Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors: synthesis and pharmacological properties of 4-(1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)benzanili de derivatives and 4'-(5,6-dihydro-4H-thiazolo[5,4-d][1]benzoazepine-6-carbonyl)benzanilid e derivatives

Arginine vasopressin (AVP) has a dual action mainly in the periphery, i.e., vasoconstriction and water reabsorption via V1A and V2 receptors; it may play a role in a number of diseases, including congestive heart failure (CHF), hypertension, renal disease, edema, and hyponatremia. We have attempted to develop a new series of orally active AVP antagonists for both V1A and V2 receptors based on the hypothesis that the blockade of both V1A and V2 receptors might be beneficial to CHF patients. In this report, a series of compounds structurally related to 4'-(1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6- carbonyl)benzanilide and 4'-(5,6-dihydro-4H- thiazolo[5,4-d][1]benzoazepine-6-carbonyl)benzanilide were synthesized and examined for AVP antagonist activity for both V1A and V2 receptors. As a result, it was found that the 4'-(1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbon yl)-2- phenylbenzanilide derivatives showed potent binding affinity for both V1A and V2 receptors. Especially, 4'-(2-methyl-1,4,5,6- tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phe nylbenzanilide monohydrochloride (18, YM087 = conivaptan hydrochloride) exhibited potent binding affinity and AVP antagonist activity, after intravenous administration, for both V1A and V2 receptors. Furthermore, YM087 exhibited the most potent oral activity for the V2 receptor. Details of the synthesis and pharmacological properties of this series are presented.     

Additive telluromolybdates. Structure and catalysis in oxidation

Additive telluromolybdates, MoO₃·2TeO₂ and M^IIO·TeO₂·MoO₃ (M^IITeMoO₆; M^II = Co, Mn, Zn), converted ethyl lactate selectively to pyruvate in a vaporphase fixedbed flow system at 250–300 °C. A synergy in activity was observed for binary TeO₂–MoO₃, and crystalline Te₂MoO₇ was suggested as the active species. The Rietveld analysis of powder XRD patterns of ternary CoTeMoO₆ revealed the layer structure quite different from that of the reference Te₂MoO₇, but tellurium was again located adjacent to molybdenum linked through lattice oxygen.     

Activity of artificial mutant variants of human growth hormone deficient in a disulfide bond between Cys53 and Cys165

In order to understand the role of Cys53 and Cys165 of human growth hormone (hGH) in receptor-binding and biological activity, artificial mutant variants of hGH were prepared in Escherichia coli by in vitro mutagenesis. Variants of hGH were constructed by replacement of Cys165 with Ala ([Ala165]hGH) or Ser ([Ser165]hGH), by replacement of Cys53 with Ala ([Ala53]hGH), by replacement of Cys53 and Cys165 with Ala ([Ala53, Ala165]hGH), or by replacement of Cys53 with Ala and Cys165 with Ser ([Ala53,Ser165]hGH). All of the variants constructed as well as reduced hGH exhibited less biological activity than that of intact hGH, and the decreases in biological activity were almost equal, as measured by a sensitive biological assay for growth hormone: adipose conversion assay using 3T3-F442A cells. These variants also showed less receptor-binding activity than that of intact hGH. These results suggest that it is possible neither the residue Cys53 nor Cys165 is directly involved in the receptor binding, and that the disulfide bridge between Cys53 and Cys165 in hGH may not always be crucial for the biological activity, though necessary to express full hGH activity.     

Practical asymmetric synthesis of (S)-MA20565, a wide-spectrum agricultural fungicide

A practical asymmetric synthesis of a wide-spectrum agricultural fungicide, (S)-MA20565 (1), is described. The convergent synthesis was achieved starting from commercially available 3-(trifluoromethyl)aniline (7) in 44% overall yield through five steps and 2-bromobenzaldehyde (9) in 48% overall yield through four steps, respectively. (S)-O-[1-(3-Trifluoromethylphenyl)ethyl]hydroxylamine (2), a key intermediate of 1, was prepared via ruthenium(II)-catalyzed asymmetric transfer hydrogenation of 1-(3-trifluoromethylphenyl)ethanone (6) followed by chlorination using methanesulfonyl chloride and oxyamination using potassium acetohydroxamate with high level of stereocontrol.     

Some vanadium(V) complexes as reagents for the photometric determination of alcohols

Vanadiuin(V) com: with an acidic hydroxy group attached to the metal form the crorrresponding.; with alcohols. These esters show a characteristic absorption at 445–480 that alcoholic hydroxy groups can be determined photometrically. The formation constant of the n-butanol esters of vanadium maltolate and 2-methyl-.S-hydroxyquinolinate Were determined in benzene or benzenechloroform (1:1). Simple methods are determined for the determination of alcohol in the concentration range 10^-1–10^-4M.     

Asymmetric halogenation and hydrohalogenation oftrans-cinnamic acid in crystalline cyclodextrin complexes

Asymmetric halogenation and hydrohalogenation oftrans-cinnamic acid have been achieved in the microcrystals of cyclodextrin complexes. The bromination of the organic acid in the cavity of -cyclodextrin gave theerythro-dibromide in 40 % optical yield which was much larger than that from the resolution treatment of the racemic dibromide with -cyclodextrin and the absolute configuration was opposite in sign. The asymmetric induction in the gas-solid reaction was not due to optical resolution but to the reaction itself which was influenced by the chiral frame of cyclodextrin. The reaction shows the molecular size effect that the acid in the cavity of -cyclodextrin reacted with smaller hydrogen bromide but did not with larger bromine and chlorine. In contrast, the guest molecule in the wider cavity of -cyclodextrin reacted with bromine and chlorine as well as hydrogen bromide. The stereospecificities of the gas-solid halogenations of the acid in -cyclodextrin were similar to those of the both reactions in the solid state and in carbon tetrachloride solution without -cyclodextrin: bromination of the acid yieldederythro-2, 3-dibromo-3-phenylpropionic acid stereospecifically in 100 % in three different conditions, but chlorination gave an excess ofthreo-2, 3-dichloro-3-phenylpropionic acid to theerythro-isomer in 7287 % yields.     

The study of electron beam flue gas treatment for coal-fired thermal plant in Japan

The fundamental research work with simulated coal-fired flue gas was performed in JAERI to get basic data for electron beam treatment of flue gas from thermal power plants in Japan. The standard condition of the experiments was set to be the same as that of next large scale pilot test in Nagoya. The concentrations of NO_x and SO_x were 225 ppm and 800 ppm, respectively. The temperature of the system was 65°C. The effect of multiple irradiation was observed for NO_x removal. The target SO_x and NO_x removals (94% and 80%, respectively) with low NH₃ leakage (less than 10 ppm) were achieved at 9 kGy irradiation with 0.9 NH₃ stoichiometry during 7 hours continuous operation. The facility for the pilot plant (12,000 Nm³/hr) has just built at the site of Shin-Nagoya power plant of Chubu Electric Power Company and will be started in full operation in November 1992.     

Chiral β-dimethylaminoalkylphosphines. Highly efficient ligands for a nickel complex catalyzed asymmetric grignard cross-coupling reaction

Chiral β-dimethylaminoalkylphosphines were prepared starting with amino acids, (S)-alanine, (S)-phenylalanine, (R)-phenylglycine, (S)-valine, and (R)-tert-leucine. The chiral phosphines were found to be highly efficient ligands for a nickel catalyzed asymmetric Grignard cross-coupling reaction (38～94% optical yield).     

Synthetic studies on (−)-FR182877: construction of the ABCD ring system via the intramolecular cycloadditions (2)

Construction of the ABCD ring system of (−)-FR182877 via the intramolecular Diels-Alder (IMDA) reaction and the highly diastereoselective intramolecular hetero-Diels-Alder (IMHDA) reaction is described. The IMHDA reactions of the substrates incorporating the oxabutadiene with the E- or Z-alkene were examined, revealing that the sole product was obtained from both substrates and the E-alkene geometry was found to be crucial to obtaining the desired product.     

Relieving effect of saline on cephaloridine nephrotoxicity in rats

To elucidate the mechanism(s) of the relieving effect of saline on cephaloridine (CER) nephrotoxicity, rats were given CER in equal quantity (1 g/kg body weight; i.v.), but at two different concentrations (4 and 25%) in saline. Urinary excretion of glucose, which was investigated as an index for renal proximal tubular injury, revealed that the renal damage was less in the 4% CER 25 ml/kg group than in the 25% CER 4 ml/kg group. As to urinary excretions of CER, sodium, potassium and water, no significant differences were observed between the two groups in the first 2 h, but chloride in the 4% CER 25 ml/kg group showed higher values than in the 25% CER 4 ml/kg group. Plasma concentrations of sodium, potassium, chloride and CER, did not show any definite distinctions between the two groups. At the time-point of 20 min after the CER administration, renal CER content was significantly lower in the 4% CER 25 ml/kg group than in the 25% CER 4 ml/kg group. These results suggest that the sodium ion which is needed for cellular trapping of CER is competitively expended for cellular entry of the chloride ion in the kidney, and that the relieving effect of the saline on CER nephrotoxicity is ascribable to the loaded quantity of chloride ion.