- A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction
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The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up
- Surmiak, Ewa,Twarda-Clapa, Aleksandra,Zak, Krzysztof M.,Musielak, Bogdan,Tomala, Marcin D.,Kubica, Katarzyna,Grudnik, Przemyslaw,Madej, Mariusz,Jablonski, Mateusz,Potempa, Jan,Kalinowska-Tluscik, Justyna,D?mling, Alexander,Dubin, Grzegorz,Holak, Tad A.
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Read Online
- Identification of BR102910 as a selective fibroblast activation protein (FAP) inhibitor
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Fibroblast activation protein (FAP) belongs to the family of prolyl-specific serine proteases and displays both exopeptidase and endopeptidase activities. FAP expression is undetectable in most normal adult tissues, but is greatly upregulated in sites of tissue remodeling, which include fibrosis, inflammation and cancer. Due to its restricted expression pattern and dual enzymatic activities, FAP inhibition is investigated as a therapeutic option for several diseases. In the present study, we described the structure–activity relationship of several synthesized compounds against DPPIV and prolyl oligopeptidase (PREP). In particular, BR102910 (compound 24) showed nanomolar potency and high selectivity. Moreover, the in vivo FAP inhibition study of BR102910 (compound 24) using C57BL/6J mice demonstrated exceptional profiles and satisfactory FAP inhibition efficacy. Based on excellent in vitro and in vivo profiles, the potential of BR102910 (compound 24) as a lead candidate for the treatment of type 2 diabetes is considered.
- Jung, Hui Jin,Nam, Eun Hye,Park, Jin Young,Ghosh, Prithwish,Kim, In Su
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supporting information
(2021/02/26)
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- A CO2-mediated base catalysis approach for the hydration of triple bonds in ionic liquids
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Herein, we report a CO2-mediated base catalysis approach for the activation of triple bonds in ionic liquids (ILs) with anions that can chemically capture CO2 (e.g., azolate, phenolate, and acetate), which can achieve hydration of triple bonds to carbonyl chemicals. It is discovered that the anion-complexed CO2 could abstract one proton from proton resources (e.g., IL cation) and transfer it to the CN or CC bonds via a six-membered ring transition state, thus realizing their hydration. In particular, tetrabutylphosphonium 2-hydroxypyridine shows high efficiency for hydration of nitriles and CC bond-containing compounds under a CO2 atmosphere, affording a series of carbonyl compounds in excellent yields. This catalytic protocol is simple, green, and highly efficient and opens a new way to access carbonyl compounds via triple bond hydration under mild and metal-free conditions.
- Han, Buxing,Ke, Zhengang,Li, Ruipeng,Liu, Zhimin,Tang, Minhao,Wang, Yuepeng,Zeng, Wei,Zhang, Fengtao,Zhao, Yanfei
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supporting information
p. 9870 - 9875
(2021/12/27)
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- Direct synthesis of amides from nonactivated carboxylic acids using urea as nitrogen source and Mg(NO3)2or imidazole as catalysts
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A new method for the direct synthesis of primary and secondary amides from carboxylic acids is described using Mg(NO3)2·6H2O or imidazole as a low-cost and readily available catalyst, and urea as a stable, and easy to manipulate nitrogen source. This methodology is particularly useful for the direct synthesis of primary and methyl amides avoiding the use of ammonia and methylamine gas which can be tedious to manipulate. Furthermore, the transformation does not require the employment of coupling or activating agents which are commonly required.
- Blacker, A. John,Chhatwal, A. Rosie,Lomax, Helen V.,Marcé, Patricia,Williams, Jonathan M. J.
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p. 5808 - 5818
(2020/06/21)
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- PYRROLIDINE DERIVATIVES AS INHIBITOR OF FIBROBLAST ACTIVATION PROTEIN (FAP) AND PHARMACEUTICAL COMPOSITION INCLUDING THE SAME
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The FAP inhibitor is represented by the following formula X. The present invention relates to a pyrrolidine derivative or a pharmaceutically acceptable salt thereof. Chem. X.
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Paragraph 1516; 1520-1522
(2020/11/24)
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- Lithiation Substitution of Unprotected Benzyltetrazoles
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1H-Tetrazoles occupy an important role in modern medicinal chemistry, but few methods for their modification exist. Many extant protocols require the use of a difficult to remove N-alkyl-protecting group, precluding the products from use as carboxylate bioisosteres, the major role of tetrazoles in pharmaceuticals. We herein report a convenient, protecting-group-free lithiation-substitution protocol for benzylic tetrazoles. Metalation with n-BuLi at 0 °C followed by electrophilic trapping gave a range of α-functionalized benzyltetrazoles in up to 91% yield.
- Wong, Jeff Y. F.,Lewandowska, Agnieszka,Trowse, Benjamin R.,Barker, Graeme
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supporting information
p. 7069 - 7072
(2019/09/30)
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- Clean synthesis of primary to tertiary carboxamides by CsOH-catalyzed aminolysis of nitriles in water
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Using CsOH as the only catalyst and utilizing its "cesium effect", a clean synthesis of a wide range of primary, secondary, and tertiary carboxamides was achieved by aminolysis reactions of nitriles with ammonia, primary, or secondary amines in water. Studies on the control reactions revealed that the reactions with ammonia most probably proceed via an aminolysis path by the initial addition of ammonia to Cs-activated nitriles to form unsubstituted amidine intermediates, while the reactions with primary or secondary amines may proceed via a hydration/transamidation path by the initial hydration of the Cs-activated nitriles to form primary carboxamide intermediates followed by their transamidation with amines through the formation of substituted amidine intermediates.
- Li, Yang,Chen, Haonan,Liu, Jianping,Wan, Xujun,Xu, Qing
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supporting information
p. 4865 - 4870
(2016/10/06)
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- Synthesis of aryl anilinomaleimide based derivatives as glycogen synthase kinase-3β inhibitors with potential role as antidepressant agents
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A series of aryl anilinomaleimide based derivatives has been synthesized and evaluated for in vitro glycogen synthase kinase-3β (GSK-3β) inhibitory activity. A large number of compounds from the series exhibited moderate to potent inhibitory activity against GSK-3β, with more than one-third of the compounds showing inhibition with IC50 values 50 values of 0.09, 0.12, 0.17, 0.19, 0.21 and 0.23 μM respectively), were further investigated for antidepressant activity by the widely accepted forced swim test and tail suspension test (FST and TST) models. All the tested compounds displayed antidepressant-like effects, particularly compounds 8j and 8b, which exhibited significant antidepressant activity, about 1.4-fold higher than fluoxetine, a standard antidepressant drug in both FST and TST. Preliminary structure-activity relationships have also been generated based on the experimental data obtained.
- Tantray, Mushtaq A.,Khan, Imran,Hamid, Hinna,Alam, Mohammad Sarwar,Dhulap, Abhijeet,Kalam, Abul
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p. 6109 - 6119
(2016/07/16)
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- Sodium azide as a catalyst for the hydration of nitriles to primary amides in water
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The selective conversion of aromatic nitriles to primary amides has been accomplished using sodium azide. The corresponding amides were obtained efficiently in excellent yields. This reaction was carried out under eco-friendly conditions using water in the absence of organic solvents.
- Bahrami, Kiumars,Khodaei, Mohammad Mehdi,Roostaei, Mohsen
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p. 267 - 269
(2015/06/02)
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- Efficient and selective hydration of nitriles to amides in aqueous systems with Ru(II)-phosphaurotropine catalysts
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A simple and efficient synthesis of amides by selective hydration of aromatic and aliphatic nitriles is described. The catalysts are prepared in situ from easily available Ru-precursors and ligands using water as the solvent. The most active catalyst, is obtained from [RuCl2(dmso)4] and benzylated 1,3,5-triaza-7-phosphaadamantane. Of the 16 substrates examined, 92-99% conversions of 14 nitriles were achieved in one hour at reflux temperature.
- Bolyog-Nagy, Evelin,Udvardy, Antal,Joó, Ferenc,Kathó, ágnes
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supporting information
p. 3615 - 3617
(2014/06/23)
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- Amberlyst A26 OH as a recyclable catalyst for hydration of nitriles and water-based synthesis of 4(1 H)-quinazolinones from 2-aminobenzonitrile and carbonyl compounds
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Selective hydration of nitriles to primary amides as well the base-catalyzed synthesis of 2-substituted 4(1H)-quinazolinones via reaction of 2-aminobenzonitrile with carbonyl compounds using macroporous Amberlyst A26 OH in H2O-EtOH is described. The latter reaction proceeds via tandem hydration of 2-aminobenzonitrile, condensation of the in situ generated 2-aminobenzamide with carbonyl compounds, and cyclization of the imine intermediate to give the quinazolinone derivatives. Georg Thieme Verlag Stuttgart New York.
- Tamaddon, Fatemeh,Pouramini, Farzaneh
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p. 1127 - 1131
(2014/05/20)
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- Efficient and selective nitrile hydration reactions in water catalyzed by an unexpected dimethylsulfinyl anion generated in situ from CsOH and DMSO
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Unexpected dimethylsulfinyl anions (I), generated in situ from the superbase system CsOH-DMSO, was found to be a highly active catalyst for controllable nitrile hydration reactions in water, which selectively afforded the versatile amides via interesting Cs-activated I-catalyzed direct and indirect hydration mechanisms involving an O-transfer process from DMSO onto the nitriles. the Partner Organisations 2014.
- Chen, Haonan,Dai, Wujie,Chen, Yi,Xu, Qing,Chen, Jianhui,Yu, Lei,Zhao, Yajuan,Ye, Mingde,Pan, Yuanjiang
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supporting information
p. 2136 - 2141
(2014/04/17)
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- NOVEL CANNABINOID RECEPTOR 2 (CB2) INVERSE AGONISTS AND THERAPEUTIC POTENTIAL FOR MULTIPLE MYELOMA AND OSTEOPOROSIS BONE DISEASES
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Cannabionid receptor-2 inverse antagonists include compounds represented by Formula IV, or a pharmaceutically acceptable salt thereof: wherein: R1 and R2 are independently H, alkyl, or alkenyl; R3 is alkyl, alkenyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl; R4 and R5 are independently a bond, alkylenyl, or alkenylenyl; each R6 and R7 is independently selected from the group consisting of OH, F, Cl, Br, I, (C1-C6)alkyl, alkoxy, amino, COOH, CONH2, SO3H, PO3H2, CN, SH, NO2 and CF3; and p and q are independently 0, 1, 2, 3, 4, or 5. Such compounds may be used to treat osteoporosis or multiple myeloma.
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Paragraph 0147; 0148; 0149
(2013/07/19)
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- Synthesis of α-Arylcarboxylic acid amides from silyl enol ether via migratory Amidation with 2-azido-1,3-dimethylimidazolinium hexafluorophosphate
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α-Arylcarboxylic acid amides were synthesized by reacting silyl enol ethers of aryl ketones and 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP,1). Silyl enol ethers react with ADMP 1 to give N-(α-arylacyl) guanidines via the migration of aryl groups in enol ethers. The products were transformed to the corresponding α-aryl acetamides by treating with LiAlH4.
- Kitamura, Mitsuru,Murakami, Kento,Shiratake, Yuichiro,Okauchi, Tatsuo
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p. 691 - 693
(2013/07/26)
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- Hypervalent iodine catalyzed hofmann rearrangement of carboxamides using oxone as terminal oxidant
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Hofmann rearrangement of carboxamides to carbamates using Oxone as an oxidant can be efficiently catalyzed by iodobenzene. This reaction involves hypervalent iodine species generated in situ from catalytic amount of PhI and Oxone in the presence of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) in aqueous methanol solutions. Under these conditions, Hofmann rearrangement of various carboxamides affords corresponding carbamates in high yields.
- Yoshimura, Akira,Middleton, Kyle R.,Luedtke, Matthew W.,Zhu, Chenjie,Zhdankin, Viktor V.
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p. 11399 - 11404
(2013/02/23)
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- Lead discovery, chemistry optimization, and biological evaluation studies of novel biamide derivatives as CB2 receptor inverse agonists and osteoclast inhibitors
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N,N′-((4-(Dimethylamino)phenyl)methylene)bis(2-phenylacetamide) was discovered by using 3D pharmacophore database searches and was biologically confirmed as a new class of CB2 inverse agonists. Subsequently, 52 derivatives were designed and synthesized through lead chemistry optimization by modifying the rings A-C and the core structure in further SAR studies. Five compounds were developed and also confirmed as CB2 inverse agonists with the highest CB2 binding affinity (CB2Ki of 22-85 nM, EC50 of 4-28 nM) and best selectivity (CB 1/CB2 of 235- to 909-fold). Furthermore, osteoclastogenesis bioassay indicated that PAM compounds showed great inhibition of osteoclast formation. Especially, compound 26 showed 72% inhibition activity even at the low concentration of 0.1 μM. The cytotoxicity assay suggested that the inhibition of PAM compounds on osteoclastogenesis did not result from its cytotoxicity. Therefore, these PAM derivatives could be used as potential leads for the development of a new type of antiosteoporosis agent.
- Yang, Peng,Myint, Kyaw-Zeyar,Tong, Qin,Feng, Rentian,Cao, Haiping,Almehizia, Abdulrahman A.,Alqarni, Mohammed Hamed,Wang, Lirong,Bartlow, Patrick,Gao, Yingdai,Gertsch, Jürg,Teramachi, Jumpei,Kurihara, Noriyoshi,Roodman, Garson David,Cheng, Tao,Xie, Xiang-Qun
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p. 9973 - 9987
(2013/01/16)
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- N-Butylammonium carboxylates/Tf2O: Ionic liquid based systems for the synthesis of unsymmetrical imides via a Ritter-type reaction
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We have developed a new method for the preparation of unsymmetrical imides using liquid carboxylate salts via a Ritter-type process. The reactions were carried out with nitriles and n-butylammonium carboxylates as ionic liquids in the presence of triflic anhydride (Tf2O) as the promoter. Mild reaction conditions, simplicity of the procedure, and proton-free conditions are the main advantages of this procedure.
- Khodaei, Mohammad Mehdi,Nazari, Ehsan
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experimental part
p. 2881 - 2884
(2012/07/28)
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- A heterogeneous catalytic method for the conversion of nitriles into amides using molecular sieves modified with copper(II)
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A heterogenous catalytic method is developed for the hydration of nitriles into amides with acetaldoxime. Copper(II) supported on 4 molecular sieves is an efficient catalyst for this reaction.
- Kiss, árpád,Hell, Zoltán
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experimental part
p. 6021 - 6023
(2011/11/28)
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- Arene-ruthenium(II) complexes containing inexpensive tris(dimethylamino) phosphine: Highly efficient catalysts for the selective hydration of nitriles into amides
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The catalytic hydration of nitriles into amides, in water under neutral conditions, has been studied using a series of arene-ruthenium(II) derivatives containing the commercially available and inexpensive ligand tris(dimethylamino)phosphine. Among them, best results were obtained with the complex [RuCl2(η6-C6Me6) {P(NMe2)3}], which selectively provided the desired amides in excellent yields and short times (TOF values up to 11 400 h-1). The process was operative with both aromatic, heteroaromatic, aliphatic, and α,β-unsaturated organonitriles and showed a high functional group tolerance. The stability of [RuCl2(η6-C 6Me6){P(NMe2)3}] in water was evaluated, observing its progressive decomposition into the less-active dimethylamine-ruthenium(II) complex [RuCl2(η6-C 6Me6)(NHMe2)] by hydrolysis of the coordinated P(NMe2)3 ligand. The X-ray crystal structure determination of the toluene complex [RuCl2(η6-C6H 5Me){P(NMe2)3}] is also included.
- Garcia-Alvarez, Rocio,Diez, Josefina,Crochet, Pascale,Cadierno, Victorio
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experimental part
p. 5442 - 5451
(2011/12/13)
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- Arene-ruthenium(II) complexes containing amino-phosphine ligands as catalysts for nitrile hydration reactions
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Three different series of novel mononuclear arene-ruthenium(II) complexes containing amino-phosphine ligands, namely, [RuCl2{κ 1(P)-2-Ph2PC6H4CH 2NHR}(η6-arene)], [RuCl2{κ 1(P)-3-Ph2PC6H4CH 2NHR}(η6-arene)], and [RuCl2{κ 1(P)-4-Ph2PC6H4CH 2NHR}(η6-arene)] (arene = C6H6, p-cymene, 1,3,5-C6H3Me3, C6Me 6; R = iPr, tBu; all combinations), have been synthesized and fully characterized. These readily accessible species are efficient catalysts for the selective hydration of organonitriles into amides under challenging reaction conditions, i.e., pure aqueous medium in the absence of any cocatalyst, being much more active than their corresponding nonfunctionalized triphenylphosphine counterparts [RuCl2(PPh 3)(η6-arene)]. The results obtained in this study indicate that the (amino-phosphine)ruthenium(II) complexes operate through a "bifunctional catalysis" mechanism in which the ruthenium center acts as a Lewis acid, activating the nitrile molecule, and the P-donor ligand acts as a Brnsted base, the pendant amino group generating the real nucleophile of the hydration process, i.e., the OH- group.
- Garcia-Alvarez, Rocio,Diez, Josefina,Crochet, Pascale,Cadierno, Victorio
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experimental part
p. 3955 - 3965
(2010/12/25)
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- Bis(allyl)ruthenium(rV) complexes containing water-soluble phosphane ligands: Synthesis, structure, and application as catalysts in the Selective hydration of organonitriles into amides
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The novel mononuclear ruthenium(IV) complexes [RuCl2(η 3: η3-C10H16)(L)] [L = (meta-sulfonatophenyl)diphenylphosphane sodium salt (TPPMS) (2a), 1,3,5-triaza-7-phosphatricyclo[3.3.1.13,7]decane (PTA) (2b), 1-benzyl-3,5-diaza-1-azonia-7-phosphatricyclo[3.3.1.13,7]decane chloride (PTABn) (2c), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA) (2d), and 2,4,10-trimethyl-1,2,4,5,7,10-hexaaza-3-phosphatricyclo[3.3.1. 13,7]decane (THPA) (2e)] have been synthesized by treatment of the dimeric precursor [{RuCl(μ-Cl)((η3: η3-C 10H16)}2] (C10H16 = 2,7-dimethylocta-2,6-diene-1,8-diyl) (1) with two equivalents of the corresponding water-soluble phosphane. Reaction of 1 with one equivalent of the cage-type diphosphane ligand 2,3,5,6,7,8-hexamethyl-2,3,5,6,7,8-hexaaza-1,4- diphosphabicyclo[2.2.2]octane (THDP) allowed also the high-yield preparation of the dinuclear derivative [[RuCl2(η3: η3-C10H16)}2(μ-THDP)] (2f). All these new complexes have been analytically and spectroscopically (IR and multinuclear NMR) characterized. In addition, the structure of 2b, 2c, 2d, and 2 f was unequivocally confirmed by X-ray diffraction methods. Complexes 2a-f are active catalysts for the selective hydration of nitriles to amides in pure aqueous medium under neutral conditions. The wide scope of this catalytic transformation has been evaluated by using the most active catalysts [RuCl 2(η3: η3-C10H 16)(THPA)] (2e) and [{RuCl2(η3: η3-C10H16)}2(μ-THDP)] (2f). Advantages of using MW versus conventional thermal heating are also discussed.
- Cadierno, Victorio,Diez, Josefina,Francos, Javier,Gimeno, Jose
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experimental part
p. 9808 - 9817
(2010/10/21)
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- Oxidation of amidoximes with IBX and IBX/TEAB
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Biologically important process of oxidation of amidoximes has been investigated using IBX (oiodoxybenzoic acid) and combination of IBX with TEAB (tetraethylammonium bromide). The reaction proceeds with high % conversion leading to selective formation of amide and nitrile depending upon the combination of reagents. ARKAT USA, Inc.
- Deshmukh, Swapnil S.,Huddar, Sameerana N.,Bhalerao, Dinesh S.,Akamanchi, Krishnacharya G.
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experimental part
p. 118 - 126
(2010/09/05)
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- Discovery and biological evaluation of novel cyanoguanidine P2X7 antagonists with analgesic activity in a rat model of neuropathic pain
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We disclose the design of a novel series of cyanoguanidines that are potent (IC50 ? 10-100 nM) and selective (≥100-fold) P2X7 receptor antagonists against the other P2 receptor subtypes such as the P2Y2, P2X4, and P2X3. We also found that these P2X7 antagonists effectively reduced nociception in a rat model of neuropathic pain (Chung model). Particularly, analogue 53 proved to be effective in the Chung model, with an ED50 of 38 μmol/kg after intraperitoneal administration. In addition compound 53 exhibited antiallodynic effects following oral administration and maintained its efficacy following repeated administration in the Chung model. These results suggest an important role of P2X7 receptors in neuropathic pain and therefore a potential use of P2X7 antagonists as novel therapeutic tools for the treatment of this type of pain.
- Perez-Medrano, Arturo,Donnelly-Roberts, Diana L.,Honore, Prisca,Hsieh, Gin C.,Namovic, Marian T.,Peddi, Sridhar,Shuai, Qi,Wang, Ying,Faltynek, Connie R.,Jarvis, Michael F.,Carroll, William A.
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experimental part
p. 3366 - 3376
(2010/04/03)
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- Efficient hydrolysis of nitriles to amides with hydroperoxide anion in aqueous surfactant solutions as reaction medium
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Aliphatic and aromatic nitriles are converted to corresponding amides in a single step via hydrolysis with basic H2O2 in aqueous solution of the surfactant Cetyltrimethylammonium methanesulfonate (CTAOMs). The method has several advantages: use and recycle of water as reaction medium, use of environmentally benign oxidant H2O2, easy product isolation, short reaction time, high yields and selectivity, mild conditions.
- Brinchi, Lucia,Chiavini, Lisa,Goracci, Laura,Di Profio, Pietro,Germani, Raimondo
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experimental part
p. 175 - 179
(2010/04/23)
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- Study of the microwave-assisted hydrolysis of nitriles and esters and the implementation of this system in rapid microwave-assisted Pd-catalyzed amination
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Microwave-assisted hydrolysis of benzonitriles and methyl benzoates has been studied using a toluene/concd aq KOH two phase system in the presence and absence of phase transfer catalyst. Conditions to allow and avoid smooth hydrolysis could be identified. Based on the latter, the first microwave protocol which allows the rapid Pd-catalyzed amination of aliphatic amines with chlorobenzenes containing sensitive functional groups has been developed.
- Van Baelen, Gitte,Maes, Bert U.W.
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p. 5604 - 5619
(2008/09/21)
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- Selective ruthenium-catalyzed hydration of nitriles to amides in pure aqueous medium under neutral conditions
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A study was conducted to demonstrate that water-soluble ruthenium(II) complexes can be used as catalysts for the hydration of nitriles in pure aqueous media and under neutral conditions. The hydration of benzonitrile was investigated as a model reaction and the ruthenium precursor was added to a 0.33M aqueous solution of benzonitrile at 100°C, while the reaction was monitored by gas chromatography. All the complexes checked, were found to be active and selective catalysts in the hydration process, providing benzamide as a specific reaction product. The most relevant results were obtained by using ruthenium complexes, bearing a nitrogen-containing ligand, which led to appropriate production of benzamide. The most effective ruthenium complex was found to be an efficient catalyst for the selective hydration of a large number of other nitriles.
- Cadierno, Victorio,Francos, Javier,Gimeno, Jose
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scheme or table
p. 6601 - 6605
(2009/07/10)
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- Cyanoamidine P2X7 antagonists for the treatment of pain
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Novel cyanoamidines compounds of formula (I) and (II) and their derivatives wherein R1-R12 are as defined in the specification act as antagonists of the P2X7 receptor. These compounds are particularly useful in the treatment of pain, inflammation and neurodegeneration states.
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Page/Page column 11
(2008/06/13)
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- Aromatic chlorination of ω-phenylalkylamines and ω- phenylalkylamides in carbon tetrachloride and α,α,α- trifluorotoluene
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The aromatic halogenation of simple alkylbenzenes with chlorine proceeds smoothly in acetic acid but is much less efficient in less polar solvents. By contrast chlorination of ω-phenylalkylamines, such as 3-phenylpropylamine, occurs readily in either acetic acid, carbon tetrachloride or α,α,α-trifluorotoluene, and in the latter solvents gives high proportions of ortho-chlorinated products. These effects are attributable to the involvement of N-chloroamines as reaction intermediates, with intramolecular delivery of the chlorine electrophile. ω-Phenylalkylamides, such as 3-phenylpropionamide, also easily undergo aromatic chlorination in carbon tetrachloride and α,α,α-trifluorotoluene. These reactions generally show a first-order dependence on the substrate concentration, but not on the amount of chlorine. With carbon tetrachloride, very similar reaction rates are observed with chlorine concentrations ranging from 0.1-1.5 M. In α,α,α-trifluorotoluene, the rates reach a plateau at a chlorine concentration of approximately 0.2 M. These features indicate that the reactions proceed via the formation of intermediates which evidence suggests may be the corresponding O-chloroimidates. Irrespective of the mechanistic details, the reactions are remarkably rapid, being faster than analogous reactions in acetic acid and three to four orders of magnitude more rapid than reactions of simple alkylbenzenes in carbon tetrachloride. Therefore, chlorination of the amines and amides may be accomplished without the need for highly polar solvents, added catalysts or large excesses of chlorine, which are often employed for electrophilic aromatic substitutions. Although the use of carbon tetrachloride is becoming increasingly impractical due to environmental concerns, the trifluorotoluene is a suitable alternative. The Royal Society of Chemistry 2006.
- O'Connell, Jenny L.,Simpson, Jamie S.,Dumanski, Paul G.,Simpson, Gregory W.,Easton, Christopher J.
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p. 2716 - 2723
(2008/02/08)
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- Selective hydrolysis of nitriles to amides using NaOH-PEG under microwave irradiation
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We describe here an efficient, rapid and selective method for the conversion of nitriles in to their corresponding amides in the presence of PEG-400, aqueous sodium hydroxide system under microwave irradiation.
- Bendale, Pravin M.,Khadilkar, Bhushan M.
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p. 1713 - 1718
(2007/10/03)
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- Electronic Substituent Effects in the Nitrilase-Catalyzed Hydrolysis of Para-Substituted Benzyl Cyanides
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The initial rates of the nitrilase (Novo)-catalyzed hydrolysis of a series of para-substituted benzyl cyanides (R = NO2, Cl, OCH3, OH, NH2) were found to be susceptible to the nature of the para-substituent of the substrate and a Hammett-type linear free energy correlation was observed with ρ = 0.96.In a separate study, effective solubilization of substituted benzyl cyanide substrates having electron-donating groups (OH, NH2, OCH3) was achieved upon mixing with β-cyclodextrin to form 1:1 mol ratio inclusion complexes, but para-substituted benzyl cyanides with electron-withdrawing groups (Cl, NO2) were not fully solubilized under the same conditions.In addition, it was shown that the presence of β-cyclodextrin not only had no inhibitory effect on the enzyme activity, but it actually increased the initial rate of hydrolysis of the unsubstituted benzyl cyanide:β-cyclodextrin inclusion complex.However, the initial rates of hydrolysis were observed to be smaller when β-cyclodextrin was added to the para-substituted benzyl cyanides.
- Geresh, Shimona,Giron, Yakir,Gilboa, Ygal,Glaser, Robert
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p. 10099 - 10102
(2007/10/02)
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- Ritter Reactions. V. Further Investigation of the 3-Azatricyclo4,9>undec-2-ene System
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2,6-Dimethylenebicyclononane (1) and acetonitrile react under Ritter reaction conditions to produce exo-11-acetamido-2,4,endo-11-trimethyl-3-azatricyclo4,9>undec-2-ene (2) monohydrate whose crystal structure 1, a 8.213(3), b 10.841(1), c 8.234(2) Angstroem, β 95.57(2) deg, Z 2> was determined with a final R 0.036.The diene (1) reacts similarly with benzonitrile to produce the phenyl-substituted analogue (3).In contrast, the reaction of (1) and benzyl cyanide yields a different type of product, 2-benzoyl-4,endo-11-dimethyl-exo-11-phenylacetamido-3-azatricyclo4,9>undec-2-ene (5a), where one of the two nitrile-derived groups has undergone spontaneous oxidation during the one-flask preparation. p-Bromo- and p-chloro-benzyl cyanides behave in a similar manner yielding the adducts (5b,c) respectively.
- Bong, Ivy C.C.,Ung, Alison T.,Craig, Donald C.,Scudder, Marcia L.,Bishop, Roger
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p. 1929 - 1937
(2007/10/02)
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- Synthesis and Biological Evaluation of a Series of Substituted 4,5-Diphenylpyridine-2,6(1H,5H)-diones
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We report the synthesis of a series of disubstituted 4,5-diphenylpyridine-2,6(1H,5H)-diones (8), (10), (12)-(21), their characterization by 1H and 13 C n.m.r. spectroscopy and their receptor binding affinities for catecholamine and benzodiazepine receptors.
- Andrews, Peter R.,Brinkworth, Ross I.,Partridge, Ashton C.,Reiss, James A.
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p. 1717 - 1726
(2007/10/02)
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- Design of Inhibitors from the Three-Dimensional Structure of Alcohol Dehydrogenase. Chemical Synthesis and Enzymatic Properties
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Inhibitors of liver alcohol dehydrogenase were designed from the three-dimensional structure of the enzyme.The ligand to the catalytic zinc ion is an amide group or, better, a formamide group.With the latter function, a hydrogen bond between the NH group and the hydroxyl group of Ser-48 may be formed.The hydrophobic substrate binding site brings structural restraints. α-ω bifunctional molecules show good inhibitory properties possibly due to the interactions with polar residues at the entrance of the substrate binding site.
- Freudenreich, Charles,Samama, Jean-Pierre,Biellmann, Jean-Francois
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p. 3344 - 3353
(2007/10/02)
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