- Non-alkylator anti-glioblastoma agents induced cell cycle G2/M arrest and apoptosis: Design, in silico physicochemical and SAR studies of 2-aminoquinoline-3-carboxamides
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Malignant gliomas are the most common brain tumors, with generally dismal prognosis, early clinical deterioration and high mortality. Recently, 2-aminoquinoline scaffold derivatives have shown pronounced activity in central nervous system disorders. We herein reported a series of 2-aminoquinoline-3-carboxamides as novel non-alkylator anti-glioblastoma agents. The synthesized compounds showed comparable activity to cisplatin against glioblastoma cell line U87 MG in vitro. Among them, we found that 6a displayed good inhibitory activity against A172 and U118 MG glioblastoma cell lines and induced cell cycle arrest in the G2/M phase and apoptosis in U87 MG by flow cytometry analysis. Additionally, 6a displayed low cytotoxicity to several normal human cell lines. In silico study showed 6a had promising physicochemical properties and was predicted to cross the blood–brain barrier. Moreover, preliminary structure–activity relationships are also investigated, shedding light on further modifications towards more potent agents on this series of compounds. Our results suggest this compound has a promising potential as an anti-glioblastoma agent with a differential effect between tumor and non-malignant cells.
- Gu, Xiangyu,Liu, Jianwen,Ni, Xintong,Qi, Yingxue,Qian, Xuhong,Shao, Xusheng,Xu, Xiaoyong,Yuan, Pengtao
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supporting information
(2021/09/22)
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- Exploiting excited-state aromaticity to design highly stable singlet fission materials
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Singlet fission, the process of forming two triplet excitons from one singlet exciton, is a characteristic reserved for only a handful of organic molecules due to the atypical energetic requirement for low energy excited triplet states. The predominant strategy for achieving such a trait is by increasing ground state diradical character; however, this greatly reduces ambient stability. Herein, we exploit Baird's rule of excited state aromaticity to manipulate the singlet-triplet energy gap and create novel singlet fission candidates. We achieve this through the inclusion of a [4n] 5-membered heterocycle, whose electronic resonance promotes aromaticity in the triplet state, stabilizing its energy relative to the singlet excited state. Using this theory, we design a family of derivatives of indolonaphthyridine thiophene (INDT) with highly tunable excited state energies. Not only do we access novel singlet fission materials, they also exhibit excellent ambient stability, imparted due to the delocalized nature of the triplet excited state. Spin-coated films retained up to 85% activity after several weeks of exposure to oxygen and light, while analogous films of TIPS-pentacene showed full degradation after 4 days, showcasing the excellent stability of this class of singlet fission scaffold. Extension of our theoretical analysis to almost ten thousand candidates reveals an unprecedented degree of tunability and several thousand potential fission-capable candidates, while clearly demonstrating the relationship between triplet aromaticity and singlet-triplet energy gap, confirming this novel strategy for manipulating the exchange energy in organic materials.
- Fallon, Kealan J.,Budden, Peter,Salvadori, Enrico,Ganose, Alex M.,Savory, Christopher N.,Eyre, Lissa,Dowland, Simon,Ai, Qianxiang,Goodlett, Stephen,Risko, Chad,Scanlon, David O.,Kay, Christopher W. M.,Rao, Akshay,Friend, Richard H.,Musser, Andrew J.,Bronstein, Hugo
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supporting information
p. 13867 - 13876
(2019/09/30)
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- A depression drug impurity of preparing method (by machine translation)
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The invention relates to a depression drug impurity of preparing method, it comprises the following steps: (a) the high sodium iodate, water and mixed DMF; (b) is poured into ice water, adjusting pH with alkali and layered extraction, purification to obtain compound 4; in the 120 - 150 °C reaction after column chromatography separation to obtain compound 5; (c) the compound 3 and said compound 5 by adding ethylene glycol dimethyl ether, in the ice water bath under the conditions of the adding sodium hydride to, heating up to 40 - 60 °C reaction 20 - 40 minutes, further heating up to reflux; (d) the compound 6 with the [...] catalyst, morpholine, methanol and ethanol are mixed, the reaction is carried out in a hydrogen atmosphere, filtered [...] filtrate to obtain compound 7; (e) the compound 7 with formic acid, a sodium mixed, heated to 100 - 120 °C refluxing reaction; (g) the compound 10 in toluene soluble, in an inert gas atmosphere by adding sodium hydride, temperature reaction. This can obtain the high purity of the depression drug impurity isomer, for impurity accurate control. (by machine translation)
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Paragraph 0021; 0031; 0033; 0034
(2018/09/11)
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- Preparation method of impurity isomer key intermediate of anti-depressive drug
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The invention relates to a preparation method of an impurity isomer key intermediate of an anti-depressive drug. The preparation method comprises the following steps: (a) mixing sodium periodate, water and DMF (Dimethylformamide); (b) pouring in ice water, adjusting pH with an alkaline solution, extracting by layers, purifying to obtain a compound 4, and performing column chromatography isolationafter reacting at 120 to 150 DEG C to obtain a compound 5; (c) adding the compound 3 and the compound 5 into 1,2-dimethoxyethane, adding sodium hydride under the condition of ice water bath, heating to 40 to 60 DEG C for reacting for 20 to 40 minutes, and heating and refluxing; (d) mixing the compound 6 with a rhodium carbon catalyst, morpholine, methanol and ethanol, reacting under a hydrogen atmosphere, and performing suction filtration and spin drying on filtrate to obtain a compound 7; (e) mixing the compound 7 with formic acid and sodium formate, and heating to 100 to 120 DEG C for refluxreaction; (f) adding anhydrous K2CO3,Cu powder and CuBr, performing reaction under the protection of insert gas at the temperature of 150 to 180 DEG C to obtain a compound 9; cooling to 30 to 60 DEGC, adding NaOH solution to perform reaction, filtering, and purfying to obtain a compound 10.. By adopting the preparation method, a high-purity impurity isomer of the anti-depressive drug can be obtained for accurate control of impurities.
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Paragraph 0018; 0031
(2018/09/11)
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- Preparation method of chloronitrophenyl intermediate serving as impurity isomer of medicine for treating depression
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The invention relates to a preparation method of a chloronitrophenyl intermediate serving as an impurity isomer of medicine for treating depression. The method includes the following steps that a, sodium periodate, water and DMF are mixed, then a DMF solution of a compound 2 is added for a reaction, and after the reaction, a filtrate is taken and purified to obtain a compound 3; b, 2-bromo-4-chlorotoluene, N-bromosuccinimide, dibenzoyl peroxide and carbon tetrachloride are mixed, stirred, heated to 80-100 DEG C for a reaction and then poured into ice water, the pH is adjusted with lye, and layered extraction and purification are conducted to obtain a compound 4; c, the compound 3 and a compound 5 are added into glycol dimethyl ether, sodium hydride is added under the condition of an ice water bath, the temperature is raised to 40-60 DEG C for a reaction for 20-40 minutes, then the temperature is raised for reflux, after the reaction is completed, water and ethyl acetate are added in avolume ratio of 1:1, and solid is precipitated, subjected to suction filtration and dried to obtain a compound 6. In this way, the nitrophenyl intermediate with high purity can be obtained to be usedfor subsequent preparation of the high-purity and high-yield impurity isomer of medicine for treating depression.
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Paragraph 0013; 0023-0024; 0026
(2018/11/22)
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- Iron promoted C3-H nitration of 2H-indazole: direct access to 3-nitro-2H-indazoles
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An efficient C3-H functionalization of indazole has been demonstrated. Notably, this method involves chelation-free radical C-H nitration on 2H-indazole. The radical mechanism was confirmed by control experiments and quantum chemical calculations. The synthetic utility has been proven by the synthesis of bio-relevant benzimidazoindazoles via reductive cyclization.
- Murugan, Arumugavel,Gorantla, Koteswar Rao,Mallik, Bhabani S.,Sharada, Duddu S.
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supporting information
p. 5113 - 5118
(2018/07/29)
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- A 3 - amino -7 - chloroquinolin synthetic method (by machine translation)
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The invention provides a 3 - amino - 7 - chloroquinolin synthetic method. Synthesis method of the invention, in order to 4 - chloro - 1 - methyl - 2 - nitrobenzene as the raw materials, and N, N - dimethyl formamide dimethyl acetal to hydroformylation reaction to produce 4 - chloro - 2 - nitrobenzaldehyde, with 3, 3 - diethyl oxygen radical propionic acid ethyl ester to ring-closure reaction to produce 7 - chloro - 3 - quinoline carboxylic acid ethyl ester, under basic condition to produce 7 - chloro - 3 - quinoline carboxylic acid, with the azido diphenyl phosphate through Curtius rearrangement reaction to 3 - tert-butoxycarbonyl amino - 7 - chloroquinolin, finally through takes off uncle butoxycarbonyl to obtain 3 - amino - 7 chloroquinolin. The invention of 3 - amino - 7 - chloroquinolin synthetic method, the synthetic route is simple, reasonable process, low material cost, simple and easy to obtain, operation and after treatment is convenient, the total yield is high, easy to enlarge, can be large-scale production of 3 - amino - 7 - chloroquinolin. (by machine translation)
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-
Paragraph 0045; 0046; 0066; 0067
(2018/09/26)
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- Enamine compound synthesis method and aromatic aldehydes synthetic method of the compound (by machine translation)
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The invention provides a method for synthesis of a enamine compound and aromatic aldehydes synthetic method of the compound. Enamine compound of synthetic method comprises the starting raw materials with A N, N - dimethyl formamide dimethyl acetal to form a mixed solution; and the mixed solution is continuously fed into the continuous reactor in the alkene amination reaction to obtain the enamine compound B, and alkene amination reaction in continuous enamine compound discharged from the continuous reactor in B; A starting material of formula (1) shown in the structural formula of, enamine compound B formula (2) shown in the structural formula. The reaction of the raw material of the mixed solution and continuously fed into the reactor by way of the alkene amination reaction alkene amination reaction of continuous, then also the continuous production of aromatic aldehyde compound, shortens the reaction time, the reaction efficiency is improved. The continuous reaction method can be stopped at any time according to the actual conditions the reaction or the termination of the reaction, after-treatment can also be based on the need to batch processing or merging processing, is convenient and simple. (by machine translation)
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-
Paragraph 0064; 0065; 0069; 0070; 0075; 0084; 0085; 0086
(2017/12/09)
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- Synthetic process of aromatic acetaldehyde compound
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The invention provides a synthetic process of an aromatic acetaldehyde compound; the synthetic method includes forming a mixed solution via starting material A with N,N-dimethylformamide dimethyl acetal; continuously feeding the mixed solution into a continuous reactor to carry out enamination reaction to obtain enamide B, and discharging the enamide B from the continuous reactor during enamination reaction; preparing aromatic acetaldehyde compound C with the enamide B, wherein the starting material A has a structural formula shown as formula (1), the enamide B has a structural formula shown as formula (2), and the aromatic acetaldehyde compound C has a structural formula shown as formula (3). By continuously feeding the mixed solution of reaction materials into the reactor to carry out enamination reaction, enamination reaction is continuously performed; continuous production of aromatic acetaldehyde compounds is achieved, reaction time is shortened, and reaction efficiency is improved.
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Paragraph 0063; 0067; 0068; 0069; 0087
(2017/11/30)
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- Stable TEMPO and ABNO Catalyst Solutions for User-Friendly (bpy)Cu/Nitroxyl-Catalyzed Aerobic Alcohol Oxidation
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Two solutions, one consisting of bpy/TEMPO/NMI and the other bpy/ABNO/NMI (bpy =2,2′-bipyridyl; TEMPO = 2,2,6,6-tetramethylpiperidine N-oxyl, ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl; NMI = N-methylimidazole), in acetonitrile are shown to have good long-term stability (≥1 year) under air at 5 °C. The solutions may be combined in appropriate quantities with commercially available [Cu(MeCN)4]OTf to provide a convenient catalyst system for the aerobic oxidation of primary and secondary alcohols.
- Steves, Janelle E.,Stahl, Shannon S.
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p. 11184 - 11188
(2015/11/18)
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- Copper(I)/ABNO-catalyzed aerobic alcohol oxidation: Alleviating steric and electronic constraints of Cu/TEMPO catalyst systems
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Cu/TEMPO catalyst systems promote efficient aerobic oxidation of sterically unhindered primary alcohols and electronically activated substrates, but they show reduced reactivity with aliphatic and secondary alcohols. Here, we report a catalyst system, consisting of (MeObpy)CuI(OTf) and ABNO (MeObpy =4,4′-dimethoxy-2,2′-bipyridine; ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl), that mediates aerobic oxidation of all classes of alcohols, including primary and secondary allylic, benzylic, and aliphatic alcohols with nearly equal efficiency. The catalyst exhibits broad functional group compatibility, and most reactions are complete within 1 h at room temperature using ambient air as the source of oxidant.
- Steves, Janelle E.,Stahl, Shannon S.
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supporting information
p. 15742 - 15745
(2013/11/06)
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- Synthetic studies on indolocarbazoles: Total synthesis of staurosporine aglycon
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A synthesis of staurosporine aglycon and its analogs was achieved in a 28-36% overall yield starting from 2-methylindole. The prominent key steps for the synthesis of the indolocarbazole alkaloids involved electrocyclization and nitrene insertion reactions.
- Rajeshwaran, Ganesan Gobi,Mohanakrishnan, Arasambattu K
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supporting information; experimental part
p. 1418 - 1421
(2011/05/04)
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- Facile, environmentally friendly synthesis of benzaldehyde and phenylacetaldehyde analogs from readily available toluene derivatives
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A facile environmentally friendly synthesis of bezaldehyde and phenylacetaldehyde analogs from readily available toluene derivatives is described. Oxidation of the styrylamines by H2O2 H2O2 affords benzaldehydes in moderate yields, while the hydrolysis of styrylamines afforded phenylacetaldehyde analogs in good yields. Copyright
- Dai, Liyan,Yu, Jie,Chen, Yingqi,Yu, Shichao
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scheme or table
p. 3078 - 3084
(2011/09/14)
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- METHOD FOR MAKING BIARYL COMPOUNDS, COMPOUNDS MADE BY THE METHOD, AND METHOD FOR THEIR USE
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Certain disclosed embodiments of the present invention concern a method for making biaryl compounds by combining a diene with a dienophile under reaction conditions that facilitate a Diels-Alder reaction. Certain embodiments are particularly directed to making a tetra-ortho-substituted biaryl compounds. The disclosed method may involve using novel dienes, dienophiles, or both. Similarly, certain of the biaryl compounds are novel compounds too. Additional disclosed embodiments concern a method for making useful compounds by first making a Diels-Alder adduct. The Diels-Alder adduct is then further modified or coupled to other compounds. The method can be used to make carbazoles, such as Siamenol. Disclosed biaryl compounds are useful for a number of applications, such as pharmacophores and organocatalysts.
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Page/Page column 44; 178
(2009/01/23)
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- Dioxomolybdenum(VI)-catalyzed reductive cyclization of nitroaromatics. Synthesis of carbazoles and indoles
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Reductive cyclization of nitrobiphenyls and nitrostyrenes to carbazoles and indoles, respectively, is carried out by triphenylphosphine under mild conditions catalyzed by a dichlorodioxomolybdenum(VI) complex. A one-pot procedure for the synthesis of regioselectively functionalized indoles has been developed from commercially available onitrobenzaldehydes and phosphoranes.
- Sanz, Roberto,Escribano, Jaime,Pedrosa, Maria R.,Aguado, Rafael,Arnaiz, Francisco J.
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p. 713 - 718
(2008/02/09)
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- Diels - Alder approach for the construction of halogenated, o-nitro biaryl templates and application to the total synthesis of the anti-HIV agent siamenol
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(Chemical Equation Presented) A rapid Diels - Alder approach to halogenated biaryl templates is described. These biaryl templates are available in two steps from the corresponding aromatic aldehydes. The scope of subsequent Suzuki couplings on the biaryl chlorides is explored. Good tolerance for both electron-donating and electron-withdrawing groups in the coupling process can be achieved. Further functionalization of the biaryl templates is described. Hydrogenation of the nitro moiety with concomitant removal of the benzyl ether yields the o-anilino, o-phenolic polyaryls. Selective reduction of the nitro group can be accomplished. Alternatively, the benzyl ether can be selectively removed under Lewis acidic conditions. The utilization of the Diels - Alder adducts for the synthesis of a series of chlorinated carbazoles via the Cadogan cyclization is also demonstrated. Finally, application of this technology to the total synthesis of siamenol, an anti-HIV agent, is reported.
- Naffziger, Michael R.,Ashburn, Bradley O.,Perkins, Johanna R.,Carter, Rich G.
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p. 9857 - 9865
(2008/04/05)
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- Synthesis and biological evaluation of conformationally constrained analogs of the antitumor agents XK469 and SH80. Part 5
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Conformational restriction of bioactive molecules offers the possibility of generating structures of increased potency. To this end, a synthesis has been achieved of (R,S)-2-[(8-chlorobenzofurano[2,3-b]quinolinyl)oxy]propionic acid (12a), a highly rigidified, polycyclic analog of 2-{4-[(7-chloro-2-quinoxalinyl) oxy]phenoxy}propionic acid (2a, XK469). Efforts to effect the same synthesis of the corresponding 8-bromo-derivative led to a mixture of intermediate, 8-chloro (9a), and 8-bromo-2-hydroxybenzofurano[2,3-b]quinoline (9b), generated by halogen-exchange, via an aromatic SRN1(ARN1) reaction of precursor, 8b, with pyridine hydrochloride. The presumption that conformational restriction of 1b-12a might enhance the antitumor potency of the latter has not been sustained. In fact, 12a proved to be significantly less active than 1b. However, it is apparent that virtually all of the spatial and steric properties of 12a, necessary for improved activity, including the disposition of the 2-oxypropionic acid side chain remain to be identified.
- Hazeldine, Stuart T.,Polin, Lisa,Kushner, Juiwanna,White, Kathryn,Corbett, Thomas H.,Horwitz, Jerome P.
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p. 2462 - 2467
(2007/10/03)
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- 6,6-BICYCLIC RING SUBSTITUTED HETEROBICYCLIC PROTEIN KINASE INHIBITORS
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Compounds of the formula (I) and pharmaceutically acceptable salts thereof, wherein XI, X2, X3, X4, X5, X6, X7, R1, and Q1 are defined herein, inhibit the IGF-1R enzyme and are useful for the treatment and/or prevention of hyperproliferative diseases such as cancer, inflammation, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system.
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Page/Page column 416-417
(2008/06/13)
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- FIBROSIS INHIBITOR
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Medicament being useful as a fibrosis inhibitor for organs or tissues, which comprises a compound of the formula (I): wherein Ring Z is optionally substituted pyrrole ring, etc.; W2 is -CO-, -SO2-, optionally substituted C1-C4 alkylene, etc.; Ar2 is optionally substituted aryl, etc.; W1 and Ar1 mean the following (1) and (2):(1) W1 is optionally substituted C1-C4 alkylene, etc.; Ar1 is optionally substituted bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms:(2) W1 is optionally substituted C2-C5 alkylene, optionally substituted C2-C5 alkenylene, etc.; and Ar1 is aryl or monocyclic heteroaryl, which is substituted by carboxyl, alkoxycarbonyl, etc. at the ortho- or meta-position thereof with respect to the binding position of W1, or a pharmaceutically acceptable salt thereof.
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- Efficient synthesis of [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid, a novel COX-2 inhibitor
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The synthesis of 6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-ylacetic acid (1), a selective cyclooxygenase 2 (COX-2) inhibitor, is described. The synthesis relied on a novel indole formation that involved an alkylation/1,4-addition/elimination/isomerization cascade. It was demonstrated that the entire sequence from sulfonamide 13 and bromoketone 14 to the desired indole (1) could be executed in a single pot.
- Caron, Ste?phane,Vazquez, Enrique,Stevens, Rodney W.,Nakao, Kazunari,Koike, Hiroki,Murata, Yoshinori
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p. 4104 - 4107
(2007/10/03)
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- Pyrrole derivatives
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Pyrrole derivatives represented by the following formula: wherein Ring Z is an optionally substituted pyrrole ring, etc.; W2 is —CO—, —SO2—, an optionally substituted C1-C4 alkylene, etc.; Ar2 is an optionally substituted aryl, etc.; W2 and Ar1 mean the following (1) and (2): (1) W1 is an optionally substituted C1-C4 alkylene, etc.; Ar1 is an optionally substituted bicyclic heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms: (2) W1 is an optionally substituted C2-C5 alkylene, an optionally substituted C2-C5 alkenylene, etc.; and Ar1 is an aryl or monocyclic heteroaryl, which are substituted by carboxyl, an alkoxycarbonyl, etc. at the ortho- or meta-position thereof with respect to the binding position of W1, or a pharmaceutically acceptable salt thereof These compounds are useful as medicaments such as a fibrosis inhibitor for organs or tissues.
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- Enantioselective syntheses of no-carrier-added (n.c.a.) (S)-4-chloro-2-[18F] fluorophenylalanine and (S) - (α-methyl) -4-chloro-2-[18F]fluorophenylalanine
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(S)-4-Chloro-2-fluorophenylalanine and (S)-(α-methyl)-4-chloro-2-fluorophenylalanine were synthesized and labeled with no carrier added (n.c.a.) fluorine-18 through a radiochemical synthesis relying on the highly enantioselective reaction between 4-chloro-2-[18F]fluorobenzyl iodide and the lithium enolate of (2S)-1-(tert-butyloxycarbonyl)-2-(tert-butyl)-3-methyl-1,3-imidazolidine-4-one for (S)-4-chloro-2-[18F]fluorophenylalanine and (2S,5S)-1-(tert-butyloxycarbonyl)-2-(tert-butyl)-3,5-dimethyl-1,3-imidazolidine-4-one for (S) - (α-methyl)-4-chloro-2-[18F] fluorophenylalanine. Quantities of about 20-25 mCi were obtained at the end of synthesis, ready for injection after hydrolysis and high performance liquid chromatography (HPLC) purification, with a radiochemical yield of 17%-20% corrected to the end of bombardment after a total synthesis time of 90-105 min from [18F]fluoride. The enantiomeric excesses were shown to be 97% or more for both molecules without chiral separation and the radiochemical and chemical purities were 98% or better.
- Al-Darwich,Plenevaux,Lemaire,Fiore,Christiaens,Comar,Luxen
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p. 117 - 124
(2007/10/03)
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- Polyaza Heterocycles. Part 2. Nucleophilic Substitution of Halogens in Halogenoquinoxalinocinnolines
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10-Chloroquinoxalinocinnoline readily undergoes methoxydechlorination when treated with sodium methoxide.The 1-, 2-, 3-, 4- and 9-chloro isomers are unreactive towards this reagent, but the 9,10-dichloro derivative undergoes substitution of both chlorines (the 10-position being much the more reactive).The 9- and 10-bromo analogues are both unreactive towards sodium methoxide, but the 9- and 10-fluoro analogues are both highly reactive, to the extent that it has not been possible even to isolate the 10-fluoro compound.Routes to 9- and 10-piperidinoquinoxalinocinnolines are described.
- Ahmad, Arshad,Dunbar, Linda J.,Green, Iain G.,Harvey, Ian W.,Shepherd, Thomas,et al.
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p. 2751 - 2758
(2007/10/02)
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