- Organoiridium catalyzed hydrogen isotope exchange: Ligand effects on catalyst activity and regioselectivity
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Several iridium complexes [Ircod)L2]X (L = phosphine ligand) were used as precatalysts for the exchange labeling of a range of model compounds with deuterium gas. Complexes with monodentate L (e.g. PMePh2, PPh3 and substituted derivatives thereof) catalyzed exchange selectively of hydrogens four bonds away from a coordinative heteroatom in the substrate, while those with bidentate L (bis(diphenylphosphino)ethane (dppe) and bis(diphenylphosphino)butane) catalyzed exchange of hydrogens both four and five bonds away from a coordinative heteroatom. At heavier loadings, some monodentate complexes also catalyzed five-bond labeling of some substrates. [Ir(cod)(dppe)]BF4 catalyzed the tritium labeling of methyl 6-methoxynaphth-2-ylacetate at C1 and C3.
- Shu,Chen,Heys
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Read Online
- Indole derivatives as cyclooxygenase inhibitors: Synthesis, biological evaluation and docking studies
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A new series of 2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-[(E)-(substituted phenyl) methylidene] acetohydrazide derivatives (S1–S18) were synthesized and evaluated for their anti-inflammatory activity, analgesic activity, ulcerogenic activity, lipid peroxidation, ulcer index and cyclooxygenase expression activities. All the synthesized compounds were in good agreement with spectral and elemental analysis. Three synthesized compounds (S3, S7 and S14) have shown significant anti-inflammatory activity as compared to the reference drug indomethacin. Compound S3 was further tested for ulcerogenic index and cyclooxygenase (COX) expression activity. It was selectively inhibiting COX-2 expression and providing the gastric sparing activity. Docking studies have revealed the potential of these compounds to bind with COX-2 enzyme. Compound S3 formed a hydrogen bond between OH of Tyr 355 and NH2 of Arg 120 with carbonyl group and this hydrogen bond was similar to that formed by indomethacin. This study provides insight for compound S3, as a new lead compound as anti-inflammatory agent and selective COX-2 inhibitor.
- Bhat, Mashooq Ahmad,Mohamed, A. Al-Omar,Mohammad, Raish,Ansari, Mushtaq Ahmad,Abuelizz, Hatem A.,Bakheit, Ahmed H.,Naglah, Ahmed M.
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- Photolysis of indomethacin in methanol
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A novel photo-oxidation product containing a six-membered 1,2-dioxane ring was isolated from the photolysis of indomethacin in methanol and a possible mechanism is proposed.
- Wu, An-Bang,Cheng, Hui-Wen,Hu, Chien-Ming,Chen, Fu-An,Chou, Tzu-Chang,Chen, Chau-Yang
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Read Online
- 1H NMR and molecular modeling study on the inclusion complex β-cyclodextrin-indomethacin
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The solution structure of the inclusion complex between β-cyclodextrin (2) and the nonsteroidal anti-inflammatory agent indomethacin sodium salt (1) [1-(p-chlorobenzoyl)-5-methoxy-2-methylin-doleacetic acid sodium salt] is investigated in D2O solution via 1H NMR spectroscopy. The guest molecule 1 exists in solution as a mixture of E and Z isomers in fast exchange on the NMR time scale, as shown by NOE experiments. Low-temperature 1H NMR spectra on indomethacin methyl ester (3) (soluble in CH2Cl2-d2) showed that the Z isomer is the most thermodynamically stable. Geometrical features of the host-guest inclusion complex between 2 and 1 are inferred from intermolecular dipolar contacts obtained by 1D NOE difference spectra and 2D ROESY experiments. A more detailed picture of the solution structure of the complex is obtained by combining NMR structural information and molecular dynamics and energy calculations on the inclusion complexes. Computations took into account the existence of two diastereomeric forms of the guest (E and Z), the two possible sites of interaction of the guest molecule with the cavity (i.e. the p-chlorobenzoyl ring and the indole ring system), and the different topologies for the entry of the guest into the host's cavity. The main finding that can be obtained from both experimental and theoretical data is that the complexation selectively stabilizes the E isomer with respect to Z. The inclusion complex is characterized by the interaction of the p-chlorobenzoyl moiety of 1E with the lipophilic cavity of the host 2, the entry being through the larger rim of the truncated cone of 2.
- Fronza,Mele,Redenti,Ventura
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Read Online
- Preparation method of carboxylic ester compound
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The invention relates to a preparation method of a carboxylic ester compound, which comprises the following steps: reacting carboxylic acid with methanol in air under the catalysis of nitrite to obtain an ester compound, the preparation method disclosed by the invention has the advantages of rich raw material sources, cheap and easily available catalyst, mild reaction conditions, simplicity and convenience in operation and the like, a series of fatty carboxylic acids can be modified with high yield, and particularly, the traditional esterification method is generally not suitable for esterification of drug molecules. By utilizing the method, a series of known drug molecules can be modified, so that a shortcut is provided for discovering new drug molecules.
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Paragraph 0028-0029
(2021/03/30)
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- Green Esterification of Carboxylic Acids Promoted by tert-Butyl Nitrite
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In this work, the green esterification of carboxylic acids promoted by tert-butyl nitrite has been well developed. This transformation is compatible with a broad range of substrates and exhibits excellent functional group tolerance. Various drugs and substituted amino acids are applicable to this reaction under near neutral conditions, with good to excellent yields.
- Cheng, Xionglve,Jiang, Gangzhong,Li, Xingxing,Tao, Suyan,Wan, Xiaobing,Zhao, Yanwei,Zheng, Yonggao
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supporting information
p. 2713 - 2718
(2021/06/25)
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- A Metal-Free Direct Arene C?H Amination
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The synthesis of aryl amines via the formation of a C?N bond is an essential tool for the preparation of functional materials, active pharmaceutical ingredients and bioactive products. Usually, this chemical connection is only possible by transition metal-catalyzed reactions, photochemistry or electrochemistry. Here, we report a metal-free arene C?H amination using hydroxylamine derivatives under benign conditions. A charge transfer interaction between the aminating reagents TsONHR and the arene substrates enables the chemoselective amination of the arene, even in the presence of various functional groups. Oxygen was crucial for an effective conversion and its accelerating role for the electron transfer step was proven experimentally. In addition, this was rationalized by a theoretical study which indicated the involvement of a dioxygen-bridged complex with a “Sandwich-like” arrangement of the aromatic starting materials and the aminating agents at the dioxygen molecule. (Figure presented.).
- Wang, Tao,Hoffmann, Marvin,Dreuw, Andreas,Hasagi?, Edina,Hu, Chao,Stein, Philipp M.,Witzel, Sina,Shi, Hongwei,Yang, Yangyang,Rudolph, Matthias,Stuck, Fabian,Rominger, Frank,Kerscher, Marion,Comba, Peter,Hashmi, A. Stephen K.
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supporting information
p. 2783 - 2795
(2021/04/05)
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- Anti-Markovnikov hydroarylation of alkenes via polysulfide anion photocatalysis
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A protocol for anti-Markovnikov hydroarylation of alkenes with aryl halides has been developed using polysulfide anions as photocatalysts in the presence of the Hantzsch ester and water under irradiation with visible light.
- Chiba, Shunsuke,Li, Haoyu,Liu, Yuliang
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supporting information
p. 6264 - 6267
(2021/07/02)
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- Imidazotetrazines as Weighable Diazomethane Surrogates for Esterifications and Cyclopropanations
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Diazomethane is one of the most versatile reagents in organic synthesis, but its utility is limited by its hazardous nature. Although alternative methods exist to perform the unique chemistry of diazomethane, these suffer from diminished reactivity and/or correspondingly harsher conditions. Herein, we describe the repurposing of imidazotetrazines (such as temozolomide, TMZ, the standard of care for glioblastoma) for use as synthetic precursors of alkyl diazonium reagents. TMZ was employed to conduct esterifications and metal-catalyzed cyclopropanations, and results show that methyl ester formation from a wide variety of substrates is especially efficient and operationally simple. TMZ is a commercially available solid that is non-explosive and non-toxic, and should find broad utility as a replacement for diazomethane.
- Svec, Riley L.,Hergenrother, Paul J.
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supporting information
p. 1857 - 1862
(2019/12/27)
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- REAGENTS AND PROCESS FOR DIRECT C-H FUNCTIONALIZATION
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Thianthrene derivative of the Formula (I): wherein R1 to R8 may be the same or different and are selected from hydrogen, Cl, F, a partially or fully fluorinated C1 to C6 alkyl group, and wherein n is 0 or 1, with the proviso that at least one of R1 to R8 is not hydrogen and process for C-H functionalization of aromatic compounds using this compound.
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Page/Page column 54
(2020/06/01)
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- Catalytic Access to Functionalized Allylic gem-Difluorides via Fluorinative Meyer–Schuster-Like Rearrangement
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An unprecedented approach for efficient synthesis of functionalized allylic gem-difluorides via catalytic fluorinative Meyer–Schuster-like rearrangement is disclosed. This transformation proceeded with readily accessible propargylic fluorides, and low-cost B–F reagents and electrophilic reagents by sulfide catalysis. A series of iodinated, brominated, and trifluoromethylthiolated allylic gem-difluorides that were difficult to access by other methods were facilely produced with a wide range of functional groups. Importantly, the obtained iodinated products could be incorporated into different drugs and natural products, and could be expediently converted into many other valuable gem-difluoroalkyl molecules as well. Mechanistic studies revealed that this reaction went through a regioselective fluorination of alkynes followed by a formal 1,3-fluorine migration under the assistance of the B–F reagents to give the desired products.
- An, Rui,Li, Huimin,Liao, Lihao,Wu, Jin-Ji,Xu, Yang,Zhao, Xiaodan
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supporting information
p. 11010 - 11019
(2020/05/18)
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- PROCESS FOR FORMING A CARBON-CARBON BOND
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A process for forming a carbon-carbon bond to couple an aryl or heteroaryl group of a first compound with an aryl or heteroaryl group of a second compound, the process comprising reacting the first compound with the second compound in the presence of a catalytically effective amount of a neutral or cationic ruthenium(II) catalyst of formula (I):
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Page/Page column 73-74
(2019/11/28)
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- Palladium-Catalyzed Late-Stage Direct Arene Cyanation
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Methods for direct benzonitrile synthesis are sparse, despite the versatility of cyano groups in organic synthesis and the importance of benzonitriles for the dye, agrochemical, and pharmaceutical industries. We report the first general late-stage aryl C–H cyanation with broad substrate scope and functional-group tolerance. The reaction is enabled by a dual-ligand combination of quinoxaline and an amino acid-derived ligand. The method is applicable to direct cyanation of several marketed small-molecule drugs, common pharmacophores, and organic dyes. Benzonitriles are some of the most versatile building blocks for organic synthesis, in particular in the pharmaceutical industry, but general methods to make them by direct C–H functionalization are unknown. In this issue of Chem, Ritter and coworkers describe a late-stage aryl C–H cyanation with broad substrate scope and functional-group tolerance, enabled by a palladium-dual-ligand catalyst system. The reaction may serve for the late-stage modification of drug candidates. Aryl nitriles constitute an important class of organic compounds that are widely found in natural products, pharmaceuticals, agricultural chemicals, dyes, and materials. Moreover, nitriles are versatile building blocks to access numerous other important molecular structure groups. However, no general method for direct aromatic C–H cyanation is known. All approaches to date require either an appropriate directing group or reactive electron-rich substrates, such as indoles, which limit their synthetic applications. Here we describe an undirected, palladium-catalyzed late-stage aryl C–H cyanation reaction for the synthesis of complex aryl nitriles that would otherwise be more challenging to produce. The wide substrate scope and good functional-group tolerance of this reaction provide direct and quick access to structural diversity for pharmaceutical and agrochemical development.
- Zhao, Da,Xu, Peng,Ritter, Tobias
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supporting information
p. 97 - 107
(2019/01/21)
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- Water-Soluble Hypervalent Iodine(III) Having an I-N Bond. A Reagent for the Synthesis of Indoles
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A readily accessible and bench-stable water-soluble hypervalent iodine(III) reagent (phenyliodonio)sulfamate (PISA) with an I-N bond was synthesized, and its structure was characterized by X-ray crystallography. With PISA, various indoles were synthesized via C-H amination of 2-alkenylanilines involving an aryl migration/intramolecular cyclization cascade with excellent regioselectivity in aqueous CH3CN. Notably, using this new method as the key step, not only two drug molecules, indometacin and zidometacin, but also another bioactive molecule, pravadoline, were synthesized.
- Xia, Hai-Dong,Zhang, Yan-Dong,Wang, Yan-Hui,Zhang, Chi
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supporting information
p. 4052 - 4056
(2018/07/15)
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- Application of hypervalent iodine reagent-mediated in preparation of indole derivatives
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The invention relates to application of hypervalent iodine reagent-mediated in preparation of indole derivatives, in particular to the application of organic trivalent iodine reagent iodoyl benzene aminosulfonate in preparing N-protected 2-substituted indole compounds and indomethacin, zidometacin, pravadoline. The invention relates to the application of organic trivalent iodine reagent iodoyl benzene aminosulfonate in preparing N-protected 2-substituted indole compounds, and the reaction undergoes functional group exchange of a substrate. In addition, iodoyl benzene aminosulfonate plays two important roles in this application, as an oxidant and as Bronsted acid. The application has the advantages of good regioselectivity, wide substrate range, mild conditions, simple operation and amplification of experimental steps. The application of the organic trivalent iodine reagent iodoyl benzene aminosulfonate in the preparation of indomethacin, zidomeprin and pravadoline provided by the invention has the advantages of high synthesis efficiency, simple operation and the like.
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Paragraph 0061
(2018/11/22)
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- Synthesis of Arylamines via Aminium Radicals
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Arylamines constitute the core structure of many therapeutic agents, agrochemicals, and organic materials. The development of methods for the efficient and selective construction of these structural motifs from simple building blocks is desirable but stil
- Svejstrup, Thomas D.,Ruffoni, Alessandro,Juliá, Fabio,Aubert, Valentin M.,Leonori, Daniele
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supporting information
p. 14948 - 14952
(2017/11/20)
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- Cyclooxygenase inhibitors
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Cyclooxygenase inhibitors include compounds of the formula: where R represents phenyl, nitrophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dimethoxyphenyl, 2-methoxyphenyl, 4-hydroxyphenyl, dimethylaminophenyl, 3-methoxyphenyl, 4-ethoxyphenyl, 2,4,5-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, and 2,4-dimethoxyphenyl, 3-hydroxyphenyl, 4-dimethylaminophenyl, or 2,3,4-trimethoxyphenyl.
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- 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-2-hydrogen-indole-3-yl)-N-hydroxyacetamide adopted as histone deacetylase inhibitor and preparation method and application thereof
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The invention belongs to the technical field of medicinal chemistry, particularly relates to a histone deacetylase inhibitor and a preparation method and application thereof, provides an efficient histone deacetylase inhibitor, relates to a compound of the formula (I), further relates to a pharmaceutical acceptable salt, a solvate and a prodrug of the compound, and further relates to a pharmaceutical composition containing the compound of the formula (I) and pharmaceutical application of the pharmaceutical composition. The histone deacetylase inhibitor can effectively treat diseases caused by histone deacetylase abnormal activity expression.
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Paragraph 0031
(2016/10/31)
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- Tert-Butyl Iodide Mediated Reductive Fischer Indolization of Conjugated Hydrazones
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A novel reductive Fischer indolization of readily available N-aryl conjugated hydrazones with tert-butyl iodide has been developed. In this reaction, tert-butyl iodide is used as anhydrous HI source, and the generated HI acts as a Br?nsted acid and a reducing agent. This operationally simple method allows access to various indole derivatives. Furthermore, the procedure can be applied to the synthesis of biologically active compounds.
- Ito, Yuta,Ueda, Masafumi,Takeda, Norihiko,Miyata, Okiko
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supporting information
p. 2616 - 2619
(2016/02/26)
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- Ortho-Carbaborane derivatives of indomethacin as cyclooxygenase (COX)-2 selective inhibitors
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A series of novel indomethacin analogues with carbaboranes as three-dimensional substitutes for the chlorophenyl ring have been prepared. Their cyclooxygenase (COX) inhibition and enzyme selectivity has been tested and compared to the corresponding adamantyl analogues. Surprisingly, only the ortho-carbaborane derivatives were active compounds. Preliminary biological studies gave an interesting insight into the validity of employing carbaboranes as pharmacophores.
- Scholz, Matthias,Blobaum, Anna L.,Marnett, Lawrence J.,Hey-Hawkins, Evamarie
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supporting information; experimental part
p. 4830 - 4837
(2012/09/22)
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- Synthesis and evaluation of anti-inflammatory and analgesic activity of 3-[(5-substituted-1,3,4-oxadiazol-2-yl-thio)acetyl]-2H-chromen-2-ones
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A novel series of 3-[(5-substituted-1,3,4-oxadiazol- 2-yl-thio)acetyl]-2H- chromen-2-one (7a-i) were synthesized by the condensation between the appropriately substituted 5-substituted-1,3,4-oxadiazolyl-2-thione (4a-i) derived from various existing NSAIDs and 3-(2-bromoacetyl)- 2H-chromen-2-one (6) under reflux in the presence of sodium ethoxide. Structure of the synthesized compounds was established on the basis of physicochemical, elemental analysis, and spectral data. The title compounds were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 200 mg/kg bw. Among the series, four compounds 7c, 7e, 7f, and 7h were found to possess a significant anti-inflammatory and analgesic activity profile. In addition, these compounds were also found to possess a less degree of ulcerogenic potential as compared to standard NSAIDs. Springer Science+Business Media, LLC 2010.
- Ingale, Nista,Maddi, Veeresh,Palkar, Mahesh,Ronad, Pradeepkumar,Mamledesai, Shivalingrao,Vishwanathswamy,Satyanarayana, Darbhamulla
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experimental part
p. 16 - 36
(2012/06/04)
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- Prodrugs and mutual prodrugs: Synthesis of some new pyrazolone and oxadiazole analogues of a few non-steroidal anti-inflammatory drugs
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Naproxen, probenecid, diclofenac, ibuprofen and indomethacin were converted to hydrazide derivatives via their methyl ester by reacting with hydrazine hydrate, which were further condensed with β-keto esters to get the pyrazolone derivatives. The hydrazide derivatives of probenecid and diclofenac were also reacted with biphenyl acetic acid while naproxen hydrazide was reacted with p-chloro benzoic acid besides biphenyl acetic acid to synthesize their oxadiazole analogues. Some selected members of the compounds prepared were screened for their anti-inflammatory and analgesic activity.
- Sharma, Vibha,Khan
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- Synthesis of indomethacin analogues for evaluation as modulators of MRP activity
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Synthesis of a range of indomethacin analogues, required for investigation in combination toxicity assays, bearing both N-benzyl and N-benzoyl groups, is described. Copyright
- Maguire, Anita R.,Plunkett, Stephen J.,Papot, Sébastien,Clynes, Martin,O'Connor, Robert,Touhey, Samantha
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p. 745 - 762
(2007/10/03)
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- Profiling indomethacin impurities using high-performance liquid chromatography and nuclear magnetic resonance
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The anti-inflammatory drug indomethacin was investigated regarding new related impurities. Therefore, related substances 2-9 were prepared by independent synthesis and physicochemically characterized. To determine indomethacin and its related substances, a new HPLC-UV method was developed and validated. Indomethacin and its impurities were eluted on a C18 column with a mobile phase consisting of methanol and an aqueous solution of 0.2% phosphoric acid at a flow rate of 1.5 ml/min and were quantified by UV detection at 320 nm. Overall, the HPLC-UV method was simple and reliable for the detection of eight impurities in indomethacin. In addition to the HPLC-UV method, 1H nuclear magnetic resonance (NMR) was used to investigate indomethacin regarding impurities. For that purpose, related substances 2-9 were systematically added to indomethacin and investigated. The NMR method was found to be very useful for the identification of impurities in bulk substance without prior separation. Both HPLC-UV and NMR were used to analyze 38 batches of indomethacin available on the European market. The outcome was that 42% of the batches did not meet the compendial requirements although they met the specifications of current compendial methods. Some batches contained the previously undescribed impurity 8, while other batches contained by-products from two distinct synthetic routes. The methods presented herein are important contributions to the ongoing efforts to reduce impurities and therefore the risk of adverse side-effects in drugs that are no longer under patent protection.
- Hess,Teubert,Ortwein,Eger
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p. 301 - 311
(2007/10/03)
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- Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors
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Recent studies from our laboratory have shown that derivatization of the carboxylate moiety in substrate analogue inhibitors, such as 5,8,11,14- eicosatetraynoic acid, and in nonsteroidal antiinflammatory drugs (NSAIDs), such as indomethacin and meclofenamic acid, results in the generation of potent and selective cyclooxygenase-2 (COX-2) inhibitors (Kalgutkar et al. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 925-930). This paper summarizes details of the structure-activity studies involved in the transformation of the arylacetic acid NSAID, indomethacin, into a COX-2-selective inhibitor. Many of the structurally diverse indomethacin esters and amides inhibited purified human COX-2 with IC50 values in the low-nanomolar range but did not inhibit ovine COX-1 activity at concentrations as high as 66 μM. Primary and secondary amide analogues of indomethacin were more potent as COX-2 inhibitors than the corresponding tertiary amides. Replacement of the 4- chlorobenzoyl group in indomethacin esters or amides with the 4-bromobenzyl functionality or hydrogen afforded inactive compounds. Likewise, exchanging the 2-methyl group on the indole ring in the ester and amide series with a hydrogen also generated inactive compounds. Inhibition kinetics revealed that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Conversion of indomethacin into ester and amide derivatives provides a facile strategy for generating highly selective COX-2 inhibitors and eliminating the gastrointestinal side effects of the parent compound.
- Kalgutkar, Amit S.,Marnett, Alan B.,Crews, Brenda C.,Remmel, Rory P.,Marnett, Lawrence J.
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p. 2860 - 2870
(2007/10/03)
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- New class of potent ligands for the human peripheral cannabinoid receptor
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A new class of potent ligand for the human peripheral cannabinoid (hCB2) receptor is described. Two indole analogs 13 and 17 exhibited nanomolar potencies (K(i)) with good selectivity for the hCB2 receptor over the human central cannabinoid (hCB1) receptor.
- Gallant, Michel,Dufresne, Claude,Gareau, Yves,Guay, Daniel,Leblanc, Yves,Prasit, Petpiboon,Rochette, Chantal,Sawyer, Nicole,Slipetz, Deborah M.,Tremblay, Nathalie,Metters, Kathleen M.,Labelle, Marc
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p. 2263 - 2268
(2007/10/03)
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- Rigid analogs of indomethacin
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10 Chloro 2 methoxy 5 methyl 7 H pyrrolo [3,2,1 de]phenanthrid 7 one 4 acetic acid and its deschloro analog were synthesized as rigid analogs of indomethacin. The chloro analog was found to be inactive in a standard in vivo guinea pig uv erythema assay.
- Olson,Wheeler,Wells
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p. 167 - 171
(2007/10/08)
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