- Aerobic Visible-Light Induced Intermolecular S?N Bond Construction: Synthesis of 1,2,4-Thiadiazoles from Thioamides under Photosensitizer-Free Conditions
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Aerobic visible-light induced intermolecular S?N bond construction has been achieved without the addition of photosensitizer, metal, or base. With this strategy, 1,2,4-thiadiazoles can be obtained from thioamides. Preliminary mechanistic investigation suggested that the excited state of thioamides undergoes a single-electron-transfer (SET) process to afford thioamidyl radicals, which can be further transformed into a 1,2,4-thiadiazole through desulfurization and oxidative cyclization. The reaction has good functional group tolerance and represents a green method for the construction of S?N bonds.
- Wang, Hui,Xie, Shihua,Zhu, Hongjun,Zhuo, Liang
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supporting information
p. 3398 - 3402
(2021/06/25)
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- 1,2,4-Oxadiazole Topsentin Analogs with Antiproliferative Activity against Pancreatic Cancer Cells, Targeting GSK3β Kinase
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A new series of topsentin analogs, in which the central imidazole ring of the natural lead was replaced by a 1,2,4-oxadiazole moiety, was efficiently synthesized. All derivatives were pre-screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. The five most potent compounds were further investigated in various pancreatic ductal adenocarcinoma (PDAC) cell lines, including SUIT-2, Capan-1, and Panc-1 cells, eliciting EC50 values in the micromolar and sub-micromolar range, associated with significant reduction of cell migration. These remarkable results might be explained by the effects of these new topsentin analogues on epithelial-to-mesenchymal transition markers, including SNAIL-1/2 and metalloproteinase-9. Moreover, flow cytometric analysis after Annexin V-FITC and propidium iodide staining demonstrated that these derivatives enhanced apoptosis of PDAC cells. Keeping with these data, the PathScan intracellular signaling and ELISA array revealed cleavage of caspase-3 and PARP and a significant inhibition of GSK3β phosphorylation, suggesting this kinase as a potential downstream target of our novel compounds. This was further supported by a specific assay for the evaluation of GSK3β activity, showing IC50 values for the most active compounds against this enzyme in the micromolar range.
- Carbone, Daniela,Parrino, Barbara,Cascioferro, Stella,Pecoraro, Camilla,Giovannetti, Elisa,Di Sarno, Veronica,Musella, Simona,Auriemma, Giulia,Cirrincione, Girolamo,Diana, Patrizia
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p. 537 - 554
(2020/12/01)
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- Efficient construction of diverse 3-cyanoindoles under novel tandem catalysis
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A novel and rapid construction of 3-cyanoindoles by palladium-catalyzed tandem reactions has been developed. "N-H"free unprotected, N-alkyl and N-aryl 3-cyanoindoles are obtained with good to excellent yields. The usefulness of this synthetic approach is further demonstrated by the successful synthesis of practical compounds such as the therapeutic estrogen receptor ligand A precursor. Mechanism study shows that the tandem catalysis exploits a Suzuki cross-coupling with subsequent base-induced isoxazole fragmentation, followed by the aldimine condensation.
- Wu, Jun,Liu, Jiabin,Zhou, Kerui,He, Zhenni,Wang, Qian,Wu, Fen,Miao, Tingting,Qian, Jinjie,Shi, Qian
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supporting information
p. 12660 - 12663
(2020/11/02)
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- Imidazo[2,1-b] [1,3,4]thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells
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A new series of eighteen imidazo [2,1-b] [1,3,4]thiadiazole derivatives was efficiently synthesized and screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. Two out of eighteen derivatives, compounds 12a and 12h, showed remarkably cytotoxic activity with the half maximal inhibitory concentration values (IC50) ranging from 0.23 to 11.4 μM, and 0.29–12.2 μM, respectively. However, two additional compounds, 12b and 13g, displayed remarkable in vitro antiproliferative activity against pancreatic ductal adenocarcinoma (PDAC) cell lines, including immortalized (SUIT-2, Capan-1, Panc-1), primary (PDAC-3) and gemcitabine-resistant (Panc-1R), eliciting IC50 values ranging from micromolar to sub-micromolar level, associated with significant reduction of cell-migration and spheroid shrinkage. These remarkable results might be explained by modulation of key regulators of epithelial-to-mesenchymal transition (EMT), including E-cadherin and vimentin, and inhibition of metalloproteinase-2/-9. High-throughput arrays revealed a significant inhibition of the phosphorylation of 45 tyrosine kinases substrates, whose visualization on Cytoscape highlighted PTK2/FAK as an important hub. Inhibition of phosphorylation of PTK2/FAK was validated as one of the possible mechanisms of action, using a specific ELISA. In conclusion, novel imidazothiadiazoles show potent antiproliferative activity, mediated by modulation of EMT and PTK2/FAK.
- Cascioferro, Stella,Petri, Giovanna Li,Parrino, Barbara,Carbone, Daniela,Funel, Niccola,Bergonzini, Cecilia,Mantini, Giulia,Dekker, Henk,Geerke, Daan,Peters, Godefridus J.,Cirrincione, Girolamo,Giovannetti, Elisa,Diana, Patrizia
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- 3-(6-phenylimidazo [2,1-b][1,3,4]thiadiazol-2-yl)-1HIndole derivatives as new anticancer agents in the treatment of pancreatic ductal adenocarcinoma
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A new series of imidazo[2,1-b][1,3,4]thiadiazole derivatives was efficiently synthesized and screened for their in vitro antiproliferative activity on a panel of pancreatic ductal adenocarcinoma (PDAC) cells, including SUIT-2, Capan-1 and Panc-1. Compounds 9c and 9l, showed relevant in vitro antiproliferative activity on all three pre-clinical models with half maximal inhibitory concentration (IC50) ranging from 5.11 to 10.8 μM, while the compounds 9e and 9n were active in at least one cell line. In addition, compound 9c significantly inhibited the migration rate of SUIT-2 and Capan-1 cells in the scratch wound-healing assay. In conclusion, our results will support further studies to increase the library of imidazo [2,1-b][1,3,4] thiadiazole derivatives for deeper understanding of the relationship between biological activity of the compounds and their structures in the development of new antitumor compounds against pancreatic diseases.
- Arizza, Vincenzo,Carbone, Daniela,Cascioferro, Stella,Cirrincione, Girolamo,Diana, Patrizia,El Hassouni, Btissame,Funel, Niccola,Giovannetti, Elisa,Padova, Alessandro,Parrino, Barbara,Perricone, Ugo,Peters, Godefridus J.,Petri, Giovanna Li
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- Optimization, Structure-Activity Relationship, and Mode of Action of Nortopsentin Analogues Containing Thiazole and Oxazole Moieties
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Plant diseases seriously endanger plant health, and it is very difficult to control them. A series of nortopsentin analogues were designed, synthesized, and evaluated for their antiviral activities and fungicidal activities. Most of these compounds displayed higher antiviral activities than ribavirin. Compounds 1d, 1e, and 12a, with excellent antiviral activities, emerged as novel antiviral lead compounds, among which 1e was selected for further antiviral mechanism research. The mechanism research results indicated that these compounds may play an antiviral role by aggregating viral particles to prevent their movement in plants. Further fungicidal activity tests revealed that nortopsentin analogues displayed broad-spectrum fungicidal activities. Compounds 2p and 2f displayed higher antifungal activities against Alternaria solani than the commercial fungicides carbendazim and chlorothalonil. Current research has laid a foundation for the application of nortopsentin analogues in plant protection.
- Guo, Jincheng,Hao, Yanan,Ji, Xiaofei,Wang, Ziwen,Liu, Yuxiu,Ma, Dejun,Li, Yongqiang,Pang, Huailin,Ni, Jueping,Wang, Qingmin
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p. 10018 - 10031
(2019/10/05)
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- GaCl3-Catalyzed C-H Cyanation of Indoles with N-Cyanosuccinimide
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An efficient GaCl3-catalyzed direct cyanation of indoles and pyrroles using bench-stable electrophilic cyanating agent N-cyanosuccinimide was achieved and afforded 3-cyanoindoles and 2-cyanopyrroles in good yields and excellent regioselectivities. Notably, this protocol exhibited high reactivity for unprotected indoles and was applicable to a broad range of indole and pyrrole substrates.
- Wang, Xue,Makha, Mohamed,Chen, Shu-Wei,Zheng, Huaiji,Li, Yuehui
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p. 6199 - 6206
(2019/05/24)
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- New thiazole nortopsentin analogues inhibit bacterial biofilm formation
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New thiazole nortopsentin analogues were conveniently synthesized and evaluated for their activity as inhibitors of biofilm formation of relevant Gram-positive and Gram-negative pathogens. All compounds were able to interfere with the first step of biofilm formation in a dose-dependent manner, showing a selectivity against the staphylococcal strains. The most active derivatives elicited IC50 values against Staphylococcus aureus ATCC 25923, ranging from 0.40–2.03 μM. The new compounds showed a typical anti-virulence profile, being able to inhibit the biofilm formation without affecting the microbial growth in the planktonic form.
- Carbone, Anna,Parrino, Barbara,Cusimano, Maria Grazia,Spanò, Virginia,Montalbano, Alessandra,Barraja, Paola,Schillaci, Domenico,Cirrincione, Girolamo,Diana, Patrizia,Cascioferro, Stella
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- Efficient Synthesis and Biological Activity of Novel Indole Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors
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A series of novel indole derivatives were synthesized as potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase. Among those, compound 10b demonstrated the highest growth inhibition rate of 66.7% against the VEGFR-2 tyrosine kinase at 10 μM which indicates that indole-benzothiazole might be the favorable structure. The binding mode of compound 10b with VEGFR-2 tyrosine kinase was evaluated by molecular docking.
- Zhang,Xu,Wang,Kang
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p. 3006 - 3016
(2018/02/21)
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- Erratum: Copper-mediated cyanation of indoles and electron-rich arenes using DMF as a single surrogate (Org. Biomol. Chem. (2015) 13 (8322-8329))
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Correction for 'Copper-mediated cyanation of indoles and electron-rich arenes using DMF as a single surrogate' by Lianpeng Zhang et al., Org. Biomol. Chem., 2015, 13, 8322-8329.
- Zhang, Lianpeng,Lu, Ping,Wang, Yanguang
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p. 1840 - 1840
(2016/02/09)
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- Aromatic heterocyclic compound and a method of producing aminonitrile
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PROBLEM TO BE SOLVED: To provide a novel method of turning an aromatic heterocyclic compound into nitrile, by which a raw material having high toxicity is not needed, the amount of a byproduct can be reduced and structural restriction of a usage raw material is reduced.SOLUTION: In the method of turning the aromatic heterocyclic compound into the nitrile, a nitrogen-containing aromatic heterocyclic compound represented by general formula (1), a silicon compound represented by general formula (2) and a nitromethane are reacted in the presence of one or more zinc catalysts selected from the group consisting of zinc sulfonate, zinc sulfonamide and a zinc halide to obtain the nitrile compound of the aromatic heterocyclic compound represented by general formula (3).
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Paragraph 0079; 0080
(2017/06/02)
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- Copper-mediated cyanation of indoles and electron-rich arenes using DMF as a single surrogate
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The copper-mediated cyanation of indoles with DMF as a single surrogate has been realized. This approach could be applied for the cyanation of some electron-rich arenes and aryl aldehydes as well. Aryl aldehydes were demonstrated to be the key intermediates in the cascade process of cyanation of indoles and electron-rich arenes.
- Zhang, Lianpeng,Lu, Ping,Wang, Yanguang
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p. 8322 - 8329
(2015/08/03)
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- Zinc-catalyzed direct cyanation of indoles and pyrroles: Nitromethane as a source of a cyano group
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With nitromethane and diphenylsilane (Ph2SiH2), zinc triflate behaves as a Lewis acid catalyst for the cyanation of nitrogen-containing heteroarenes such as indoles and pyrroles. This is the first realization of the Lewis acid-catalyzed direct cyanation of a C(aryl)-H bond with no CN group-containing cyanating agent.
- Nagase, Yuta,Sugiyama, Tetsuya,Nomiyama, Shota,Yonekura, Kyohei,Tsuchimoto, Teruhisa
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supporting information
p. 347 - 352
(2014/05/20)
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- Copper-mediated C3-cyanation of indoles by the combination of amine and ammonium
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A copper-promoted C3-cyanation of both the free N-H and N-protected indoles by N,N,N′,N′-tetramethyl-ethane-1,2-diamine (TMEDA) and ammonium is achieved. The iminium ion acts as the intermediate in this transformation, which is sequentially electrophilically attacked by indole and H2O followed by hydrolyzation to form the aldehyde. Then the reaction between the aldehyde and ammonium afforded nitriles. The reaction employs O2 as a clean oxidant with good efficiency and functional group tolerance. Thus, it represents a facile and safe procedure leading to 3-cyano indoles. The Royal Society of Chemistry 2014.
- Liu, Bin,Wang, Jiehui,Zhang, Bo,Sun, Yang,Wang, Lei,Chen, Jianbin,Cheng, Jiang
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supporting information
p. 2315 - 2317
(2014/03/21)
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- Cyanation of indoles with benzyl cyanide as the cyanide anion surrogate
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A copper-mediated direct cyanation of indoles with benzyl cyanide as the cyanide anion surrogate has been achieved. The cascade reaction furnished 3-cyanoindoles under mild reaction conditions in good to excellent yields with various functional groups tolerance.
- Zhang, Lianpeng,Wen, Qiaodong,Jin, Jisong,Wang, Chen,Lu, Ping,Wang, Yanguang
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p. 4236 - 4240
(2013/06/26)
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- Indole cyanation via CH bond activation under catalysis of Ru(III)-exchanged NaY zeolite (RuY) as a recyclable catalyst
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Selective 3-cyanation of indoles was achieved under heterogeneous catalysis of Ru(III)-exchanged NaY zeolite (RuY) as a recyclable catalyst, in combination with K4[Fe(CN)6] as a nontoxic, slow cyanide releasing agent. Under the aforementioned conditions, good yields of the desired products were obtained.
- Khorshidi, Alireza
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experimental part
p. 903 - 906
(2012/08/28)
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- A base-modulated chemoselective synthesis of 3-cyanoindoles or 4-cyanoquinolines using a palladium-catalyzed N-heterocyclization
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A selective methodology for the synthesis of either 3-cyanoindoles or 4-cyanoquinolines via a base-modulated palladium-catalyzed reductive N-heterocyclization from a common 1-cyano-1-(2-nitrophenyl)-1-alkene precursor is described. The required starting materials were prepared either by a Kosugi-Migita-Stille coupling of 2-halo-1-nitrobenzenes with a tributyl(1-alkenyl)stannane or by a vicarious nucleophilic substitution (VNS) of nitrobenzenes followed by a Knoevenagel condensation with an aldehyde.
- Banini, Serge R.,Turner, Michael R.,Cummings, Matthew M.,S?derberg, Bj?rn C.G.
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experimental part
p. 3603 - 3611
(2011/06/21)
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- Synthesis and in-vitro anticancer activity of 3,5-bis(indolyl)-1,2,4- thiadiazoles
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A series of 3,5-bis(indolyl)-1,2,4-thiadiazoles were synthesized and evaluated for their cytotoxicity against selected human cancer cell lines. The reaction of indole-3-thiocarboxamide 3 with iodobenzene diacetate underwent oxidative dimerization to give 3,5-bis(indolyl)-1,2,4-thiadiazoles 4a-n. Among the synthesized bis(indoly)-1,2,4-thiadiazoles, the compound 4h with 4-chlorobenzyl and methoxy substituents showed the most potent activity.
- Kumar, Dalip,Kumar, N. Maruthi,Chang, Kuei-Hua,Gupta, Ritika,Shah, Kavita
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scheme or table
p. 5897 - 5900
(2011/10/18)
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- Pd(OAc)2-catalyzed C-H activation of indoles: a facile synthesis of 3-cyanoindoles
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Indoles undergo smooth cyanation with CuCN in the presence of 20 mol % Pd(OAc)2 and 40 mol % CuBr2 in DMF to produce a wide range of the corresponding 3-cyanoindoles in good yields with high regioselectivity.
- Subba Reddy,Begum, Zubeda,Jayasudhan Reddy,Yadav
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experimental part
p. 3334 - 3336
(2010/07/06)
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- NITROGENATED HETEROCYCLIC COMPOUND AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention relates to novel compounds having a xanthine oxidase inhibitory effect and an uricosuric effect and pharmaceutical compositions comprising the same as an active ingredient. That is, the present invention relates nitrogen-containing heterocyclic compounds represented by the following general formula (I): wherein Y1 represents N or C(R4) ; Y2 represents N or C(R5) ; R4 and R5 independently represent an alkyl group, a hydrogen atom etc. ; one of R1 and R2 represents an optionally substituted aryl group, an alkoxygroup or an optionally substituted heterocyclic group; the other of R1 and R2 represents a haloalkyl group, a cyanogroup, ahalogenatometc.; and R3 represents a 5-tetrazolyl group or a carboxy group, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same as an active ingredient.
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Page/Page column 15; 20
(2008/12/06)
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- Sodium bis(trimethylsilyl)amide in the oxidative conversion of aldehydes to nitriles
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The feasibility of the Me3Si species acting as a nucleofuge was investigated in compounds containing the NSiMe3 moiety. Treatment of various aromatic aldehydes with 2.2 equiv. of NaN(SiMe3)2 at 185°C in a sealed tube produced the corresponding nitriles in high yields (81-98%). In these reactions, NaN(SiMe3)2 acted as an oxidizing agent. Results from control experiments indicate that the Me 3Si unit can depart efficiently from the NSiMe3 moiety of N-silylimine intermediates. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Jih, Ru Hwu,Fung, Fuh Wong
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p. 2513 - 2516
(2007/10/03)
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- Spirocyclic compounds incorporating five-membered rings with two heteroatoms for treating psychotic disorders, etc.
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The present invention provides a compound of formula I or a salt or prodrug thereof: STR1 wherein the dotted line represents an optional chemical bond in one of the two possible positions; A represents a group of formula II: STR2 in which R1 represents hydrogen, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, benzyloxy, hydroxy (C1-6)alkyl, halogen, amino, cyano, nitro, --CONR6 R7 or --SO2 NR6 R7, in which R6 and R7 independently represent hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; R2 represents hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy or C1-6 alkylcarbonyl; V represents nitrogen, --CH or --C--; and W represents oxygen, sulphur or --NR8, in which R8 represents hydrogen, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; two of X, Y and Z are the same or different and each represents oxygen, sulphur or nitrogen; and the remaining group X, Y or Z is carbon, or Y is carbonyl (C=O); and Q is the residue of an azacyclic or azabicyclic ring system; which compounds are useful in the treatment of psychotic disorders (e.g. schizophrenia and mania); anxiety; alcohol or drug withdrawal or dependence; pain; gastric stasis; gastric dysfunction (such as occurs with dyspepsia, peptic ulcer, reflux oesophagitis and flatulence); migraine, nausea and vomiting; movement disorders; and presenile and senile dementia.
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- AN INTRAMOLECULAR PHOTOCYCLIZATION TO FORM THE AZEPINOINDOLE SYSTEM
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Azepinoindoles 5a and 5b are formed in good yield via the intramolecular photocyclization of N-chloroacetyl-3-aminomethylindoles.
- Klohr, Steven E.,Cassady, John M.
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p. 671 - 674
(2007/10/02)
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