It has generally known that combinations of drugs often gave repressive effects on each metabolic rate. Here, we report the metabolic interactions of aniline and phenylbutazone hydroxylations. Simultaneous addition of aniline and phenylbutazone as the substrates to the same incubation mixture showed increased activity of phenylbutazone hydroxylation, on the other hand, activity of aniline hydroxylation was reduced than the activities obtained from the additions of each substrate respectively. The increased phenylbutazone hydroxylation was found not only in the case of addition of p-aminophenol, one of the metabolites of aniline, to the same incubation mixture, but in the livers of rats received aniline intraperitoneally relatively short time before sacrifice.

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Thermal rearrangements of three types of optically active open chain α-hydroxy-imines (I) were attempted. In all cases two optically active isomeric α-aminoketones (II) were obtained with almost full retention of optical activity, regardless of the species of the migrated groups in the 38-53% total yield. Stereospecifically, this thermal rearrangement was assumed to proceed via the intramolecular cyclic mechanism. The presence of a fragmentation reaction was shown. Thus, the coexistence of cleavage in all carbon-carbon bonds attached to the carbon atom bearing the hydroxy group was demonstrated for the first time. Preliminary experiments using racemic compounds were also described.

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Es wird die Struktur des Corynoloxins, C₂₁H₁₉O₅N, ein neues Alkaloid aus Corydalis incisa, beschrieben. Bei der Reduktion liefert es Corynolin, das Hauptalkaloid dieser Pflanzen. Auch bei der Oxydation des Corynolins entsteht Corynoloxin. Diese Tatsachen zeigen, dass das Corynoloxin auch zu der Benzo (c)-phenanthridine-Alkaloide gehort. Durch den Emde-Abbau sind zwei Hydromethinbasen entstanden. Das Des N-Produkt, C₂₀H₁₈O₅, wurde durch die katalytischen Reduktion aus der beiden Hydromethinbasen abgeleitet. Die infrarot und Kernresonanz Spektren dieser Derivaten weisen die Struktur und die Konstellation des Corynoloxins.

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The cell wall fraction was isolated from cytoplasm by sonicating and washing the mycelia of Cochliobolus miyabeanus, and its chemical composition was studied. The cell wall was constituted by the polymer of neutral sugars (51.68%), amino sugars (38.03%), peptide (10.75%), lipid (0.57%) and ash (2.33%). A great deal of α- and β-glucose and traces of galactose, mannose, arabinose, rhamnose, fucose and xylose were found in the hydrolysate of poly neutral sugar fraction, and amount of glucosamine and trace of galactosamine in the hydrolysate poly amino sugar fraction by gas liquid chromatography (GLC) and paper parttion chromatography (PPC) analyses. When these two fractions were allowed to react with α- or β-glucosidase and chitinase, glucose was liberated from neutral sugars fraction only when β-glucosidase was used, and acetyl-glucosamine was liberated from amino sugars fraction by chitinase. Sixteen kinds of amino acids were detected from peptide on amino acid analyser. From these results, it is concluded that the cell walls of our fungus are constituted with β-glucan and chitin-like layers associated with a small amount of other sugars and peptides.

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Die Hydromethinbase (V), die durch den Emde-Abbau des Corynolin-O-Acetats (III) erhalten wurde, lieferte durch den Hofmann-Abbau ein Neutralprodukt (VII), C₂₀H₁₉O₅, vom Schmp. 157-158°. Es stimmt mit der N-freien Verbindung aus dem Corynoloxin (I) uberein. Weiterhin wurde die Abbaureaktion der Hydromethinbase B des Corynoloxins (VII) untersucht. Damit wurde die sterische Struktur des Corynoloxins (I) und Corynolins (II) gesichert.

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A new synthesis of 1-(2-diethylaminoethyl)-substituted 1, 4-benzodiazepin-2-ones by ring enlargement of the corresponding 2-aminomethylindole derivatives is reported. A number of related compounds leading to these compounds were synthesized. Attempted chlorination of 5-chloro-1-(2-diethylaminoethyl)-3-(o-fluorophenyl) indole-2-carboxylic acid (VI) with thionyl chloride yielded 8-chloro-3, 4-dihydro-2-ethyl-10-(o-fluorophenyl)-pyrazino [1, 2-a] indol-1 (2H)-one (VII). Chlorination of 5-chloro-3-phenylindole-2-carboxylic acid derivative (VIII) with thionyl chloride gave two products, the expected acid chloride (XVI) and the dimer (XVII).

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In the previous paper, the authors reported the kinetic studies on the factors affecting the biliary excretion with azo dyes and indigoid dye. The further investigation was tried with triphenylmethane dyes in rat. Six triphenylmethane dyes, i.e., Brilliant Blue FCF, Light Green SF, Fast Green FCF, Guinea Green B, Acid Violet 6B and Acid Violet 5B were used. (1) The excretion behaviors were similar to those of azo dyes which had the dose dependency. And the excretion ratios were generally larger than those of azo dyes except Light Green SF and Acid Violet 5B. (2) It was concluded that a sulfonate group beyond other groups had a remarkable effect on the biliary excretion ratio and pattern, and that the position of a sulfonate group as well as the number was important to determine its effect. (3) The possibility of the compartmental analysis for the biliary excretion process was suggested in the excretion pattern of Brilliant Blue FCF.

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The upper ground portions of Rhodea japonica ROTH were proved to contain a glycoside mixture. A new glycoside, Rhodexin D (oleandrigenin-glucose-glucose), was isolated and its structure was determined.

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Hydroxyethyl starch (HES) was studied concerning the relationships between its physicochemical properties and biological activities to obtain the most desirable plasma expander. Since degree of substitution (DS) had been clarified to have influences on the biological activities, the molecular weight was then examined with designing DS in the constant range of 0.43-0.55. After infusion of 15 ml/kg of 6% HES solution in saline into rabbits, persistence of polysaccharides in blood was determined. HES with higher molecular weight was more persistent when DS was identical. The molecular weight, however, had little influences on the amount of formed reducing sugars when resistance against pig pancreas α-amylase was tested in vitro. HES with DS 0.54 and molecular weight about 216000 was hydrolyzed with various concentrations of HCl, and the physicochemical properties and the biological activities of the hydrolysates were also examined. Comparing the lowering tendency of the viscosity with the amount of formed reducing sugar and from the gel filtration patterns of the hydrolysates, it was assumed that the hydrolysis of HES with HCl resulted in separation to two or more intermediate lower molecular weight polysaccharides besides the reducing sugar liberation. Mode of hydrolysis was partly discussed in connection with stability of HES in blood.

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The reaction of diketene with α-aminoketone derivatives was studied. Ethyl α-aminoacetoacetate (IIIa) and 3-aminoacetylacetone (IIIb) react with diketene to give 3-acetyl-5-carbethoxy-2-hydroxypyrrole (IVa) and 3, 5-diacetyl-2-hydroxy-4-methylpyrrole (IVb), respectively. α-Aminoacetone (IIIc) and phenacylamine (IIId) afford N-acetonylaceto-acetamide (Ic) and N-phenacylacetoacetamide (Id). On treatment with dilute alkali, Ic and Id are transformed to 3-acetyl-4-methyl-3-pyrrolin-2-one (IVc) and 3-acetyl-4-phenyl-3-pyrrolin-2-one (IVd), respectively.

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In the previous papers, the authors reported the kinetic studies on the factors affecting the biliary excretion using Azo, Indigoid and Triphenylmethane dyes. The further study was tried using Xanthene dyes, Fluorescein and Bromsulphthalein, and the effect of halogenation was discussed. Four Xanthene dyes, i.e. Eosine Y, Phloxine B, Erythrosine B, Rose Bengal, and Fluorescein and Bromsulphthalein were used. (1) The excretion behaviors were similar to those of Azo and Triphenylmethane dyes which had the dose dependency, but the excretion ratios showed common larger values than 75% except Fluorescein which had no halogen group. (2) It was found that the halogen group had great influence on the biliary excretion as well as the sulfonate group. And it was also suggested that the effect of halogen group depended on the total electro negativity of substituents. And furthermore it was found that the increasing in molecular weight had not so much effect than the increasing of polarity. (3) It was also suggested that the -I gave the delay of excretion in the early period and this was probably due to the larger uptake into liver cells. (4) BSP showed markedly concentrical excretion pattern and large excretion ratio in a short period and it was found that these characteristic behavior was mainly ascribed to both halogen groups and sulfonate groups.

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The adduct of photoproduct of anhydromethylberberine with dimethyl acetylene-dicarboxylate has been investigated by means of the nuclear magnetic resonance spectroscopyand the nuclear Overhauser effect measurements to establish the structure, in which the B/C ring juncture is cis and the conformation of B ring is a flattened boat form. Theselective reduction of adduct with lithium aluminum hydride and the reduction of adduct with hydrazine in the presence of oxygen are studied.

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The determination of the proton ionization constant of N'-methyl-2-aminoethyl-isothiuronium (N'-methyl-AET) was attempted. This compound was also transguanylated, as in AET, during the potentiometric titration. The first conjugate base of N'-methyl-AET is relatively stable and subsequently ionized to the second base with its rapid transguanylation to the sulfhydryl compound. The first ionization is due to amino group, pK 8.05 and ΔH 12 kcal/mole, and the second is due to isothiuronium group, pK 9.88 and ΔH 18 kcal/mole. The reactivity of two conjugate bases of N'-methyl-AET was discussed.

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The absorption and excretion of ¹⁴C-labeled 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide (AF-2), 2-amino-5 [2-(5-nitro-2-furyl)-1-(2-furyl) vinyl]-1, 3, 4-oxadiazole (NF-161) and 5-nitro-2-furfural semicarbazone (nitrofurazone) were examined following oral administration to rats. In the cases of AF-2 and NF-161 the radioactivity was mainly recovered in feces, whereas in the case of nitrofurazone it was found more in urine than in feces. In all the cases, the summation of the radioactivity which was excreted in urine and feces 96 hr after drug administration, was approximately equal to the administered radioactivity. It was also found that the hepatobiliary system played a considerably important role in the excretion of these labeled drugs. Considering this biliary excretion, the percentages of the radioactivity absorbed from gastrointestinal tract were calculated to be 59, 33 and 88% for AF-2, NF-161 and nitrofurazone, respectively. The unchanged compounds recovered in urine, feces and bile were very small amount in all the cases. In the feces of rats given NF-161, however, about 20% of the dose was excreted unchanged.

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The wine red complex of iron (III)-L-ascorbic acid 3-phosphate was investigated spectrophotometrically. The color which showed a maximum absorption at 480 mμ was observed in aqueous solution over the acidity range from -2.0 (Ho) up to pH 5. The maximum intensity of the color was approximately at pH 0.9. Addition of an organic solvent prevented the coloration. The composition of the chelate was observed to be 1 : 1 in the molar ratio, L-ascorbic acid 3-phosphate/iron (III). Similarly, L-ascorbic acid 2-phosphate, 3-pyrophosphate, bis (L-ascorbic acid-3, 3') phosphate, L-ascorbic acid 2- and 3-phenylphosphates gave the corresponding iron (III)-chelates. Whereas, L-ascorbic acid 2- and 3-diphenylphosphate and L-ascorbic acid 3-sulfate gave no coloration. As a result of the test, acid stable colorations in the former group of compounds are probably due to the presence of the enolic group which can take part in the chelate formation with the vicinally located primary or secondary phosphoryl group. The coloration was applied to a colori metric method in the determination of L-ascorbic acid 3-phosphate.

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The rate constants for the hydrolysis of L-ascorbic acid 3-phosphate were measured in aqueous solutions at 50-100° from pH 1 to 9.6 and also in strong acid solutions up to 4M hydrochloric acid. The first order kinetics with respect to the unreacted phosphate were obtained by determining the remaining phosphate. The pH rate profile (Fig. 3) for the hydrolysis of L-ascorbic acid 3-phosphate is represented by the rate equation. K_obsd=k_a [H⁺] [H₃A]/C+k_N [H₃A]/C+k₁ [H₂A^-]/C+k₂ [HA^2-]/C+k₃ [A₃^-]/C. Where [H₃A]/C, [H₂A^-]/C, [HA^2-]/C and [A^3-]/C are molar fractions of the neutral species, monoanion, dianion and trianion, and k_a, k_N, k₁, k₂, and k₃ are their associated specific rate constants. From the observed hydrolysis rate and pK values, these specific rate constants were evaluated. The pK values of L-ascorbic acid 3-phosphate were determined to be pK₁=0.01, pK₂=3.27, and pK₃=6.70 at 28.5°. In hydrochloric acid solutions (1-4M), the rate of hydrolysis is proportional to the hydrogen ion concentration. This result coupled with the moderately large solvent isotope effect and with the activation parameters suggests that the hydrolysis of the conjugate acid of L-ascorbic acid 3-phosphate is bimolecular and a water molecule is participated in the transition state. Hydrolysis of the monoanion which is predominant at pH ∼2 involves mainly P-O bond fission. Measurements of the solvolysis product composition indicated that the molar ratio, methyl phosphate/inorganic phosphate, was slightly smaller than the ratio, methanol/water, present in the reaction mixture. Decrease in the rate by the addition of an organic solvent, the large negative value of the activation entropy and the insignificant D₂O effect suggested the reaction mechanism as in Chart 2. When the dianion was hydrolyzed in H₂¹⁸O, ¹⁸O was introduced mainly into inorganic phosphate. Different from those of common monoalkyl- or monoarylphosphates, the solvolysis in methanol-water mixture afforded almost exclusively inorganic phosphates. These data taken in conjunction with the relatively large solvent isotope effect and with the negatively large entropy value led to the postualation that the hydrolysis of the dianion underwent through a slow proton transfer to the carbonyl oxygen concerted with the nucleophilic attack by hydroxide ion which brought about the rapid scission of the P-O bond. In the case of the trianion an extremely low hydrolysis rate was observed and possible mechanistic discussion was given to account for the stability.

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Interaction of Ponceau 3R with bovine serum albumin was studied by spectrophoto-metric, equilibrium dialysis and gel filtration method. In the presence of bovine serum albumin, absorption spectrum of Ponceau 3R shifted to higher wavelength from 503 mμ to 515 mμ with lowering optical density. The results of equilibrium dialysis and gel filtration showed that binding of Ponceau 3R to bovine serum albumin is essentially based on the Langmuir-type equation. Number of binding sites of bovine serum albumin to Ponceau 3R was approximately 5 over the pH range of 6 and 9, although it increased abruptly in further acidic region. Equilibrium constant of this reaction system was approximately 10⁵M^-1 in neutral and alkaline region, whereas it increased in acidic region.

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o-, m- and p-alkyloxybenzohydroxamic acids were synthesized and subjected to the examination for antibacterial and antifungal activity. All the hydroxamic acids tested were almost ineffective for pathogens examined of Enterobacteriaceae, but some of alkyloxybenzo- and fatty acyl-hydroxamic acid were found to be as highly effective for pathogenic fungi as butyl p-hydroxybenzoate being used as a comparison. The increase of carbon number of p-alkyloxybenzo- and fatty acyl-hydroxamic acid led to the increase in their antifungal activity, reached to the maximum at C₆ in alkyloxy moiety and C₁₀ in fatty acyl derivatives, and then the gradual decrease in both series. Considering the inhibitory power of hydroxamic acid on plant and bacterial urease, we discussed the possible correlation between antimicrobial activity and inhibitory powers on urease activity of the compounds.

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The synthesis and hydrolysis study in boiling 6.04N hydrochloric acid of lactams have been extended to include 1-benzyl-2-pyrrolidinone (I), 1-benzyl-2-oxo-5-piperidineacetic acid (II), 1-benzyl-2-oxo-4-piperidinecarboxylic acid (III), and 1-benzyl-2-oxo-5-piperidinecarboxylic acid (IV). In all cases, the hydrolysis was found to proceed to an equilibrium as shown in Table III. Substituents at the 4- or 5-position of the 2-piperidone ring seemed to favor the lactam form in the lactam-ω-amino acid hydrochloride equilibrium. The lactam form was somewhat more favored in the case of the simple 5-membered lactam (I) than in the case of the simple 6-membered lactam, 1-benzyl-2-piperidone. Such a trend was more evident in the cases of II and III ; the 5- and 6-membered lactams were equilibrated in the ratio 4.5 : 1. It was also observed that III was thermally converted into the 5-membered lactam (XV), whereas II was stable at 180°for 5hr. Infrared frequency data on several lactams are collected in Table I in order to visualize the lower shift of lactam vco exhibited in the solid state by the lactams possessing the carboxyl group else where in the molecule.

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The phospholipid class composition and the ratio of the amounts of two sphingomyelin fractions, supposed to have different fatty acid compositions, were determined by quantitative thin-layer chromatography on the erythrocytes and plasma of four representative mammalian species, man, pig, cow and rabbit. A remarkable species difference was confirmed on the phospholipid class compositions between bovine erythrocyte and those of three other species. The phospholipid distribution in plasma was rather relatively similar each other in these species, with the predominant presence of choline phospholipids. The ratio of two sphingomyelin fractions varied appreciably from species to species. The bovine erythrocyte gave the highest value whereas the bovine plasma gave the lowest value of the F/S fractional ratio among these four species.

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Phospholipid class composition was determined on the aorta from normal rabbits and those with experimental atherosclerosis, fed high-cholesterol diet, by means of quantitative thin-layer chromatography with Silica gel G plate. Relative increase in the phosphatidyl choline and relative decrease in phosphatidyl ethanolamine percentage of the total phospholipids were noted on the atherosclerotic aorta in comparison with the normal aorta. Though no change in the percentage of sphingomyelin was observed in the atheromatous aorta, a significant change in the fatty acid composition of this phospholipid was revealed by gas-liquid chromatographic determination of the fatty acids liberated from the purified sphingomyelin preparation, characterized by remarkably high percentage of C₁₆ acids and lower percentage of the acids with 20 or more carbon atoms in comparison with the values on the normal aorta. With the blood plasma of atherosclerotic animals, only a decrease in phosphatidyl ethanolamine, which is not the major component of plasma phospholipids, was detected, with the other phospholipid class composition almost unchanged.

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An investigation of Grignard reaction of succinimide revealed that, when more than one molar equivalent amount of Grignard reagent was used, a reaction proceeds to give γ-ketoamide. Using a variety of aliphatic and aromatic Grignard reagents this reaction has been generalized and provided a useful method for preparation of γ-ketoamides.

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The nuclear magnetic resonance spectra of anomeric pairs of acetylated D-gluco-pyranosylglucopyranoses and 1→4 and 1→6 linked D-glucans were measured in deuteriochloroform at 60 or 100 MHz. The spectral pattern difference between anomers, due to the 1, 3-diaxial deshielding effect in α-anomer, proved to be an useful means to assign the configuration of glucosidic linkage. Low and high field shifts of acetoxy signals were observed in some acetylated D-glucans.

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Reactions of 2-azido-1-methylbenzimidazole (I) with such reagents as aluminum chloride in toluene, thiobenzophenone, hydrogen bromide, and acetic anhydride were investigated and compared with those of phenyl azide. In reaction of I with acetic anhydride, 3-acetyl-1-methyl-2-benzimidazolinone (VI) and 6-acetoxy-2-diacetylamino-1-methylbenzimidazole (VII) were obtained and its reaction mechanism was discussed. Bromination of 2-amino-1-methylbenzimidazole (IIIa) with bromine in glacial acetic acid selectively occurred at C₆-position and this selectivity was also discussed.

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Nanogram order determination of catecholamines in rat tissues and serum was achieved. The recovery of added catecholamines to the acid homogenates was about 50%. The presence of epinephrine in brain was confirmed. The amount of dopamine was unexpectedly low in lung.

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The adsorbability of 22 ortho-, meta- and para-mono- or-disubstituted benzoic acid derivatives by carbon black from aqueous solution (pH 7.4) was correlated with that on graphite from solution (pH 7.0), but not with pK_a, partition coefficient and plain size of molecule. The adsorbability of o-nitro, -methyl, -chloro and -bromobenzoic acids was less than that of the respective metha- and para-substituted compounds. The thermodynamic functions for ortho-substituted benzoic acids also were different from those for meta- and para-substituted ones, except for amino- and hydroxybenzoic acids. Plotting the solubility of caffein in the solutions containing benzoic acid derivatives and the free energy change of complex formation with caffein, respectively, against the adsorbability of the acid derivatives on carbon black, there were found correlations in both cases without excepting for ortho-substituted ones. A linear relationship was observed between the free energy change of binding to serum albumin and the adsorbability on carbon black of benzoic acid derivatives without excepting for ortho-substituted ones. These two results suggested that both the complex formation with caffein and the protein binding of benzoic acid derivatives take place on the basis of the electrostatic and the hydrophobic interactions.

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