Studies on antiallergic agents. I. Synthesis and antiallergic activity of novel pyrazine derivatives.

Various pyrazine derivatives were synthesized and their antiallergic activity was examined. The inhibitory activity on allergic histamine release of the compounds bearing a 5-tetrazolyl group was more potent than that of the corresponding carboxyl derivatives. The introduction of -CONH- or -NHCO- between the pyrazine ring and the 5-tetrazolyl group as a spacer greatly enhanced the activity. N-(1H-Tetrazol-5-yl)-2-pyrazinecarboxamide (I-3) was estimated to exhibit nearly the same potency as disodium cromoglycate (DSCG). The structure-activity relationship among various derivatives modified by introducing some substituents onto the 3-, 5- or 6-position of the pyrazine ring of I-3 was investigated. The activity remained unchanged or was reduced when such substituents as methyl, chloro, methoxy, methylamino and dimethylamino were introduced at the 3- or 5-position. In contrast, 6-substitution with various alkylamino groups more or less increased the activity. Among them, the 6-dimethylamino (I-17c) and 6-(1-pyrrolidinyl) (I-34) derivative were proved to be most potent. The IC50 values (concentration which produces 50% inhibition of the allergic histamine release) of I-17c and I-34 were determined to be 4.7 x 10(-10) and 4.6 x 10(-10) M, respectively. These two compounds produced a potent inhibitory activity on passive cutaneous anaphylaxis (PCA) in rat, not only by the intravenous route (ED50 = 0.0096 mg/kg for both compounds) but also by the oral route (ED50 = 0.19 and 0.18 mg/kg, respectively). On the other hand, when the pyrazine ring of some representative compounds was replaced with a pyridine ring, the inhibitory activity on histamine release was significantly reduced.     

Structure-activity relationship (SAR) studies on oxazolidinone antibacterial agents. 1. Conversion of 5-substituent on oxazolidinone

A structure-activity relationship (SAR) study on 5-substituted oxazolidinones as an antibacterial agent is described. The oxazolidinones, of which 5-acetylaminomethyl moiety was converted into other functions, were prepared and evaluated for antibacterial activity. Elongation of the methylene chain (8) and conversion of the acetamido moiety into guanidino moiety (12) decreased the antibacterial activity. The replacement of carbonyl oxygen (=O) by thiocarbonyl sulfur (=S) enhanced in vitro antibacterial activity. Especially, compound 16, which had the 5-thiourea group, showed 4-8 stronger in vitro activity than linezolid. Our SAR study revealed that the antibacterial activity was greatly affected by the conversion of 5-substituent.     

Synthesis and reactivities of 10-S-3 trithiadiazapentalene derivatives

1,3-Bis(p-substituted-phenylthiocarbamoyl)-2-imidazolidinethiones 3a-f reacted with bromine to give trithiadiazapentalene derivatives 5a-f , bearing the exocyclic C-N double bonds, in moderate yields. The molecular structure of 5b was elucidated by the X-ray crystallographic analysis. The treatment of 5b-f with hydrochloric acid gave the ring-opening products, 1,3-bis(p-substituted-phenylthiocarbamoyl)-2-imidazo-lidinones 9b-f , accompanied by the production of elemental sulfur. Reduction of 5b , 5d , and 5e with sodium borohydride gave the ring-opening compounds, 1,3-bis(p-substituted-phenylthiocarbamoyl)-2-imidazolidines 13b , 13d , and 13e respectively.     

Ultra-slow muon facility for advanced μSR studies

A concept, a construction and an account of commissioning experiments up to May 1993 are given for the recently completed ultra-slow positive muon facility at the pulsed muon facility of UT-MSL/KEK. The intense and ultra-slow ⁺ beam with an extremely small phase-space volume to be produced in this facility will open new muon sciences includingSR studies on material surfaces.     

Magnetic structure of graphite ribbon

Anoble mechanism of spin polarization is proposed for finite graphite sheet with edge. For graphite ribbon with zigzag edge, there appear peculiar ‘edge states’. These localized states comprise nearly flat band at the Fermi level, which easily causes magnetic instability. Magnetic structure is suggested from Hartree-Fock analysis of the Hubbard model, where huge magnetic moments are induced at around both of edges by weak HubbardU and are coupled antiferromagnetically with each other.     

Remarkably Selective Ag(+) Extraction and Transport by Thiolariat Ethers

Synthesis and metal binding properties of thiolariat ethers, where a sulfide side chain is introduced into a framework of a crown ether, have been performed. Remarkably high Ag(+) selectivity among heavy metal ions was observed in solvent extraction and transport across a liquid membrane using thiolariat ethers with a 15-crown-5 ring as carriers. Thiolariat ethers with a 12-crown-4 or a 18-crown-6 do not exhibit such a high Ag(+) selectivity. The former binds metal ions weakly, and the latter recognizes Pb(2+) as well as Ag(+). The corresponding oxygen analogs, i.e. lariat ethers, do not show Ag(+) selectivity. The Ag(+) binding strength of the sulfoxide and sulfone analogs is much lower than that of thiolariat ethers. Thiolariat ethers with a benzocrown framework containing a sulfide chain at the 4 position of the benzene nucleus showed very low affinity to Ag(+). Extractability and transport ability using various thiolariat ether derivatives strongly suggested that this high Ag(+) selectivity is a result of the synergistic coordination of the ring oxygen and the sulfur atom of the thiolariat ether. NMR chemical shifts of protons and carbons in the proximity of the sulfur atom of the thiolariat ether were changed significantly in accordance with the synergistic coordination described above. 1:1 Complexation between a thiolariat ether and Ag(+) were supported by a Job plot using the chemical shift of the methylene protons adjacent to the sulfur atom.     

Towards slow μ− production via muon catalyzed fusion

Slow ^– production via dd-CF using a two-layer arrangement is investigated. To determine its feasibility, experimental measurements are now in progress using the muonic X-ray detection method. The following experimental steps are being considered: (1) measurement of the number of ^– stopped inside a solid H₂/D₂ layer by detecting p K X-rays, (2) hot d emission detection by placing a secondary target at a distance of 10–30 mm from the layer and by detecting specific delayed X-rays, (3) measurement of the disappearance of d emission as the added D₂ layer is increased, (4) dd-CF measurement by detecting fusion protons, and (5) slow ^– emission detection. Results of the initial test experiment are presented.     

Ultra-slow muon facility for surface HFI studies

A concept, a design, a construction and an account of commissioning experiments are given for the recently completed ultra-slow muon facility at the pulsed muon facility of UT-MSL/KEK. The intense (more than 10³/s) slow ⁺ beam with an extremely narrow phase-space volume (0.2 eV×(3 cm)²) to be produced in this facility will open a new muon science including surface physics and chemistry and fundamental atomic physics.Post-doctoral fellow of Swiss National Science Foundation.