to their dihydroxy analogues in excellent yields upon treatment with boron tribromide and the 4,10-dihydroxy analogue could be prepared by directly from 4-hydroxyaniline. The synthetic utility of the dihydroxy-functionalised compounds as building blocks was demonstrated by the synthesis of a dialkoxy and a diester Troeger's base analogue.
- Malik, Qasim M.,Ijaz, Sadia,Craig, Donald C.,Try, Andrew C.
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experimental part
p. 5798 - 5805
(2011/08/21)
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- Fe3O4@mesoporouspolyaniline: A highly efficient and magnetically separable catalyst for cross-coupling of aryl chlorides and phenols
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A high surface, magnetic Fe3O4@mesoporouspolyaniline core-shell nanocomposite was synthesized from magnetic iron oxide (Fe 3O4) nanoparticles and mesoporouspolyaniline (mPANI). The novel porous magnetic Fe3O4 was obtained by solvothermal method under sealed pressure reactor at high temperature to achieve high surface area. The mesoporouspolyaniline shell was synthesized by in situ surface polymerization onto porous magnetic Fe3O4 in the presence of polyvinylpyrrolidone (PVP) and sodium dodecylbenzenesulfonate (SDBS), as a linker and structure-directing agent, through 'blackberry nanostructures' assembly. The material composition, stoichiometric ratio and reaction conditions play vital roles in the synthesis of these nanostructures as confirmed by variety of characterization techniques. The role of the mesoporouspolyaniline shell is to stabilize the porous magnetic Fe3O4 nanoparticles, and provide direct access to the core Fe3O4 nanoparticles. The catalytic activity of magnetic Fe3O 4@mesoporousPANI nanocomposite was evaluated in the cross-coupling of aryl chlorides and phenols. Copyright
- Arundhathi,Damodara,Likhar, Pravin R.,Kantam, M. Lakshmi,Saravanan,Magdaleno, Travis,Kwon, Sun Hee
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supporting information; experimental part
p. 1591 - 1600
(2011/08/03)
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- Synthesis and biological evaluation of 1H-benzimidazol-5-ols as potent HBV inhibitors
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A new series of 1-methyl-1H-benzimidazol-5-ol derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in the HepG2.2.15 cell line. Some of the analogues in this series displayed inhibitory activity superior to lamivudine. Of them, compound 13b was the most potent one, showing an IC50 value of 7.8 μM and a SI value of 13.0. 2010 Published by Elsevier Ltd. All rights reserved.
- Zhao, Yanfang,Liu, Yajing,Chen, Dong,Wei, Zengquan,Liu, Wenzhao,Gong, Ping
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scheme or table
p. 7230 - 7233
(2011/01/03)
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- Synthesis and in vitro anti-hepatitis B virus activity of 1H-benzimidazol-5-ol derivatives
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A series of 1H-benzimidazol-5-ol derivatives were synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in HepG2.2.15 cells. Half of the tested compounds were found to be potent against HBsAg secretion with IC50 values less than 100μmol/L. Compounds 14c, 14d, and 14e showed significant inhibitory activity to the viral antigen HBeAg.
- Chen, Dong,Zhai, Xin,Yuan, Qiu Hui,Luo, Jian,Xie, Si Chang,Gong, Ping
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scheme or table
p. 1326 - 1329
(2011/10/09)
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- Synthesis of alkyl-aryl ethers by copper-catalyzed etherization reactions of aryl fluorides with tetraalkylammonium bromides and H2O
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Synthesis of alkyl aryl ethers via copper-catalyzed etherizations of electron-deficient aryl fluorides with quaternary ammonium bromides and water has been developed. In the presence of Cu(OAc)2, POPh3 (L4) and Cs2CO3, a variety of electron-deficient aryl fluorides underwent the reaction with quaternary ammonium bromides and H 2O in moderate to good yields. The mechanism was also discussed. Synthesis of alkyl aryl ethers via copper-catalyzed etherizations of electron-deficient aryl fluorides with quaternary ammonium bromides and water has been developed. In the presence of Cu(OAc)2, POPh3 (L4) and Cs2CO3, a variety of electron-deficient aryl fluorides underwent the reaction with quaternary ammonium bromides and H 2O in moderate to good yields. Copyright
- Wang, Feng,Tang, Boxiao,Xie, Yexiang,Li, Jinheng
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experimental part
p. 2318 - 2322
(2011/10/03)
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- Efficient catalytic activity of copper/aluminum hydrotalcite in diaryl ether synthesis
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A simple copper/aluminum hydrotalcite (Cu/Al-HT) catalyzed arylation of phenols with aryl iodides afforded the corresponding diaryl ethers in moderate to excellent yields. This ligand- free Cu/Al-HT catalyzed coupling of aryl iodides with phenols resulted in high yields of diaryl ethers in the absence of an additive. The catalyst was quantitatively recovered from the reaction by simple filtration and reused for a number of cycles. Georg Thieme Verlag Stuttgart New York.
- Sreedhar,Arundhathi,Reddy, M. Amarnath,Kantam, M. Lakshmi
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experimental part
p. 483 - 487
(2009/07/11)
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- Counterattack mode differential acetylative deprotection of phenylmethyl ethers: Applications to solid phase organic reactions
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A counterattack protocol for differential acetylative cleavage of phenylmethyl ether has been developed. The phenylmethyl moiety is liberated as benzyl bromide that is isolated and reused providing advantages in terms of waste minimization/utilization and atom economy. The applicability of this methodology has been extended for solid phase organic reactions with the feasibility of reuse of the solid support.
- Chakraborti, Asit K.,Chankeshwara, Sunay V.
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supporting information; experimental part
p. 1367 - 1370
(2009/07/04)
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- Catalysis in polysiloxane gels: Platinum-catalyzed hydrosilylation of polymethylhydrosiloxane leading to reusable catalysts for reduction of nitroarenes
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Novel polysiloxane gels, to which platinum species are encapsulated, are prepared by treatment of polymethylhydrosiloxane with alkenes in the presence of Karstedt's catalyst. These gels act as reusable catalysts in the reduction of functionalized nitroarenes with H2 to the corresponding substituted anilines without leaking the catalyst species.
- Motoyama, Yukihiro,Kamo, Kazuyuki,Nagashima, Hideo
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supporting information; experimental part
p. 1345 - 1348
(2009/09/29)
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- Benzyl protection of phenols under neutral conditions: Palladium-catalyzed benzylations of phenols
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Benzyl protection of phenols under neutral conditions was achieved by using a Pd(n3-C3H5)Cp-DPEphos catalyst. The palladium catalyst efficiently converted aryl benzyl carbonates into benzyl-protected phenols through the decarboxylative etherification. Alternatively, the nucleophilic substitution of benzyl methyl carbonates with phenols proceeded In the presence of the catalyst, yielding aryl benzyl ethers.
- Kuwano, Ryoichi,Kusano, Hiroki
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supporting information; experimental part
p. 1979 - 1982
(2009/04/10)
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- An efficient chemoselective etherification of phenols in polyfunctional aromatic compounds
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A simple and efficient chemoselective alkylation of phenols in polyfunctional aromatic compounds with different alkyl halides in the presence of K2CO3/TBAB is reported. The method is successful with various hydroxy aromatic acids or oximes possessing other functional groups.
- Pandey, Jyoti,Mishra, Mridul,Bisht, Surendra Singh,Sharma, Anindra,Tripathi, Rama P.
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p. 695 - 698
(2008/09/17)
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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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- Ionic liquids as reagent and reaction medium: Preparation of alkyl aryl ethers
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Room temperature ionic liquid, [bmIm]OH, is used as a green recyclable reaction medium and reagent for the alkylation of phenols in excellent yields. The recovered ionic liquid was reused five to six times with consistent activity.
- Mohanazadeh, Farajollah,Aghvami, Majid
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- Surfactant-mediated solvent-free dealkylative cleavage of ethers and esters and trans-alkylation under neutral conditions
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A simple, surfactant-mediated, one-pot, solvent-free dealkylative cleavage of aryl ethers and esters followed by subsequent optional trans-alkylation under essentially neutral conditions has been developed.
- Bhattacharya, Apurba,Patel, Nitin C.,Vasques, Tomas,Tichkule, Ritesh,Parmar, Gaurang,Wu, Jiejun
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p. 565 - 567
(2007/10/03)
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- Optimization and SAR for dual ErbB-1/ErbB-2 tyrosine kinase inhibition in the 6-furanylquinazoline series
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Synthetic modifications on a 6-furanylquinazoline scaffold to optimize the dual ErbB-1/ErbB-2 tyrosine kinase inhibition afforded consistent SAR whereby a 4-(3-fluorobenzyloxy)-3-haloanilino provided the best enzyme potency and cellular selectivity. Changes made to the 6-furanyl group had little impact on the enzyme activity, but appeared to dramatically affect the cellular efficacy. The discovery of lapatinib emerged from this work.
- Petrov, Kimberly G.,Zhang, Yue-Mei,Carter, Malcolm,Cockerill, G. Stuart,Dickerson, Scott,Gauthier, Cassandra A.,Guo, Yu,Mook Jr., Robert A.,Rusnak, David W.,Walker, Ann L.,Wood, Edgar R.,Lackey, Karen E.
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p. 4686 - 4691
(2007/10/03)
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- Williamson reaction in [bmim][BF4]: Clean and facile synthesis of aryl benzyl ethers
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1-Butyl-3-methylimidazolium tetrafluoroborate ([bmin][BF4]) has been demonstrated to be a suitable reaction medium for the synthesis of aryl benzyl ethers by the Williamson reaction. A variety of phenols react with benzyl chloride in [bmim][BF4] to afford the desired ethers in satisfactory yields. The reaction proceeds cleanly and the use of the ionic liquid allows for easy product isolation.
- Wen, Xinmin
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p. 663 - 664
(2007/10/03)
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- ANTIFUNGAL AZOLE DERIVATIVES HAVING A FLUOROVINYL MOIETY AND PROCESS FOR THE PREPARATION THEREOF
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An azole derivative of formula (I) having a fluorovinyl moiety or a pharmaceutically acceptable salt thereof is superior to the conventional antifungal drugs in antifungal activity against a wide spectrum of pathogenic fungi, and has advantageously low toxicity.
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Page/Page column 23-24
(2010/02/10)
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- Cesium fluoride-Celite: A solid base for efficient syntheses of aromatic esters and ethers
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Coupling reactions of a number of aromatic and heteroaromatic phenols with alkyl, acyl or benzoyl halides in acetonitrile with cesium fluoride-Celite are described, demonstrating that this reagent provides an efficient, convenient and practical method for the syntheses of aromatic esters and ethers.
- Shah, Syed Tasadaque Ali,Khan, Khalid Mohammed,Hussain, Hidayat,Anwar, Muhammad Usman,Fecker, Miriam,Voelter, Wolfgang
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p. 6652 - 6656
(2007/10/03)
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- SAR, species specificity, and cellular activity of cyclopentene dicarboxylic acid amides as DHODH inhibitors
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Novel DHODH inhibitors were developed based on a previously described series by introduction of heteroatoms into the cyclopentene ring and hydroxyl groups attached to it. Also, the hydrophobic biphenyl side chain was replaced with benzyloxy phenyl groups. Activities on human, rat, and mouse enzymes indicate a species specificity of these inhibitors.
- Leban, Johann,Kralik, Martin,Mies, Jan,Gassen, Michael,Tentschert, Karin,Baumgartner, Roland
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p. 4854 - 4857
(2007/10/03)
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- Copper-catalyzed coupling of aryl halides and nitrite salts: A mild Ullmann-type synthesis of aromatic nitro compounds
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Nitration of aromatic halides proceeded smoothly in the presence of catalytic amounts of Cu bronze and N,N′-dimethylethylenediamine. Sodium nitrite-18-crown-6, or tetra-n-butylammonium nitrite (n-Bu4NNO 2) turned out to be efficient nitrating agents. The aromatic nitro compounds were synthesized under essentially neutral conditions.
- Saito, Shinichi,Koizumi, Yuichiro
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p. 4715 - 4717
(2007/10/03)
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