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.     

Femtosecond absorption study of photodissociation of diphenylcyclopropenone in solution: reaction dynamics and coherent nuclear motion

Reaction dynamics and coherent nuclear motions in the photodissociation of diphenylcyclopropenone (DPCP) were studied in solution by time-resolved absorption spectroscopy. Subpicosecond transient absorption spectra were measured in the visible region with excitation at the second absorption band of DPCP. The obtained spectra showed a new short-lived band around 480 nm immediately after photoexcitation, which is assignable to the initially populated S(2) state of DPCP before the dissociation. The dissociation takes place from this excited state (the precursor of the reaction) with a time constant of 0.2 ps, and the excited state of diphenylacetylene (DPA) is generated as the reaction product. The transient absorption after the dissociation decayed with a time constant of 8 ps that is very close to the S(2)-state lifetime of DPA, but the spectrum of this 8-ps component was different from the S(2) absorption observed with direct photoexcitation of DPA. We conclude that the dissociation of DPCP generates the S(2) state of DPA that probably has a cis-bent structure. At later delay times (>30 ps), the transient absorption signals are very similar to those obtained by direct photoexcitation of DPA. This confirmed that the electronic relaxation from the S(2) state of the product DPA occurs in a similar manner to that of DPA itself, i.e., the internal conversion to the S(1) state and subsequent intersystem crossing to the T(1) state. In order to examine the coherent nuclear dynamics in this dissociation reaction, we carried out time-resolved absorption measurements for the 480-nm band with 70 fs resolution. It was found that an underdamped oscillatory modulation with a 0.1-ps period is superposed on the decay of the precursor absorption. This indicates that DPCP exhibits a coherent nuclear motion having a approximately 330-cm(-1) frequency in the dissociative excited state. Based on a comparison with the measured and calculated Raman spectra of ground-state DPCP, we discuss the assignment of the "330-cm(-1) vibration" and attribute it to a vibration involving the displacement of the CO group as well as the deformation of the Ph-C[Double Bond]C-Ph skeleton. We consider that this motion is closely related to the reaction coordinate of the photodissociation of DPCP.     

Laser photolysis studies of the photochemical reactions of chromium(III) octaethylporphyrin and tetramesitylporphyrin complexes in toluene solution

A nanosecond laser photolysis study was carried out for the Cr(III) porphyrin complexes of 2,3,7,8,12,13,17,18-octaethylporphyrin, [Cr(OEP)(Cl)(L)], and of 5,10,15,20-tetramesitylporphyrin, [Cr(TMP)(Cl)(L)], in toluene containing water and an excess amount of L (L = axial ligand). The laser photolysis generates the triplet excited state of the parent complex as well as a five-coordinate complex, [Cr(porphyrin)(Cl)], produced by the photodissociation of the axial ligand L. The yields for the formation of the triplet state and the photodissociation of L are found to markedly depend on the nature of both L and porphyrin ligand. The five-coordinate [Cr(porphyrin)(Cl)] readily reacts with both H(2)O and L in the bulk solution to give [Cr(porphyrin)(Cl)(H(2)O)] and [Cr(porphyrin)(Cl)(L)], respectively. The axial H(2)O ligand in [Cr(porphyrin)(Cl)(H(2)O)] is then substituted by the ligand L to regenerate the original complex [Cr(porphyrin)(Cl)(L)]. In principle, the substitution reaction takes place by the dissociative mechanism: the first step is the dissociation of H(2)O from [Cr(porphyrin)(Cl)(H(2)O)], followed by the reaction of the five-coordinate [Cr(porphyrin)(Cl)] with the ligand L to regenerate [Cr(porphyrin)(Cl)(L)]. The rate constants for this ligand substitution reaction are found to exhibit bell-shaped ligand concentration dependence. The detailed kinetic analysis revealed that both ligands L and H(2)O in toluene make a hydrogen bond with the axial H(2)O ligand in [Cr(porphyrin)(Cl)(H(2)O)] to yield dead-end complexes for the substitution reaction. The reaction mechanisms are discussed on the basis of the substituent effects of the porphyrin peripheral groups and the kinetic parameters determined from the temperature dependence of the rate constants.     

Synthesis of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins via successive lateral and ortho-lithiations of 4,4-dimethyl-2-(o-tolyl)oxazoline

Sequential treatment of 4,4-dimethyl-2-(o-tolyl)oxazoline in THF with sec-BuLi, aromatic or aliphatic aldehydes, sec-BuLi, B(OMe)₃, and H₂O₂ produced the laterally alkylated and ortho-hydroxylated oxazolines in one-pot. Treatment of these products with TFA in aqueous THF provided 3-substituted 8-hydroxy-3,4-dihydroisocoumarins in 44-75% overall yields. This procedure allowed the short synthesis of (±)-hydrangenol and (±)-phyllodulcin, naturally occurring 3,4-dihydroisocoumarins of pharmacological interest. A more economical synthesis of (±)-phyllodulcin via the trianion intermediate is also described.     

Synthesis and pharmacology of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives, a new class of potent serotonin-3 (5-HT3) receptor antagonists.

A series of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activity assessed by their ability to antagonize the von Bezold-Jarish (BJ) effect in rats. Derivatives bearing 1-azabicyclo[2.2.2]oct-3-yl moiety as a basic function attached to the carboxamide at position 8 showed more potent antagonistic activity than those bearing the other three basic moieties. Structure-activity relationships of this series showed that methyl and chloro groups were more effective as substituents at positions 4 and 6, respectively. The representative compound 15 (Y-25130) in this series showed potent antagonistic activity on the BJ effect (ED50 = 1.3 micrograms/kg i.v.), high affinity for 5-HT3 receptor (Ki = 2.9 nM) and complete protection against cisplatin-induced emesis in dogs at a dose of 0.1 mg/kg i.v.     

Efficient synthesis of thioesters and amides from aldehydes by using an intermolecular radical reaction in water

The combination of the water-soluble radical initiator, 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA-044) and the surfactant, cetyltrimethyl-ammonium bromide (CTAB), was found to be the most suitable condition for the effective and direct synthesis of useful active thioesters (pentafluorophenyl thioesters) in water. In addition, the direct amidation of aldehydes was achieved by the addition of the amines to the thioesterification reaction mixture in water.     

A redox-active ionic liquid manifesting charge-transfer interaction between a viologen and carbazole and its effect on the viscosity,ionic conductivity,and redox process of the viologen

Redox-active ionic liquids (RAILs) are gaining attention as a material that can create a wide range of functions. We herein propose a charge-transfer (CT) RAIL by mixing two RAILs, specifically a carbazole-based ionic liquid ([CzC₄ImC₁][TFSI]) as a donor and a viologen-based ionic liquid ([C₄VC₇][TFSI]₂) as an acceptor. We investigated the effect of CT interaction on the physicochemical properties of the CT ionic liquid (CT-IL) using the results of temperature-dependent measurements of UV-vis absorption, viscosity, and ionic conductivity as well as cyclic voltammograms. We employed the Walden analysis and the Grunberg–Nissan model to elucidate the effect of the CT interaction on the viscosity and ionic conductivity. The CT interaction reduces the viscosity by reducing the electrostatic attraction between the dicationic viologen and TFSI anion. It also reduces the ionic conductivity by the CT association of the dicationic viologen and carbazole. The electrochemically reversible responses of the viologens in [C₄VC₇][TFSI]₂ and CT-IL are consistent with the Nernstian and the interacting two-redox site models. Notably, the transport and electrochemical properties are modulated by CT interaction, leading to unique features that are not present in individual component ILs. The inclusion of CT interaction in RAILs thus provides a powerful means to expand the scope of functionalized ionic liquids.

A redox-active ionic liquid (RAIL) consisting of a carbazole and viologen shows charge transfer (CT) interaction. The physicochemical properties are modulated by the CT interaction by comparison with the individual RAILs.