Anti-isoproterenol activity of 26 new derivatives of 1, 2-disubstituted catechol was measured in the isolated guinea pig tracheal strip preparation. All the compounds tested antagonized the action of isoproterenol. The derivatives which had 3-tert-butylamino-2-hydroxypropyl in 1 position showed a potent activity. Among them, the compounds which had allyloxymethyl (XIII), tetrahydrofurfuryl (XVIII), or furfuryl (XIX) as a substituent at 2 position was more active than the others. 1-tert-Butylamino-3-[o-(tetrahydrofurfuryloxy) phenoxy]-2-propanol hydrochloride (XVIII), which was chemically stable among these three compounds, may be the most hopeful compound as an adrenergic β-receptor blocking agent.
Tritium-labeled compound (3H-Y-4153) of a new iminodibenzyl derivative, 3-chloro-5-[3-(4-piperidino-4-carbamoylpiperidino) propyl]-10, 11-dihydro-5H-dibenz [b, f] azepine dihydrochloride monohydrate (Y-4153), was synthesized and its absorption, distribution, excretion and metabolism were investigated. When 3H-Y-4153 was orally or intraperitoneally administered to rats, less than 2% of the administered radioactivity (3H) was excreted in the urine and more than 80% of it in the feces, during 3 days. About 40% of the given 3H was also excreted in the bile during 24 hr after oral administration. The highest concentration of 3H in most organs was found 0.5-1 hr after its oral administration and 3H was concentrated in the liver, adrenals and lung. Similar levels of 3H were maintained in the brain and blood during 6 hr but their level was relatively low. More than 30% of radioactive metabolites in the bile was estimated to be a glucuronide, and three kinds of radioactive substances were extracted by the continuous extraction procedure with ethyl acetate. These radioactive substances were clarified to be the hydroxy derivatives of 3H-Y-4153 using a thin-layer chromatography, silicagel column chromatography, color reactions and other techniques.
Microscopic observations of ashed tissues provided by the low-temperature plasma ashing of plant leaves and other specimens have been extensively applied in plant taxonomical and morphological studies. In the present work, calcium oxalate crystals in the ashed tissues were taken up for the identification of the crude drug, "Uvae Ursi Folium", the analogous drug "Vitis-Idaeae Folium, " and other closely related plants involving Gaultheria miqueliana TAKEDA, Gaultheria adenothrix (MIG.) MAXIM., and Vaccinium uliginosum LINN. "Uvae Ursi Folium" has been characterized by solitary crystals and crystals sands deposited along the netted vein in extremely high density, while practically no crystal has been observed other than along the vein. In "Vitis-Idaeae Folium", clustered crystals are irregularly arranged in low density almost only along the costa. Gaultheria miqueliana TAKEDA contains clustered crystals distributed homogeneously in the ashed tissue with low density. Gaultheria adenothrix (MIG.) MAXIM. has been characterized by clustered crystals deposited along the costa in high density. No crystal has been found in the ashed tissue of Vaccinium uliginosum LINN. under crossed Nicols.
D-Arabinosone was oxidized by molecular oxygen under mild conditions, at neutral pH and 37.5°. The autoxidation increased with increasing pH. Metal ions had little effect on this autoxidation. The autoxidation was influenced by the buffer system used, even though the pH and other conditions were the same. It was accelerated by phosphate, pyrophosphate, and barbital buffers, but prevented by Tris-HCl and borate buffers. When D-arabinosone was oxidized completely, the oxygen consumption was one atom per mole of the osone. As the products of the autoxidation, carbon dioxide, glycolic acid, glyceric acid, and erythrono-γ-lactone (erythronic acid) were identified.
Addition of D-arabinosone to rat or swine liver homogenate accelerated the rate of oxygen consumption. The substance in the liver responsible for this reaction was confirmed as phosphatidylethanolamine. Incubation of phospha tidylethanolamine in the presence of D-arabinosone resulted in the formation of lipid peroxides, and it was apparent that D-arabinosone stimulated the peroxidation of the phospholipid. The autoxidation of D-arabinosone was not affected by the phospholipid. D-Xylosone and D-glucosone also stimulated the peroxidation. In the course of this investigation, it was also found that some substance preventing the autoxidation of D-arabinosone might exist in liver.
Michael cyclization of keto ester (VII), which was obtained by condensation of 2, 3, 4-trimethoxybenzaldehyde (V) and ethyl 2-oxobutyrate (VI), with cyanoacetamide afforded a pyridone derivative (IX), which was further methylated with diazomethane to an unexpected mixture of X and XI. Esterification of IX with methyl iodide in the presence of sodium hydrogen carbonate gave the expected compound (XII). Futhermore, condensation of VII with aceturic amide gave dihydropyridone (XVI), which was methylated to afford an ester (XVII). Dehydrogenation of XVII with palladium-black afforded a hydrogenated compound (XVIII). The same reaction of XVII with platinum oxide gave methyl 3-acetamido-1, 2-dihydro-4-(2, 3, 4-trimethoxyphenyl)-5-methyl-2-oxo-6-pyridinecarboxylate (XIX).
Activity of β-amylase was not changed by the addition of newly prepared aqueous solution of nonionic detergents such as Tween, Span, and others. Tweens, especially Tween 80, had inhibitory action on β-amylase when the solution is stored over a long period. Tweens were hydrolyzed during storage and the fatty acids liberated from Tweens had inhibitory action on the enzyme. Hydrolyzate from Tween 80 by the action of lipase produced from Rhizopus delemar had no inhibitory action on β-amylase. Therefore, there seems to be a difference in the mechanism of hydrolysis of Tween solution between that produced by storage and that due to lipase added.
Rosein III, C20H28O4, mp 226°, a metabolite of Trichothecium roseum LINK, was converted to ros-5, 10-en-16-oic acid (9), and also more directly to a mixture of dihydrorosenono-(16) and dihydroisorosenono-lactone (17) via a novel cyclopropane intermediate (12). These correlations of rosein III with rosenonolactone (1) in association with the spectroscopic evidences of derivatives substantiated its structure and absolute configuration as 11-β-hydroxyrosenonolactone (2). The conformation of isorosein III, a C-8-isomer of rosein III, was also clarified as (14c) in which ring B has 7, 10-RT-twist conformation.
When making granules by a rotary wet granulator, the amount of a binder is experientially known to have a great effect on granulating state and properties of the granules formed. The main purpose of the present study was to obtain fundamental information on relationship between the amount of a binder and several characters indicating granulating state and properties of the granules formed. It was found that the amount of a binder at flexion point of several characteristic curves was almost the same, and that the amount of a binder at this flexion point was different from plastic limit measured by JIS A-1206 method.
Gelatinized starch in aqueous solution combines with some chemicals which are waterinsoluble or sparingly soluble and solubility of these chemicals is increased 5-to 10-fold. Solubility of the arrow root starch is the best among many starches, because arrow root starch is easy to gelatinize. In the extraction method of Gegen Tang which is decided by "Shang Han Lun" ( ?? ?? ?? ) gelatinized arrow root starch is considered to form a conjugate with ephedrine so that ephedra herb (ephedrine) and pueraria radix (arrow root starch) are extracted before other drugs are extracted. The complex ephedrine, combined with arrow root starch, is stable and interferes with isolation of ephedrine by steam distillation and dialysis. The extraction method of Shang Han Lun is correct and suitable by the presentday standards.
Analgesic and antiinflammatory effects of "Toki" (the root of Angelica acutiloba KITAGAWA) inferred from the literatures of Chinese medicine were investigated by the Whittle method. The results of the experiments clearly showed that the aqueous extract of Toki administered orally to mice inhibitedboth writhing and capillary permeability, suggesting an analgesic effect and an anti inflammatory effect, respectively. Toki extract was 1.7 times more effective than sodium acetylsalicylate regarding writhing inhibition, on the basis of the dry weight of Toki root. As for the inhibition of capillary permeability, Toki extract was 1.1 times as effective as sodium acetylsalicylate. It may be estimated from the above results that the analgesic effect expected from the daily dose of Toki used in prescription of Chinese medicine would be equivalent or even more effective as compared with acetylsalicylate. Chemical separation of "Toki" extract was carried out to examine the active components. The analgesic activity was mainly found in Fraction 6 (Chart 1), whereas a higher inhibitory activity on capillary permeability was observed in Fraction 7.
A flavone (Ia) was isolated from the peel oil of Citrus natsudaidai HAYATA, and the structure of this compound has been revealed as 3-hydroxy-5, 6, 7, 8, 3', 4'-hexamethoxyflavone through its degradation by alcoholic alkali. The experimental data of Ia agreed with those of flavone which Sastry, et al. obtained by derivation of the flavanone, citromitin (II), from Citrus mitis BLANCO. However, it is the first time that this flavone has been found in nature, the name of natsudaidai is proposed for this compound.
Irradiation of 4-tosyl-1, 2, 3, 4-tetrahydro [1, 4] diazepino [3, 2, 1-kl] phenoxazine (V) in 70% ethanol with 100 W high-pressure mercury lamp in the presence of sodium borohydride and sodium carbonate gave 1, 2, 3, 4-tetrahydro [1, 4] diazepino [3, 2, 1-kl] phenoxazine (VI) and 1-(2'-hydroxyphenyl)-2, 3, 4, 5-tetrahydro-1H-benzo [b]-1, 4-diazepine (VII), accompanied with the opening of the phenoxazine ring. Photochemical reaction of V in dry ethanol or dry benzene afforded VI and 7-tosyl-1, 2, 3, 4-tetrahydro [1, 4] diazepino [3, 2, 1-kl] phenoxazine (XIII), with rearrangement of the tosyl group. Similar reaction of 3-tosyl-1, 2-dihydro-3H-pyrazino [3, 2, 1-kl] phenoxazine (I) gave 1, 2-dihydro-3H-pyrazino [3, 2, 1-kl] phenoxazine (III) and 6-tosyl-1, 2-dihydro-3H-pyrazino [3, 2, 1-kl] phenoxazine (XVII). The synthetic mechanisms of these reaction were examined.
The corresponding 2-benzyl-3H-pyrido [3, 2, 1-kl] phenoxazin-3-ones (II-VI) were obtained by condensation of 1, 2-dihydro-3H-pyrido [3, 2, 1-kl] phenoxazin-3-one (1) with benzaldehyde, p-dimethylaminobenzaldehyde, p-chlorobenzaldehyde, p-methoxybenzaldehyde, and m-nitrobenzaldehyde, in ethanol containing sodium hydroxide. Reaction of I with semicarbazide, thiosemicarbazide, phenylsemicarbazide, and phenylthiosemicarbazide respectively gave the semicarbazone compounds (VII-X). Treatment of 3-hydrazono-1, 2-dihydro-3H-pyrido [3, 2, 1-kl] phenoxazine (XI) with the foregoing aromatic aldehydes afforded 3-benzylidenehydrazono-1, 2-dihydro-3H-pyrido [3, 2, 1-kl] phenoxazines (XII-XVI). On the other hand, application of acetyl chloride or benzoyl chloride to XI, 3-hydroxy-1, 2-dihydro-3H-pyrido [3, 2, 1-kl] phenoxazine (XX), 3-amino-1, 2-dihydro-3H-pyrido [3, 2, 1-kl] phenoxazine (XXIII), and 1, 2-dihydro-3H-pyrazino [3, 2, 1-kl] phenoxazine (XXVI) in pyridine afforded the corresponding acetyl compounds (XVIII, XXI, XXIV, XXVII) or benzoyl compounds (XIX, XXII, XXV, XXVIII). When phenyl isocyanate and phenyl isothiocyanate were reacted with XXVI, 3-phenylcarbamoyl-1, 2-dihydro-3H-pyrazino [3, 2, 1-kl] phenoxazine (XXIX) and 3-phenylthiocarbamoyl-1, 2-dihydro-3H-pyrazino [3, 2, 1-kl] phenoxazine (XXX) were obtained.
Structure of the phenolic glucoside (I), mp 206-207°, reported as compound IX in the preceding paper, was discussed. I gave an aglycone (II) and D-glucose by acid hydrolysis. II was identified as syringic acid by a mixed fusion, and comparison of ultraviolet and infrared spectra and thin-layer chromatography with the authentic sample. Therefore, I was assumed to be glucosyringic acid and confirmed by synthesis. I was isolated for the first time from a natnral source.
A new compound (I), mp 155-158°, C12H12O3, reported as compound (III) in the preceding paper, was elucidated as 2, 2-dimethyl-2H-1-benzopyran-6-carboxylic acid on the basis of spectrometric data of I and its derivatives. The structure of I was also confirmed by synthesis.
Sixteen kinds of DL-α-hydrazinocarboxylic acids were synthesized and their effect on the activity of enzymes related to amino acid metabolism was examined. These derivatives strongly inhibited the activity of diamine oxidase (substrate : histamine) and of amino acid decarboxylase (L-glutamic acid and 5-hydroxy-L-tryptophan). The inhibiting potency was dependent on the chain length of alkyl group in these derivatives. The maximum inhibition against the diamine oxidase activity was obtained with α-hydrazinocaprylic acid ; the I50 value was about 1.0×10-5M. Inhibition of the diamine oxidase activity was non-competitive for substrate and prevented by preincubation with an α-keto acid, probably due to the formation of a non-inhibitory complex between the α-hydrazino group and keto group of the acid added. All of these α-hydrazinocarboxylic acids did not affect the activities of monoamine oxidase (butylamine, β-phenethylamine and tyramine), aminotransferase (aspartate : α-ketoglutarate) and D-amino acid oxidase (D-alanine). From comparison with known inhibitors of related structure, it is assumed that the inhibition with α-hydrazinocarboxylic acids is due mainly to the reactivity of hydrazino group and is affected by carboxyl group in their structure.
The methanol extract of the stems of Anodendron affine DURCE was treated as shown in Chart 1. β-Sitosterol (I), its glucoside (II), wogonin (V), dambonitol (VII), and sucrose (VIII) were identified. A cardenolide (VI) and two unknown compounds (III and IX) were also isolated.
In connection with the synthesis of 2-(2-pyridyl) benzimidazole derivatives with a substituent in 1-position, reactivity of vinylpyridines and vinyl cyanide was examined. The reaction was found to progress smoothly when glacial acetic acid is used as a catalyst with vinylpyridines and a quaternary salt for vinyl cyanide, affording the desired 1-(2-pyridylethyl) and 1-(2-cyanoethyl)-2-(2-pyridyl) benzimidazoles, respectively. In order to convert the cyano group into acid amide derivatives, hydrolysis with acid or alkali was examined and a reaction whereby the acid amide compound (VIb) and carboxylic acid (VIc) are obtained at the same time was established. Hydrolysis by the use of barium hydroxide, however, resulted in dealkylation from the nitrogen in 1-position to produce the starting material. Hydrolysis with hydrochloric acid did not produce this dealkylation.