Studies on the synthesis of condensed pyridazine derivatives. IV. Synthesis and anxiolytic activity of 2-aryl-5,6-dihydro-(1)benzothiepino[5,4- c]pyridazin-3(2H)-ones and related compound.

A series of 2-aryl-5,6-dihydro-(1)benzothiepino[5,4-c]pyridazin-3(2H)- ones and related compounds were synthesized and evaluated for their ability to displace 3H-diazepam from rat brain membranes in vitro, and to prevent bicuculline induced convulsions in mice in vivo. Compounds with a 4'-methoxyphenyl (36) or 4'-chlorophenyl group (37, 39--42) as 2-aryl substituents showed prominent activities in both the in vitro and in vivo tests. Among them, 2-(4'-chlorophenyl)-5,6-dihydro- (37) and 2-(4'-chlorophenyl)-5,6-dihydro-10-fluoro-(1)benzothiepino[5,4-c]+ ++pyridazin- 3(2H)-one 7-oxides (41) showed activity twice as potent as diazepam in an anticonflict test (Vogel type, rats) while exhibiting less muscle relaxation (rotarod test, mice) and augmentation of gamma-aminobutyric acid-induced chloride current (Icl) in isolated frog sensory neurones than diazepam. Compound 37 (Y-23684) was selected from this series as a candidate for further development. The structure-activity relationships are discussed.     

Alkyl Ammonium Ion Selectivity of Hexahomotrioxacalix[3]arene Triamide Derivative having the Intramolecular Hydrogen-Bonding Group

The lower rim functionalized hexahomotrioxacalix[3]arene triamide 4 with cone-conformation was synthesized from triol 1 by a stepwise reaction. The different extractability for alkali metal ions, transition metal ions, and alkyl ammonium ions from water into dichloromethane is discussed. Due to the strong intramolecular hydrogen bonding between the neighboring NH and CO groups in triamide 4, its affinity to metal cations was weakened. Triamide 4 shows a single selectivity to n-BuNH ₃ ⁺ . The anion complexation of triamide 4 was also studied by ¹H NMR titration experiments. Triamide 4 binds halides through the intermolecular hydrogen bonding among the NH hydrogens of amide in a 1:1 fashion in CDCl₃. The association constants calculated from these changes in chemical shifts of the amide protons are K _a = 223 M^?1 for Cl^? and K _a = 71.7 M^?1 for Br^?. Triamide 4 shows a preference for Cl^? complexation than Br^? complexation.     

Alkyl Ammonium Ion Selectivity of Hexahomotrioxacalix[3]arene Triamide Derivative having the Intramolecular Hydrogen-Bonding Group

The lower rim functionalized hexahomotrioxacalix[3]arene triamide 4 with cone-conformation was synthesized from triol 1 by a stepwise reaction. The different extractability for alkali metal ions, transition metal ions, and alkyl ammonium ions from water into dichloromethane is discussed. Due to the strong intramolecular hydrogen bonding between the neighboring NH and CO groups in triamide 4, its affinity to metal cations was weakened. Triamide 4 shows a single selectivity to n-BuNH₃⁺. The anion complexation of triamide 4 was also studied by ¹H NMR titration experiments. Triamide 4 binds halides through the intermolecular hydrogen bonding among the NH hydrogens of amide in a 1:1 fashion in CDCl₃. The association constants calculated from these changes in chemical shifts of the amide protons are K_a = 223 M⁻¹ for Cl⁻ and K_a = 71.7 M⁻¹ for Br⁻. Triamide 4 shows a preference for Cl⁻ complexation than Br⁻ complexation.     

Catalytic enantioselective synthesis of atropisomeric 2-aryl-4-quinolinone derivatives with an N–C chiral axis

In the presence of an (R)-MOP-Pd₂(dba)₃ catalyst, the reaction of ortho-tert-butylaniline with 2-bromophenyl arylethynyl ketone proceeded via a tandem amination (1,4-addition of aniline to an ynone and subsequent intramolecular Buchwald–Hartwig amination) to afford axially chiral N-(2-tert-butylphenyl)-2-aryl-4-quinolinone derivatives with moderate enantioselectivity (up to 72% ee).     

Discovery of Oxysterol-Derived Pharmacological Chaperones for NPC1: Implication for the Existence of Second Sterol-Binding Site

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Highlights? Niemann-Pick disease type C is caused by folding defect in NPC1 protein ? Oxysterols and chemically optimized derivatives act as pharmacological chaperones ? Defects in localization, stability, maturation, and function were corrected in cell ? These derivatives bind to second sterol-binding site on NPC1 protein     

Effect of γ irradiation on the surface properties of wet polysulfone films containing poly(vinylpyrrolidone)

In Japan, hemodialyzers are usually sterilized by γ irradiation. However, the polymer materials used in the dialysis membrane, such as polysulfone (PSf) and poly(vinylpyrrolidone) (PVP), undergo crosslinking or degradation on exposure to γ radiation. In the present study, we prepared PSf/PVP films (PVP content, 0–50 wt%) and used atomic force microscopy (AFM) to perform nanoscale evaluations of the effect of γ irradiation (25 and 50 kGy) on the surface properties of wet PSf/PVP surfaces. Force‐curve measurements were used to evaluate the hardness of and fibrinogen adsorbability on the wet PSf/PVP surface; fibrinogen adsorbability on the wet PSf/PVP surface was evaluated using AFM probes with fibrinogen immobilized on the tips of the probes. At PVP levels greater than 5 wt%, the wet PSf/PVP film surface was completely covered with hydrated and swollen PVP particles. The surface hardness of the wet PSf/PVP films exposed to 25‐kGy γ irradiation greatly decreased with increasing PVP content, whereas the surface hardness of the wet PSf/PVP films exposed to 50‐kGy γ irradiation did not decrease significantly. At higher PVP levels, the reduction in the fibrinogen adsorbability on a wet PSf/PVP film exposed to 25‐kGy γ irradiation was more significant than that on a wet PSf/PVP film exposed to 50‐kGy γ irradiation. PVP particles on the wet PSf/PVP film surface exposed to 50‐kGy γ irradiation did not show significant hydration and swelling because the polymer materials PVP–PSf and PVP‐PVP in these membranes has undergone excessive crosslinking due to γ irradiation. Copyright © 2010 John Wiley & Sons, Ltd.     

Identification of low chlorinated biphenyls in human milk by gas chromatography--mass spectrometry.

Trichlorobiphenyl and tetrachlorobiphenyls in human milk were analysed by gas chromatography--mass spectrometry and mass fragmentography using silicone OV-1 and Apiezon L grease as stationary phases. Low-chlorinated biphenyls had been considered to be excreted rapidly from the body, but in this work quantities of tri- and tetrachlorobiphenyls amounting to approximately 30% of the total of polychlorinated biphenyls (PCBs) accumulated in the milk were identified. This result is important in relation to the quantification of PCBs and in studies of the mechanism of biological degradation.     

Lamellar structure in poly(ala-gly) determined by solid-state NMR and statistical mechanical calculations

Lamellar structure of poly(Ala-Gly) or (AG)n in the solid was examined using 13C solid-state NMR and statistical mechanical approaches. Two doubly labeled versions, [1-13C]Gly14[1-13C]Ala15- and [1-13C]Gly18[1-13C]Ala19 of (AG)15 were examined by two-dimensional (2D) 13C spin diffusion NMR in the solid state. In addition five doubly labeled [15N,13C]-versions of the same peptide, (AG) 15 and 15 versions labeled [3-13C] in each of the successive Ala residues were utilized for REDOR and 13C CP/MAS NMR measurements, respectively. The observed spin diffusion NMR spectra were consistent with a structure containing a combination of distorted beta-turns with a large distribution of the torsion angles and antiparallel beta-sheets. The relative proportion of the distorted beta-turn form was evaluated by examination of 13C CP/MAS NMR spectra of [3-13C]Ala-(AG)15. In addition, REDOR determinations showed five kinds of atomic distances between doubly labeled 13C and 15N nuclei which were also interpreted in terms of a combination of beta-sheets and beta-turns. Our statistical mechanical analysis is in excellent agreement with our Ala Cbeta 13C CP/MAS NMR data strongly suggesting that (AG)15 has a lamellar structure.     

Visible-light-triggered release of nitric oxide from N-pyramidal nitrosamines

Although many organic/inorganic compounds that release nitric oxide (NO) upon photoirradiation (phototriggered caged-NOs) have been reported, their photoabsorption wavelengths mostly lie in the UV region, because X-NO bonds (X=heteroatom and metal) generally have rather strong π-bond character. Thus, it is intrinsically difficult to generate organic compounds that release NO under visible light irradiation. Herein, the structures and properties of N-pyramidal nitrosamine derivatives of 7-azabicyclo[2.2.1]heptanes that release NO under visible light irradiation are described. Bathochromic shifts of the absorptions of these nitrosamines, attributed to HOMO (n)-LUMO (π*) transitions associated with the nonplanar structure of the N-NO moiety, enable the molecules to absorb visible light, which results in N-NO bond cleavage. Thus, these compounds are innate organic caged-NOs that are uncaged by visible light.     

Visible-Light-Induced Synthesis of 1,2,3,4-Tetrahydroquinolines through Formal [4+2] Cycloaddition of Acyclic α,β-Unsaturated Amides and Imides with N,N-Dialkylanilines

1,2,3,4-Tetrahydroquinolines should be applicable to the development of new pharmaceutical agents. A facile synthesis of 1,2,3,4-tetrahydroquinolines that is achieved by a photoinduced formal [4+2] cycloaddition reaction of acyclic α,β-unsaturated amides and imides with N,N-dialkylanilines under visible-light irradiation, in which a new Ir^III complex photosensitizer, a thiourea, and an oxidant act cooperatively in promoting the reaction, is reported. The photoreaction enables the synthesis of a wide variety of 1,2,3,4-tetrahydroquinolines, while controlling the trans/cis diastereoselectivity (>99:1) and constructing contiguous stereogenic centers. A chemoselective cleavage of an acyclic imide auxiliary is demonstrated.