- Synthesis of [1]Benzothieno[2,3- b ]quinolines via Transition-Metal-Free [3+3] Annulation of Nitroarenes and Benzo[ b ]thiophen-3-ylacetonitrile or 3-(Phenylsulfonylmethyl)benzo[ b ]thiophene Carbanions
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Benzo[ b ]thiophen-3-ylacetonitriles or 3-(phenylsulfonylmethyl)benzo[ b ]thiophenes react with nitrobenzene derivatives in the presence of potassium tert -butoxide and chlorotrimethylsilane to form, in good yields, 11-cyano- or 11-(phenylsulfonyl)[1]benzothieno[2,3- b ]quinolines, respectively.
- Nowacki, Micha?,Wojciechowski, Krzysztof
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Read Online
- Thiophenol-mediated hydrogen atom abstraction: An efficient tin-free procedure for the preparation of cyclopentane derivatives
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(Matrix Presented) An efficient procedure for running a cascade reaction involving 1,5-abstraction of a hydrogen atom followed by a radical cyclization is reported. Alkenyl radicals are generated from easily available terminal alkynes and thiophenol. This procedure eliminates the need of using the toxic tributyltin hydride and gives a greater amount of radical translocation products.
- Beaufils, Florent,Denes, Fabrice,Renaud, Philippe
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Read Online
- Method for synthesizing 3 - halo methyl benzofuran compounds
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The invention provides a method for efficiently synthesizing a 3-halomethylation benzofuran class compound by one step through a 2-propargyloxy aniline class compound. Compared with an existing method, the method can adapt to substrates for a wide range, the compound is convenient and easy to obtain, the reaction condition is mild, the operation is easy and convenient, and the reaction efficiency is high. By means of the method, metal salt compounds do not need to be added, and the production and processing for drugs are facilitated.
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Paragraph 0028; 0029; 0047; 0048; 0049
(2019/03/21)
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- IDO inhibitors
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Presently provided are methods for (a) modulating an activity of indoleamine 2,3-dioxygenase comprising contacting an indoleamine 2,3-dioxygenase with a modulation effective amount of a compound as described in one of the aspects described herein; (b) treating indoleamine 2,3-dioxygenase (IDO) mediated immunosuppression in a subject in need thereof, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; (c) treating a medical conditions that benefit from the inhibition of enzymatic activity of indoleamine-2,3-dioxygenase comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; (d) enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound as described in one of the aspects described herein; (e) treating tumor-specific immunosuppression associated with cancer comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount of a compound as described in one of the aspects described herein; and (f) treating immunosuppression associated with an infectious disease, e.g., HIV-I infection, comprising administering an effective indoleamine 2,3-dioxygenase inhibiting amount a compound as described in one of the aspects described herein.
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Page/Page column 313
(2018/09/02)
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- D1-like receptors distinguishing thieno-azecine regioisomers
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Designing ligands with D1/D5 subtype selectivity is a challenge because of the high identity within the receptor helices. Based on the lead compounds 1-3, the thieno-benzazecine regioisomers 4 and 5 were synthesized and biologically evaluated for their affinity towards the five dopamine receptor subtypes utilizing a radioligand binding affinity technique. Within the D1-like family, compound 4 showed 20 fold selectivity for the D5 subtype over D1 subtype (Ki = 3 nM, D1: 60 nM), while its regioisomer, compound 5 with a reversed thiophene position, prefers the D1 subtype over the D5 subtype (Ki = 4 nM, D5: 15 nM). The benzothieno-benzazecine analog 6 was shown to be one of the few azecine derivatives with high affinity for both the D1- and the D2-like family members in the same order of magnitude (Ki = 1.5 nM for D2 and 1.9 nM for D5). Thorough analysis of the amino acid residues constituting the binding pockets of the target dopamine receptor subtypes revealed that at the D5 receptor, either serine S 6.62 and threonine T 7.33 residues or a water network, stabilized by anionic amino acids could contribute to the selectivity pattern of the synthesized compounds.
- Abdel-Fattah, Mohamed A. O.,Abadi, Ashraf H.,Lehmann, Jochen,Schweikert, Peter M.,Enzensperger, Christoph
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p. 1679 - 1686
(2015/09/21)
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- Preparation and reactions of heteroarylmethylzinc reagents
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We report a general preparation of heteroarylmethylzinc chlorides by direct zinc insertion into heteroarylmethyl chlorides, along with a facile and straightforward synthesis of these heterocyclic chloromethyl precursors. We demonstrate that heteroarylmethylzinc reagents undergo various reactions including cross-couplings, allylations, acylations, and addition reactions to aldehydes, leading to polyfunctional heterocyclic products. Furthermore, these heteroaromatic zinc compounds prove to be versatile reagents for the preparation of various N- and O-heterocycles and give access to an analogue of a CB1 modifier.
- Barl, Nadja M.,Sansiaume-Dagousset, Elodie,Monzon, Gabriel,Wagner, Andreas J.,Knochel, Paul
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supporting information
p. 2422 - 2425
(2014/05/20)
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- Discovery of highly potent and selective D4 ligands by interactive SAR study
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A series of thienylmethylphenylpiperazins was synthesized and tested for affinity towards the five subtypes of dopaminergic receptors. Compound 5f showed more than 1000 folds selectivity to D4 receptors; analogue 5e showed the highest affinity to D4 receptors with Ki 3.9 nM. An interactive SAR approach was adopted and lead to compound 14a with Ki (D4) as low as 0.03 nM. Molecular docking studies showed a potential, first to report arene cation interaction between the D4 unique residue Arg-186 and the ligands' arene moiety, explaining the importance of having a strong negative electrostatic potential at this area of the compound structure.
- Abdelfattah, Mohamed A.O.,Lehmann, Jochen,Abadi, Ashraf H.
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supporting information
p. 5077 - 5081
(2013/09/12)
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- Simplifying nickel(0) catalysis: An air-stable nickel precatalyst for the internally selective benzylation of terminal alkenes
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The synthesis and characterization of the air-stable nickel(II) complex trans-(PCy2Ph)2Ni(o-tolyl)Cl is described in conjunction with an investigation of its use for the Mizoroki-Heck-type, room temperature, internally selective coupling of substituted benzyl chlorides with terminal alkenes. This reaction, which employs a terminal alkene as an alkenylmetal equivalent, provides rapid, convergent access to substituted allylbenzene derivatives in high yield and with regioselectivity greater than 95:5 in nearly all cases. The reaction is operationally simple, can be carried out on the benchtop with no purification or degassing of solvents or reagents, and requires no exclusion of air or water during setup. Synthesis of the precatalyst is accomplished through a straightforward procedure that employs inexpensive, commercially available reagents, requires no purification steps, and proceeds in high yield.
- Standley, Eric A.,Jamison, Timothy F.
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p. 1585 - 1592
(2013/03/14)
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- Chemoenzymatic preparation of enantiopure l-benzofuranyl- and l-benzo[b]thiophenyl alanines
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Lipase mediated DKR followed by a chemical and an enzymatic hydrolytic step were combined for the synthesis of enantiopure l-benzofuranyl- and l-benzothienyl alanines.
- Podea, Paula Veronica,Tosa, Monica Ioana,Paizs, Csaba,Irimie, Florin Dan
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p. 500 - 511
(2008/09/19)
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- Structure-activity relationships for a novel series of dopamine D2-like receptor ligands based on N-substituted 3-aryl-8-azabicyclo[3.2.1]octan-3-ol
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Discovering dopamine D2-like receptor subtype-selective ligands has been a focus of significant investigation. The D2R-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole (1, L741,626; K i(D2R/D3R) = 11.2:163 nM) has previously provided a lead template for chemical modification. Herein, analogues have been synthesized where the piperidine was replaced by a tropane ring that reversed the selectivity seen in the parent compound, in human hD2LR- or hD3R-transfected HEK 293 cells (31, Ki(D2R/D3R) = 33.4: 15.5 nM). Further exploration of both N-substituted and aryl ring-substituted analogues resulted in the discovery of several high affinity D2R/D3R ligands with 3-benzofurylmethyl-substituents (e.g., 45, Ki(D2R/D3R) = 1.7:0.34 nM) that induced high affinity not achieved in similarly N-substituted piperidine analogues and significantly (470-fold) improved D3R binding affinity compared to the parent ligand 1. X-ray crystallographic data revealed a distinctive spatial arrangement of pharmacophoric elements in the piperidinol vs tropine analogues, providing clues for the diversity in SAR at the D2 and D3 receptor subtypes.
- Paul, Noel M.,Taylor, Michelle,Kumar, Rakesh,Deschamps, Jeffrey R.,Luedtke, Robert R.,Newman, Amy Hauck
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experimental part
p. 6095 - 6109
(2009/10/01)
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- The interaction of heteroaryl-acrylates and alanines with phenylalanine ammonia-lyase from parsley
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Acrylic acids and alanines substituted with heteroaryl groups at the β-position were synthesized and spectroscopically characterized (UV, HRMS, 1H NMR, and 13C NMR spectroscopy). The heteroaryl groups were furanyl, thiophenyl, benzofuranyl, and benzothiophenyl and contained the alanyl side chains either at the 2- or 3-positions. While the former are good substrates for phenylalanine ammonia lyase (PAL), the latter compounds are inhibitors. Exceptions are thiophen-3-yl-alanine, a moderate substrate and furan-3-yl-alanine, which is inert. Possible reasons for these exceptions are discussed. Starting from racemic het eroaryl-2-alanines their D-enantiomers were prepared by using a stereodestructive procedure. From the heteroaryl-2- acrylates, the L-enantiomers of the heteroaryl-2-alanines were prepared at high ammonia concentration. These results can be best explained by a Friedel - Crafts-type electrophilic attack at the aromatic part of the substrates as the initial step of the PAL reaction.
- Paizs, Csaba,Katona, Adrian,Retey, Janos
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p. 2739 - 2744
(2008/02/03)
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- FUSED HETEROCYCLIC COMPOUNDS USEFUL AS INHIBITORS OF HISTONE DEACETYLASE
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Disclosed are compounds of formula (I) that inhibit histone deacetylase (HDAC) enzymatic activity, pharmaceutical compositions comprising such compounds, as well as methods to treat conditions, particularly proliferative conditions, mediated at least in part by HDAC, wherein A, W, W1, W2, Ar2, and G are described herein.
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Page/Page column 170-172
(2008/06/13)
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- BENZOTHIENOPYRIDINES FOR USE AS INHIBITORS OF EG5 KINESIN
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Compounds of a certain formula I, in which R1, R2, R3, R4 and X have the meanings indicated in the description, are novel effective compounds with Eg5 inhibitory, anti-proliferative and/or apoptosis inducing activity.
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Page/Page column 27
(2008/06/13)
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- Thiophenol-mediated 1,5-hydrogen atom abstraction: Easy access to mono- and bicyclic compounds
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A thiophenol-mediated method for cyclization of alkynes is described. The reaction cascade involves the intermolecular addition of a phenylthiyl radical to a terminal triple bond generating an alkenyl radical, followed by a 1,5-hydrogen atom transfer and a 5-exo-trig radical cyclization. This very efficient tin-free procedure allows one to prepare highly functionalized cyclopentane derivatives as well as fused bicyclic and spirocyclic compounds from easily available precursors. During this cyclization process, a phenylthio moiety is incorporated into the final cyclized products. This functionalization is particularly attractive for further transformation of the products.
- Beaufils, Florent,Denes, Fabrice,Becattini, Barbara,Renaud, Philippe,Schenk, Kurt
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p. 1587 - 1594
(2007/10/03)
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- Benzo(b)thiophene derivatives and process for producing the same
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The present invention is 3,4-disubstituted-benzo[b]thiophene derivatives represented by general formula (I) and processes for preparing compounds represented by general formula (V) from compounds represented by general formula (IV), preparing a mixture of compounds represented by the following formula (II) and the following formula (III) and preparing the benzo[b]thiophene derivatives represented by the above formula (I). wherein, R1 and R2 represent each a halogen atom, a trihalomethyl group, a C1-4 alkyl group or a C14 alkoxy group; X represents a hydroxy group or a halogen atom; R3 and R4 represent each a hydrogen or a halogen atom, a trihalomethyl group, a C1-4 alkyl group or a C1-4 alkoxy group; and R5 represents a C1-3 alkyl group or a trifluoromethyl group.
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- Modified ibogaine fragments: Synthesis and preliminary pharmacological characterization of 3-ethyl-5-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5- b]benzothiophenes
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Five phenyl-substituted derivatives and analogues of 1,2,3,4,5,6- hexahydroazepino[4,5-b]indole, 5, a major fragment of ibogaine (1), were synthesized and tested for binding to monoamine transporters, the NMDA receptor-coupled cation channel, and dopamine and opioid receptors. All five derivatives, 9 and 17a-d, displayed 8-10-fold higher affinity at the DA transporter than ibogaine and noribogaine (4). At the serotonin transporter, two compounds (9 and 17a) exhibited higher potency than ibogaine, while the rest had weaker binding affinities than the lead compound. In keeping with their structural similarity to ibogaine, all five compounds displayed weak to poor affinity for dopamine D1 and D2 receptors. However, two compounds, 17a,c, demonstrated moderate binding affinities at dopamine D3 receptors. All five compounds displayed weak to poor affinities for μ and κ opioid receptors and for the NMDA receptor-coupled cation channel. Despite the qualitative differences, derivatives and analogues of 5 may serve as useful substitutes for ibogaine.
- Efange, Simon M. N.,Mash, Deborah C.,Khare, Anil B.,Ouyang, Quinjie
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p. 4486 - 4491
(2007/10/03)
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- Bioactive tricyclic ibogaine analogs
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Ibogaine analogs are provided, which are phenyl-substituted-hexahydroazepino[4,5-b]indoles useful to treat cocaine addiction and the use of other addictive substances.
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- Antihyperglycemic activity of novel substituted 3H-1,2,3,5-oxathiadiazole 2-oxides
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A series of substituted 3H-1,2,3,5-oxathiadiazole-2-oxides (6) was prepared and tested for antihyperglycemic activity in the db/db mouse, a model for type 2 (non-insulin dependent) diabetes mellitus. The oxathiadiazoles 6 were synthesized by a two-step sequence: treatment of a substituted acetonitrile (4) with hydroxylamine to give the corresponding amidoxime (5) and cyclization with thionyl chloride to yield 6. In terms of potency, the 2-naphthalenylmethyl group (as in compound 3) was found to be the optimal substituent in this series. Compound 3 was approximately 5 times more potent than ciglitazone (1).
- Ellingboe,Alessi,Dolak,Nguyen,Tomer,Guzzo,Bagli,McCaleb
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p. 1176 - 1183
(2007/10/02)
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- FURAN DERIVATIVES HAVING ANTI-ULCER ACTIVITY
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Compounds of formula (I): STR1 wherein: A represents a CH-NO 2 group or a N-CN group;B represents CH 2, O, S or a direct bond;R represents a bicyclic or polycyclic residue, variously substituted and functionalized;R 1 and R 2, which may be the same or different, are hydrogen or C 1-C 4 alkyl groups; andn and m, which may be the same or different, are 0, 1, 2, 3 or 4; are valuable pharmacological agents.
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