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AZASPIRO[4.5] DECANE DERIVATIVES AND USE THEREOF

The invention provides azaspiro[4.5]decane derivatives of Formula (A): and pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof, wherein A1, X, A2, Rr, R2′, W1, W2, R3′, R4′, a, and b are defined in the disclosure. The invention also provides compounds of Formulae I, and B-G, and pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof. Further, the invention provides use of the compounds of Formulae A-G and I, and the pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof, to treat pain. In certain embodiments, Compounds of the Disclosure are useful for treating a disorder responsive to blockade of one or more sodium channels.

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Identification, characterization and pharmacological profile of three metabolites of (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenylcyclohexen-1- yl)methyl]pyridine (CI-1007), a dopamine autoreceptor agonist and potential antipsychotic agent

Liquid chromatographic-mass spectrometric (LC-MS) analysis of plasma taken from cynomolgus monkeys dosed orally with (R)-(+)-1,2,3,6-tetrahydro-4- phenyl-1-[(3-phenylcyclohexen-1-yl)methyl]pyridine (1), a dopamine (DA) autoreceptor agonist and potential antipsychotic agent, revealed several metabolites. The molecular masses of three major metabolites suggested that they were mono- and dihydroxylated derivatives of 1. We synthesized compounds 2 and 3, the two possible mono-p-hydroxyphenyl derivatives of 1, along with the bis-p-hydroxyphenyl derivative 4. These compounds coeluted by HPLC with the three hydroxylated metabolites of 1. Compounds 2-4 all had high affinities for DA D2 and D3 receptors and moderate affinities for D4 receptors. Like 1, compound 2 decreased DA synthesis and neuronal firing in rat brain, indicative of DA autoreceptor activation. Compound 2 inhibited exploratory locomotor activity in rodents and was active in the Sidman avoidance test in squirrel monkeys, predictive of antipsychotic activity in humans. Compounds 3 and 4 showed weak activity in all these tests. After squirrel monkeys were dosed with 1 orally at the ED100 dose of the Sidman avoidance test, the plasma concentration of 2 was below the limit of quantitation. Therefore, these metabolites are unlikely to contribute greatly to the potent activity seen with 1 in the Sidman avoidance test.

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Synthesis and antibacterial and antifungal properties of novel S-, N-, N,S-, and S,O-substituted 1,4-naphthoquinone derivatives

A novel series of substituted 1,4-naphthoquinone derivatives were synthesized and evaluated for their antibacterial and antifungal activity. The structures of the novel products were characterized by spectroscopic methods. Among the tested compounds, 2,2?,3,3?-alkoxy substituted naphthoquinones, S,O-substituted naphthoquinone, and N,S-substituted naphthoquinone derivatives are the most potent antifungals against C. tenuis. 2,3-Thio-2?,3?-alkoxy substituted naphthoquinones are the most effective antifungal compounds against A. niger. Supplemental materials are available for this article. Go to the publisher’s online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

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Nickel-Catalyzed Amide Bond Formation from Methyl Esters

Despite being one of the most important and frequently run chemical reactions, the synthesis of amide bonds is accomplished primarily by wasteful methods that proceed by stoichiometric activation of one of the starting materials. We report a nickel-catalyzed procedure that can enable diverse amides to be synthesized from abundant methyl ester starting materials, producing only volatile alcohol as a stoichiometric waste product. In contrast to acid- and base-mediated amidations, the reaction is proposed to proceed by a neutral cross coupling-type mechanism, opening up new opportunities for direct, efficient, chemoselective synthesis.

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Discovery of 1,4-Dioxa-8-azaspiro[4.5]decane

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Re-evolution of the 2-phenylquinolines: Ligand-based design, synthesis, and biological evaluation of a potent new class of staphylococcus aureus NorA efflux pump inhibitors to combat antimicrobial resistance

Overexpression of efflux pumps is an important mechanism by which bacteria evade the effects of antimicrobial agents that are substrates. NorA is a Staphylococcus aureus efflux pump that confers reduced susceptibility to many structurally unrelated agents, including fluoroquinolones, biocides, and dyes, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 2-phenylquinoline derivatives was designed by means of ligand-based pharmacophore modeling in an attempt to identify improved S. aureus NorA efflux pump inhibitors (EPIs). Most of the 2-phenylquinoline derivatives displayed potent EPI activity against the norA overexpressing strain SA-1199B. The antibacterial activity of ciprofloxacin, when used in combination with some of the synthesized compounds, was completely restored in SA-1199B and SA-K2378, a strain overexpressing norA from a multicopy plasmid. Compounds 3m and 3q also showed potent synergistic activity with the ethidium bromide dye in a strain overexpressing the MepA MDR efflux pump.

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SULFONAMIDES AS INHIBITORS OF BCL-2 FAMILY PROTEINS FOR THE TREATMENT OF CANCER

The present invention includes novel compound and methods of treating a disease or disorder by antagonizing Bcl-2 family proteins, particularly compounds of Formula (I) or pharmaceutically acceptable salt thereof, as well as methods of treating a disease, disorder, or syndrome associated with Bcl-2 inhibition, particularly hyper proliferative diseases. The present invention also includes pharmaceutical compositions including compounds of formula (I) and pharmaceutically acceptable salts thereof

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Synthesis of C-4-modified zanamivir analogs as neuraminidase inhibitors and their anti-AIV activities

With the introduction of bioisosteres of the guanidinium group together with scaffold hopping, 35 zanamivir analogs with C-4-modification were synthesized, and their inhibitory activities against both group-1 and group-2 neuraminidase (H5N1 and H3N2) were determined. Compound D26 exerts the most potency, with IC50 values of 0.58 and 2.72 muM against N2 and N1, respectively. Further preliminary anti-avian influenza virus (AIV, H5N1) activities against infected MDCK cells were evaluated, and D5 exerts ?58% protective against AIV infection, which was comparable to zanamivir (?67%). In a rat pharmacokinetic study, compound D5 showed an increased plasma half-life (t1/2) compared to zanamivir following either intravenous or oral administration. This study may represent a new start point for the future development of improved anti-AIV agents.

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Copper-Catalyzed Dihydroquinolinone Synthesis from Isocyanides and O-Benzoyl Hydroxylamines

A copper-catalyzed protocol has been realized for the rapid assembly of dihydroquinolinones from readily accessible isocyanides and O-benzoyl hydroxylamines. The reactions (10 mol % of CuOAc, 10 mol % of dppe, 3 equiv of PhONa, 30 C) deliver various structurally interesting dihydroquinolinones in moderate to good yields (up to 76%). The reactions may proceed in a cascade manner involving isocyanide insertion into the N-O bond, Mumm-type rearrangement, and intramolecular nucleophilic substitution.

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Benzothiazole derivatives with activity as adenosine receptor ligands

The present invention relates to substituted benzothiazole derivitives and to their pharmaceutically acceptable salts useful for the treatment of diseases related to the adenosine receptor.

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Compounds useful as reversible inhibitors of cysteine proteases

Disclosed are novel cathepsin S, K, F, L and B reversible inhibitory compounds of the formulas (I), (II), (Ia) and (Ib) further defined herein. The compounds are useful for treating autoimmune diseases. Also disclosed are processes for making such novel compounds. 1

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