The effect of various combinations of four drugs, isopropylantipyrine, allylisopropylacetylurea, phenacetin, and caffeine, on the acute toxicity in rats was examined. Acute toxicity of a combination of all four in 0.15, 0.06, 0.25, and 0.05 g, respectively, was compared with each of three combinations of these drugs and the following results were obtained. (1) The departure from parallelism of dose-mortality line was not significant except for a group of females given a combination of three drugs excluding isopropylantipyrine. The toxicity was compared by using these dose-mortality lines, and expressed by expreimentally obtained LD₅₀. It was found that the combination of all four drugs was least toxic. (2) The ratio of the predicted LD₅₀ value, which was calculated on the basis of assumption that each component drug would be additively toxic when combined, to the experimentally observed LD₅₀ was used for comparison. The combination of all four drugs gave values of LD₅₀ significantly greater than additive, while the three combinations had LD₅₀ values which were not significantly different from the additive model. (3) Compared with the reference groups treated with phenacetin, etc., alone, the cases in which the abnormal signs were observed in the general conditions and histopathological observations were fewer in the group treated with the combined drug. Particularly the splenic hemosiderin deposit which was induced in the phenacetin group was light in the combination of all four drugs, which seems to show that toxicity of the combined drug is moderate.

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1) The plasma level profiles of isopropylantipyrine and phenacetin in beagle dogs, were investigated by oral administration. Each drug was used alone, combined with each other, or in various combinations with caffeine or allylisopropylacetylurea. These four compounds are ingredients of an analgesic combined drug on the market. 2) The individual plasma levels of isopropylantipyrine and phenacetin were both elevated by being combined with each other. The areas under the plasma-level curves for isopropylantipyrine and phenacetin in dogs were enlarged by the combination with allylisopropylacetylurea. 3) Distribution of isopropylantipyrine in several organs and tissues was compared in rats between its single use and in combination as the analgesics. The concentration of isopropylantipyrine in all organs tested was found to be twice higher in rats receiving the analgesic combination drug than in those treated with isopropylantipyrine alone. 4) Metabolism of isopropylantipyrine by hepatic microsomal enzymes in rats was inhibited non-competitively by the addition of phenacetin or allylisopropylacetylurea. 5) Based on these findings, possible reasons for combining ingredients for an analgesic combined drug were discussed.

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The substance of mp 207°, obtained by the application β-naphthylamine and formaldehyde to phenylglycine, aspartic acid, or urethan, was determined as 7, 8, 15, 16-tetrahydro-7, 15-methanodinaphtho [2, 1-b] [2', 1'-f] [1, 5] diazocine (II) from its elemental analytical values and measurement of mass and nuclear magnetic resonance spectra.

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5-Hydroxy-6-(4-methoxybenzyl)-4, 5-dimethyl-1-(3-methyl-2-butenyl) piperidin-2-one (15) was synthesized and subjected to Grewe cyclization, in which the product obtained was not identified. During the synthesis of this compound (15), the improved sequence for 1-benzyl-6-(4-methoxybenzyl)-4-methoxycarbonylpiperidine-2, 5-dione (23) was found.

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The analgesic effect, solubility, stability, partition coefficient, protein binding ratio, and chemical mutagenic property of 4-formylaminoantipyrine which is a new metabolite of aminopyrine, were examined and compared with those of aminopyrine and other metabolites. These results indicated that 4-formylaminoantipyrine is not only a stable and biologically inert compound but also one of the final metabolites of aminopyrine.

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The reaction of quinoline 1-oxide (I) with both methanesulfonyl chloride (S) and potassium cyanide in a mixture of acetone-water gave 2-(methylsulfonyl) quinoline (II) containing a small proportion of 4-(methylsulfonyl) quinoline (III). As a result of the application of this reaction to other 16 kinds of substituted quinoline 1-oxides, it was proved that in all cases a CH₃-SO₂-group was introduced into the 2 or 4 position (when the 2 position was substituted) accompanied with the elimination of an oxygen atom from N→O group. The introduction of sulfonyl group into the 2 or 4 position was confirmed by reacting I or 2-phenylquinoline 1-oxide (I₂) with S, ethane-(Sa), benzene-(Sb) or p-toluene-(Sc)-sulfonyl chlorides. In particular, the reaction of I₂ was ascertained to produce a trace amount of 3-sulfonyl substituted compound. In this reaction step, sulfonyl chloride was first reacted with potassium cyanide to give sulfonyl cyanide, which was assumed to take part in the next step according to the following two pathways (Chart 3). (1) The reaction proceeds by nucleophilic attack of oxygen in N→O group on the carbon in -SO₂-C≡N. (2) The sulfinic acid is first produced by an attack of CN^- on the carbon in -SO₂-C≡N and the reaction further proceeds. These assumptions were confirmed on the basis of the facts below. (A) In the reaction of p-toluenesulfonyl cyanide (Sc') with I or I₂, p-tolylsulfonyl group is introduced into the 2 or 4 position. (B) Similar derivatives can be synthesized in good yield by the action of Sc and sodium p-toluenesulfinate (Sc") on I or I₂. In case of I₂, the reaction (B) afforded 3-substituted compound while the reaction (A) did not. However, when Sc"was added in the reaction (A), 3-substituted compound was also obtainable. Consequently it may be considered that this reaction proceeds mainly according to the pathway (2) accompanied with the simultaneous reaction of (1). The synthesis of 3-substituted compound will be reported in the other paper.

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Reaction of 2, 4-disubstituted quinoline 1-oxides (Ix) with methanesulfonyl chloride and potassium cyanide in acetone-water system was attempted. As the disubstituted quinoline 1-oxides, 2, 4-dimethyl-(I₂), 2-methyl-4-phenyl-(I₃), 2-ethyl-4-methyl-(I₄), and 4-methyl-2-phenyl-quinoline 1-oxide (I₅) were used. In all these compounds, the methane-sulfonyl group was introduced into the 3-position, with liberation of oxygen from the N→O group to form 2, 4-disubstituted 3-(methylsulfonyl) quinolines (IV_2-5), though the yield varied. At the same time, liberation of oxygen from the N→O group alone occurred to form the corresponding bases. Unexpected products obtained in this reaction were 3-methyl-and 3-ethyl-4-methyl-carbostyril (V₂ and V₄) from I₂ and I₄, formed by rearrangement of the methyl or ethyl group to the 3-position, and 2-acetyl-4-methylquinoline (VI) from I₄. Introduction of arylsulfonyl group into the 3-position, similar to the above, was proved by using I₂ and benzenesulfoyl chloride or tosyl chloride. It was considered that, in this reaction, sulfonyl cyanide is formed from sulfonyl chloride and cyanide ion as the first step and that this sulfonyl cyanide took part in subsequent reactions. Therefore, reaction of I₂ with p-tosyl cyanide was attempted but formation of 3-(p-tolylsulfonyl) derivative (IV_2t) was not observed, though IV_2t was produced by the addition of potassium cyanide or sodium p-toluenesulfinate. Since the sulfinate ion is formed from sulfonyl cyanide and cyanide ion, it was assumed that sulfonyl chloride and sulfinate ion would directly take part in the formation of IV from the reaction of IX with sulfonyl chloride and potassium cyanide. This assumption was proved to be true by the formation of IV_2t in a good yield by the reaction of I₂ with tosyl chloride and sodium p-toluenesulfinate. Discussions were made on the process of formation of various products from this reaction.

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Four kaempferol glycosides, I, II, III, and IV, were isolated from the leaves of Clitoria ternatea L. (Leguminosae). Kaempferol 3-glucoside (I), 3-rutinoside (II), and 3-neohesperidoside (III) were identified by UV, PMR, and mass spectrometry. IV, C₃₃H₄₀O₁₉, mp 198°, was characterized as kaempferol-3-O-rhamnosyl-(1→2)-O-[rhamnosyl-(1→6)]-glucoside from spectral data, and was named clitorin. In this connection, distinction between rutinosyl and neohesperidosyl by CMR spectrometry is discussed.

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Since the volume of immersion fluid of the disintegration test in the Japanese Pharmacopoeiae IX is not determined precisely, two different interpretations are possible. One is that the surface of the fluid coincides with the upper surface of the basket-rack assembly when the assembly is at the lowest point of the downward stroke. The other is that the surface of the fluid coincides with the surface of the assembly when the basket is at the highest position of the upward stroke. The difference in volume of these two interpretations was found to be 1000 ml in the former (method 1) and 1440 ml in the latter (method 2), and these considerable differences mgiht bring about non-negligible difference in the results of disintegration time of tablets. More than 30 tablets including uncoated and coated commercial preparations on the market were selected at random and were subjected to the disintegration test under these two conditions in volume of the immersion fluid. Although a good correlation in the disintegration time was obtained by methods 1 and 2 (γ : 0994) the time obtained by method 2 was apparently shorter than that from method 1, and this inclination became more apparent when the disintegration time was increased. Effect of the disk was also examined with these two methods. The disk accelerated the disintegration time of respective tablets, while the correlation between these two methods remained unchanged. These results suggested that a more strict prescription of immersion fluid in the J.P.IX might be necessary, because evaluations of tablet preparations might differ according to different volume in the disintegration test.

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Histology and the chemical constituenits of the fruis of Coelopleurum lucidum L. var. Gmelini (DC) HARA (Umbelliferae) are reported. The characteristics of the fruit were as follows : In cross section a large aperture was in the mesocarp surrounding a seed in the ripe fruit ; 3 dorsal ridges were smaller than 2 lateral ones but similar in form, which were papillate ; vascular bundles were the same as those in the Angelica group and different from the Ligusticum group. Three coumarin derivatives were isolated and identified as isoimperatorin, C₁₆H₁₄O₄, mp 107-109°, prangolarin, C₁₆H₁₄O₅, mp 103-104°, and (+)-oxypeucedanin hydrate, C₁₆H₁₆O₆, mp 128-129.5°. These homologous substances were not artefacts formed during separation, but derived from the fruits, and they were different in oxidation levels in the side chain.

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Effect of selenium on metabolism of mercury compounds was examined, as it had been confirmed that selenium had a protective effect against the toxicity of mercuric chloride and methylmercuric chloride in rats. In rats receiving mercuric chloride with selenium, the mercury content in the liver was significantly increased compared with that in rats receiving mercuric chloride alone, and the selenium content in the liver was also increased compared with that in rats receiving selenium alone. The molar ratio of mercury to selenium in the liver was nearly 1.0. These results suggested that selenium interacted directly with mercuric chloride to form less toxic products in the rat liver. In rats receiving methylmercuric chloride with selenium, the percentage of methylmercury contentin total mercury in the liver was decreased compared with their percentage in rats receiving methylmercuric chloride alone.

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Bis-thiosemicarbazones (bis-TS) were synthesized and for their in vitro and in vivo antibacterial effect against Mycoplasma gallisepticum was examined. Among the tested compounds, α-ketoaldehyde bis-TS exhibited a strong in vitro activity, and minimal inhibitory concentration (MIC) of most active methylglyoxal bis-TS was 3.9-7.8×10^-3 μg/ml. α-Diketone bis-TS were inferior to α-ketoaldehyde bis-TS, but their toxicity to HeLa cells was extremely low. Eight compounds which have small MIC value or large ratio of toxic concentration to HeLa cells to MIC, were selected for examining their therapeutic effectiveness in Mycoplasma-infected chicken. When the compounds were added to feed, methylglyoxal bis (4-methyl-TS) showed 64% inhibition at a level of 25 ppm. In the case of intramuscular injection, 1-phenylpropane-1, 2-dione bis-TS exhibited 64% inhibition at a level of 20 mg/chicken administered twice daily on the day of infection and on 5th day after infection.

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Various derivatives containing acetoacetamide, β-aminocrotonamide, pyrimidine, pyridine, dihydroxybenzoic acid, quinoline, pyridone, 2-pyrone and 2-pyrrolidone were prepared mainly from diketene. Their anti-tumor activities were examined by use of ascitic or solid type of Ehrlich carcinoma, and among them eleven compounds were found to have some anti-tumor effects on this solid tumor. These compounds were derivatives of pyrimidine (No. 30), pyridine (No. 41, 42, 54, 55, 56, 57 and 63), 2-pyrone (No. 124 and 125) and pyridopyrimidine (No. 137). No correlation was found between anti-tumor activity and these derivatives. No other substances in Table I-XII ; were effective.

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Seventy-four compounds related to lactams and pyridones were synthesized and their anti-tumor activity was examined using Ehrlich carcinoma cells. 4-(2-Piperidyl) butyric acid hydrochloride was found to have some anti-tumor effect on the solid type of Ehrlich carcinoma cells, but no other substances were found to be effective. Correlation between the anti-tumor activity and structure of the tested compounds still remains uncertain.

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Forty-seven compounds related to adenine derivatives were synthesized and their anti-tumor activity was examined using Ehrlich carcinoma cells. 1-Methyladenosine was found to have some anti-tumor effect on the solid type of Ehrlich carcinoma cells, but no other substances were found to be effective. Correlation between the anti-tumor activity and structure of the tested compounds remains uncertain.

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The essential oils of Stevia rebaudiana BERTONI (Compositae) were examined in detail. The yields of oil were 0.12-0.16% of the dried herbs and 0.43% of the dried inflorescence. These oils mainly contained β-caryophyllene, trans-β-farnesene, α-humulene, δ-cadinene, caryophylleneoxide, nerolidol, and an unidentified alcohol as a sesquiterpene, and linalool, terpinen-4-ol, and α-terpineol as a monoterpene.

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Primary alcohols (I), a mixture (II) of alkyl cis-ferulate, a mixture (III) of alkyl trans-ferulate, and β-sitosteryl β-D-glucoside were isolated from the stems of Buckleya lanceolata MIQ. Content of II in the plant was less than that of III. The chain length of I and the alcohols (IIa, IIIa) obtained from II or III by hydrolysis consisted of C₁₈ to C₂₄.

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From the herba of Oenanthe javanica (BLUME) DC. isorhamnetin, camphene and β-pinene were isolated and the presence of carvacrol, eugenol, and others was confirmed by gas chromatography-mass spectrometry.

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From the leaves of Uraria crinita DESV. (Leguminosae), six C-glycosylflavones (I-VI) were isolated. Vitexin (IV) and orientin (V) were identified by direct comparison with authentic samples, and vitexin 7-O-glucoside (I), orientin 7-O-glucoside (II), saponaretin 4'-O-glucoside (III), and vicenin II (VI) were identified with the help of degradation reactions and spectral analyses.

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