- SNAr catalysis enhanced by an aromatic donor-acceptor interaction; Facile access to chlorinated polyfluoroarenes
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Selective catalytic SNAr reaction of polyfluoroaryl C-F bonds with chloride is shown. Stoichiometric TMSCl makes the reaction exergonic and allows catalysis, which involves ground state elevation of chloride, aromatic donor-acceptor interactions, and stabilization of the Meisenheimer complex. Traditional cross-coupling of the products is now possible and demonstrates the utility.
- Senaweera, Sameera,Weaver, Jimmie D.
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p. 7545 - 7548
(2017/07/12)
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- Chromium-Catalyzed Asymmetric Dearomatization Addition Reactions of Halomethyl Heteroarenes
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The first asymmetric dearomatization addition reaction of halomethyl arenes including benzofuran and benzothiophene was enabled by chromium catalysis. A variety of aldehydes served as suitable electrophiles under mild reaction conditions. Molecular complexities are quickly increased in a highly diastereo- and enantioselective manner.
- Tian, Qingshan,Bai, Jing,Chen, Bin,Zhang, Guozhu
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p. 1828 - 1831
(2016/05/19)
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- A systematic exploration of the effects of flexibility and basicity on sigma (σ) receptor binding in a series of substituted diamines
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The sigma-1 receptor (S1R) has attracted a great deal of attention as a prospective drug target due to its involvement in numerous neurological disorders and, more recently, for its therapeutic potential in neuropathic pain. As there was no crystal structure of this membrane-bound protein reported until 2016, ligand generation was driven by pharmacophore refinements to the general model suggested by Glennon and co-workers. The generalised S1R pharmacophore comprises a central region where a basic amino group is preferred, flanked by two hydrophobic groups. Guided by this pharmacophore, S1R ligands containing piperazines, piperazinones, and ethylenediamines have been developed. In the current work, we systematically deconstructed the piperazine core of a prototypic piperazine S1R ligand (vide infra) developed in our laboratories. Although we did not improve the affinity at the S1R compared to the lead, we identified several features important for affinity and selectivity. These included at least one basic nitrogen atom, conformational flexibility and, for S1R, a secondary or tertiary amine group proximal to the anisole. Furthermore, S2R selectivity can be tailored with functional group modifications of the N-atom proximal to the anisole.
- Conroy, Trent,Manohar, Madhura,Gong, Yu,Wilkinson, Shane M.,Webster, Michael,Lieberman, Brian P.,Banister, Samuel D.,Reekie, Tristan A.,Mach, Robert H.,Rendina, Louis M.,Kassiou, Michael
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p. 9388 - 9405
(2016/10/13)
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- Synthesis of iboga-like isoquinuclidines: Dual opioid receptors agonists having antinociceptive properties
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Some novel iboga-analogues consisting of benzofuran moiety and dehydroisoquinuclidine ring connected by -CH2-, (CH2)2 and (CH2)3 linkers have been synthesized with the view to develop potential antinociceptive drugs. The compounds 14 and 21 showed binding at the μ-opioid receptor (MOR), while the compound 11a exhibited dual affinities at both MOR and κ-opioid receptor (KOR). MAP kinase activation indicated all three compounds have opioid agonistic properties. The presence of a double bond and endo-methylcarboxylate group in the dehydroisoquinuclidine ring and the benzofuran and methylene spacer appeared to be essential for opioid receptor binding. Further studies demonstrated 11a caused significant antinociception in mice in the hot-plate test which was comparable to that produced by morphine. The compound 11a was also found to be nontremorigenic unlike various iboga congeners. This study identifies a new pharmacophore which may lead to the development of suitable substitute of morphine in the treatment of pain.
- Banerjee, Tuhin Suvro,Paul, Sibasish,Sinha, Surajit,Das, Sumantra
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p. 6062 - 6070
(2015/02/02)
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- Synthesis and binding assays of novel 3,3-dimethylpiperidine derivatives with various lipophilicities as σ1 receptor ligands
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Starting from two carbocyclic analogs, a series of 3,3-dimethylpiperidine derivatives was prepared and tested in radioligand binding assays at σ1 and σ2 receptors, and at Δ8-Δ7 sterol isomerase (SI) site. The novel compounds mostly bear heterocyclic rings or bicyclic nucleus of differing lipophilicities. Compounds 18a and 19a,b demonstrated the highest σ1 affinity (Ki = 0.14-0.38 nM) with a good selectivity versus σ2 binding. Among them, 18a had the lowest C log D value (3.01) and only 19b was selective versus SI too. Generally, it was observed that more planar and hydrophilic heteronuclei conferred a decrease in affinity for both σ receptor subtypes.
- Ferorelli, Savina,Abate, Carmen,Pedone, Maria P.,Colabufo, Nicola A.,Contino, Marialessandra,Perrone, Roberto,Berardi, Francesco
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experimental part
p. 7612 - 7622
(2012/01/04)
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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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- 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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- Novel cyclic amide derivatives
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Novel compounds represented by the following formula (I) that act as a ligand to sigma receptor/binding cite and a medicament comprising the same as an active ingredient: wherein X represents an alkyl group, an aryl group, a heterocyclic group or the like; Q represents a group represented by —CH2—, —CO—, —O—, —CH(OR7)— or the like wherein R7 represents a hydrogen atom, an alkyl group or the like; n represents an integer of from 0 to 5; R1 and R2 each represent a hydrogen atom, an alkyl group or the like; B represents either of the following groups: wherein R3, R4, R5, and R6 each represent a hydrogen atom, a halogen atom, an alkoxyl group or the like; m represents 1 or 2; and the ring of: represents an aromatic heterocyclic ring.
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- Compounds for treatment of cardiac arrhythmia synthesis, and methods of use
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The subject invention pertains to novel compounds, and compositions comprising the compounds, for the treatment of cardiac arrhythmias. The subject invention further concerns a method of making the novel compounds. The novel compounds are rapidly metabolized analogs of amiodarone, having the distinct and advantageous characteristic of being metabolized to a less lipophilic compound. The new compounds can have particular utility for treating life-threatening ventricular tachyarrhythmias, especially in patients with congestive heart failure (CHF). The product can also provide effective management for ventricular arrhythmias and supraventricular arrhythmias, including atrial fibrillation and re-entrant tachyarrhythmias involving accessory pathways.
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- Compound for treatment of cardiac arrhythmia, synthesis, and methods of use
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Described is a novel compound and method, useful for treatment of cardiac arrhythmias, especially useful in patients with congestive heart failure (CHF). A process for synthesizing the novel compound is also described.
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- Compound for treatment of cardiac arrhythmia, synthesis, and methods of use
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Described is a novel compound and method, useful for treatment of cardiac arrhythmias, especially useful in patients with congestive heart failure (CHF). A process for synthesizing the novel compound is also described.
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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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- N-quinolinyl alkyl-substituted 1-aryloxy-2-propanolamine and propylamine derivatives possessing class III antiarrhythmic activity
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This invention relates to N-heteroalkyl-substituted 1-aryloxy-2-propanolamine and propylamine derivatives possessing anti-arrhythmic activity, to pharmaceutical compositions and to methods for production thereof.
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- Substituted benzimidazole derivatives possessing Class III antiarrhythmic activity
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This invention relates to N-heteroalkyl-substituted 1-aryloxy-2-propanolamine and proplyamine derivatives possessing anti-arrhythmic activity, to pharmaceutical compositions and to method for production thereof.
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- Esters of benzofuranyl acids
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This invention relates to novel esters of benzofuranyl acids, novel intermediates therefor, synthesis thereof, and the control of pests.
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