Reaction of 2-(I), 3-(II), 4-(III), and 6-quinolinecarbonitrile 1-oxide (IV) with potassium cyanide in dimethyl sulfoxide was examined. It was found that the products of this reaction were compounds in which the CN group was introduced into 2- or 4-position of the quinoline ring, accompanied with liberation of oxygen from the N→O group. The products formed were 2, 4-quinolinedicarbonitrile (IIIa) from I, 3, 4-quinolinedicarbonitrile (IIa) from II, IIIa from III, and 2, 6-quinolinedicarbonitrile (IVa) from IV. Besides these major products, 4-cyano-2-quinolinecarboxamide (v) was obtained from I, 2-hydroxy-4-quinolinecarbonitrile (IIIb) from III, and 2-hydroxy-6-quinolinecarbonitrile (IVb) from IV. The state of these reactions indicated that the reactivity decreased in the order of II, IV, III, and I, because II reacted readily at room temperature (processed after 10 min), the reaction proceeded gradually at room temperature for III and IV (processed after 24 hr), while I did not react at all at room temperature and required 4 days at 50°. Quinoline 1-oxide (VI) not containing a CN group did not undergo this reaction under these conditions. I, II, III, and IV are prepared respectively from 2-(I'), 3-(II'), 4-(III'), and 6-quinolinecarbonitrile (IV') by the application of hydrogen peroxide in acetic acid by the conventional method. While I and III are obtained in a high yield, II' and IV' are resistant to this reaction and their yield is poor, although the reason for it is obscure. 3-Hydroxy-6-quinolinecarbonitrile (VII) was also formed from IV' besides IV.

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Cyclization of unsaturated nitriles and amides to lactams was investigated. The unsaturated nitriles (Ia-c) or amides (Id-g) cyclized to the lactams (IIa-g) in a good yield by heating with polyphosphoric acid or conc. phosphoric acid. By application of this reaction, N-(4, 4-diphenyl-3-butenoyl)glycines (III, VII, IX) gave 10b-phenyl-1, 10b-dihydropyrrolo[2, 1-α]isoquinoline-3, 6(2H, 5H)-diones (IV, VIII, X). Similar treatment of 4'-chloro-4, 4-diphenyl-3-butenanilide (XIII) afforded various cyclization products ; N-(p-chlorophenyl)-4-phenyl-1-naphthylamine (XIV), 7-chloro-5, 5-diphenyl-4, 5-dihydro-1H-1-benzazepin-2(3H)-one (XV), 1-(p-chlorophenyl)-5, 5-diphenylpyrrolidin-2-one (XVI), 4-phenyl-1-naphthol (XVII), and γ, γ-diphenylbutyrolactone (XVIII).

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Conversion of 10b-phenyl-1, 10b-dihydropyrrolo[2, 1-α]isoquinoline-3, 6(2H 5H)-diones (IIIa-c) to pyrrolo-benzodiazepine derivatives was investigated. The Beckmann rearrangement of the oximes of IIIa-c with polyphosphoric acid gave 10b-phenyl-1, 10b-dihydropyrrolo[2, 1-a]isoquinoline-3, 5, 6(2H)-triones (VIIa-c) as major products and IIIa-c, instead of the expected normal rearrangement products (VIIIa-c or XIVa-c). The Schmidt reaction of IIIa, b afforded two isomers of the rearrangement products; 11b-phenyl-7, 11b-dihydro-1H-pyrrolo[1, 2-d] [1, 4] benzodiazepine-3, 6(2H, 5H)-diones (VIIIa, b) and 11b-phenyl-5, 11b-dihydro-1H-pyrrolo[2, 1-d][2, 4]benzodiazepine-3, 7(2H, 6H)-diones (XIVa, b), together with VIIa, b. Similar treatment of IIIc, however, resulted in formation of a sole product VIIc. A number of derivatives of VIIIa, b were synthesized for pharmacological evaluation.

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Relationship between the transition and gastrointestinal absorption of two polymorphic forms of sulfathiazole was studied. The drug content in blood of rabbits after oral administration and intraduodenal administration of the polymorph of sulfathiazole was compared and it was found that the gastrointestinal absorption was affected by the rate of transformation of the polymorph, and the drug was absorbed from "stable" form II more efficiently than from form I when suspensions were administered orally. The effect of 0.1% gelatin on the absorption behavior was examined and conversion from form II to form I seemed slower in the presence of gelatin. From these results, it was recommended that the "stable" form II should be used in order to expect a better therapeutic efficacy in pharmaceutical preparations.

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When the shearing operation, which quantity is defined as the product of shearing distance and applied pressure, was carried out for an enzyme powder, the rate of inactivation was found to be very large and proportional to the quantity of shearing operation. The ultraviolet (UV) shift to the region of short wavelength found in inactivated enzyme by this operation is completely identical to the case of static compression process. This fact means that the mechanism of enzyme inactivation in a solid state is due to the intermolecular space deviation among particles and that the inactivation can occur most effectively by the shearing operation.

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DL-O-Acetylpantolactone was found to have two polymorphic forms. A form is the new crystals having a melting point of 20.7° and B form is the previously reported crystals³⁾ having a melting point of 13.5°. Their racemic structure was examined from melting point diagrams, solubility diagrams, and infrared absorption spectra, and it was revealed that A form is a racemic compound and B form is a racemic congromerate. The solubilities of A and B forms in hexane were determined and thermodynamic properties of these forms were experimentally evaluated. The supersaturated solution of DL-O-acetylpantolactone was seeded with these forms and the optical isomers, and the specific rotations of the deposited crystals and the rotation angles of the filtrates were measured at appropriate time intervals. From these results, the relationship between optical resolution and racemic structures was discussed.

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2-Amino-4-R₁-5-R₂-2-oxazoline (II) was synthesized by the reaction of amino alcohols (I) with cyanogen bromide. By the acetylation of II, diacetyl derivative (V) was obtained more easily than monoacetyl derivative (IV). Configuration of II was easily presumed from the vicinal coupling constant (JVIC) in the nuclear magnetic resonance spectra of V. V was hydrolysed to 3-acetyl-4-R₁-5-R₂-2-oxazolidone (VI) and 2-acetamido-2-R₁-1-R₂-ethyl acetylcarbamate (VII) with 5% hydrochloric acid at room temperature. The steric structure of VII was confirmed by its conversion to 2-acetamido-2-R₁-1-R₂-ethanol (IX) via 2-acetamido-2-R₁-1-R₂-ethyl carbamate (VIII). In the catalytic reduction of II at room temperature under ordinary pressure, IIa, b was recovered when using palladiumcarbon catalyst in ethanol, and IIa, b gave the corresponding 4-cyclohexyl-II (X) when using platinum oxide in acetic acid. High-pressure reduction of IIa afforded (1-phenylethyl)-urea (XIIa) when using palladium-carbon catalyst, and Xa when using Raney nickel catalyst.

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A fluorometric determination of sodium glyoxylate (II), using phenylephrine HCl (I) has been established and the method was applied to the determination of allantoin and aluminium chlorohydroxy allantoinate in pharmaceutical preparations. II was condensed with I into a cyclic substance (V) which was oxidized by K₃Fe(CN)₆ to a fluorescent substance (VI). Chemical structures of V and VI were found to be 4, 6-dihydroxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-1-carboxylic acid and 6-hydroxy-2-methyliso-quinolinium chloride, respectively. The analytical procedure was as follows : To 1 ml of II solution (5 μg/ml), 1 ml each of 0.2 N NaOH and 0.1% solution of I were added and the mixture was heated for 75 min at 80°. To this mixture, 1 ml each of 2.5N NaOH and 0.06% K₃Fe(CN)₆ were added and the mixture was further heated for 5 min at 80°. When cooled, it was diluted to 10 ml with methanol. The fluorescence intensity of the solution was measured at 450 nm under excitation at 370 nm.

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ATSO, an antitumor polysaccharide from Coriolus versicolor, was found to strongly suppress the growth of a solid-type sarcoma-180 in mice. The additive effect of ATSO and anticancer chemotherapeutics on antitumor activity and immune response was examined in tumor-bearing and normal mice. The delayed cutaneous hypersensitivity (DCH) of mice was depressed after implantation of tumor and treatment with antitumor chemotherapeutic drugs. ATSO inhibited the depression of DCH by intraperitoneal or oral administration, but ATSO did not increase DCH of normal mice. The combination treatment of a low dose of ATSO and drugs was found to promote tumor regression significantly in mice.

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Examination of chemical components of pollen grains of Alnus sieboldiana MATSUM. revealed the occurrence of several amino acids, hydrocarbons, β-sitosterol, quercetin, glucose, fructose, and organic acids such as formic acid and linoleic acid. A new flavone glucoside, quercetin-3-β-D-glucopyranosyl-4-O-β-D-glucopyranoside (1), was isolated and its structure was elucidated from chemical evidences and spectroscopic data.

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Tortuosity of sedimentation beds was measured by the electrical conductivity method for aqueous suspension of variously shaped particles (sphere, glass and nylon; irregular shape, calcium carbonate and chloramphenicol ; rod, glass, salycylic acid, and benzoic acid; plate, mica and naphthalene). Tortuosity at the upper part of the sedimentation beds showed low values for calcium carbonate of primary particle size γ₀=3.3 μm which constitutes an aggregated settling system, and high values for glass sphere of γ₀=22.5 μm which constitutes a monodispersed settling system. As for porosity (ε), vertical tortuosity (q_V) and horizontal tortuosity (q_H), the values obtained by the gravitational and centrifugal sedimentation methods were the same for glass spheres but were different, depending on the mode of sedimentation, for glass rods and nylon spheres. In the case of sedimentation beds of rod- and plate-shaped particles, decrease of q_V was more notable than that of q_H with increase of ε. The data plotted to see the relation between q and ε fell on different lines for coarse particles, but fell on the same line for fine particles of calcium carbonate and chloramphenicol whose γ₀ is about 0.8 μm. The ratio of q_V/q_H, which represents anisotropy of the sedimentation bed, was about 1 for glass spheres, constant independent of ε for fine particles of γ₀=0.8 μm, and decreased with increase of ε for other particles. It was concluded that the anisotropy of sedimentation beds is caused by nonspherical nature of primary particles and or aggregated secondary particles.

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Effect of sunlight and ultraviolet ray on the stability of hemin and hemoglobin heme, which were stained on a filter paper, was studied by the combined use of paper chromatography and spectrophotometry. Hemin and hemoglobin heme decreased rapidly by irradiation with sunlight in summer (maximum illuminance, 60000 lx) or with ultraviolet ray (250-400 nm) within 1-5 hr. Hemin which was allowed to stand in two places in a room (maximum illuminance 10000 and 250 lx) decreased markedly with lapse of time up to 25 days, whereas hemoglobin heme was more stable than hemin under the same conditions. Both hemin and hemoglobin heme were fairly stable in a dark place for about 40 days. A stable greenish yellow brown spot (Rf 0.00), which was insoluble in many organic solvents, acids, and alkalis, was produced from the stains of hemin and hemoglobin heme by irradiation with sunlight or with ultraviolet ray. A similar substance was also produced from hemin and hemoglobin heme when allowed to stand in the room.

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After intraperitoneal injection of estrone[6, 7-³H] into guinea pigs, its urinary metabolites were measured by reverse isotope dilution method. The formation of 2-hydroxyestrone and 2-methoxyestrone was observed in male and female animals. The conversion of radioactive estrone to estradiol was found to be negligible. No other metabolites were found.

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The sequences of reactions between 6-aminouracil or its N-methylated derivatives and the Ehrlich reagent in the presence of acid catalysts were elucidated. In the first step, 6-aminouracils react with the Ehrlich reagent to form the labile Schiff bases, which are subsequently acid-hydrolyzed to the corresponding barbiturates. The latter reaction products condense again with the reagent to afford the corresponding stable benzylidene compounds. These reactions were found to be almost quantitative. The optimal experimental conditions were also established for utilizing the above reaction to the quantitative colorimetric determination of 6-aminouracils.

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In the course of synthetic studies on analgesics, two compounds were synthesized from 2-(1-cyclohexenyl)cyclohexanone (II). N-Methyl-octahydroquinoline derivative (VII) was synthesized from 2-(β-cyanoethyl)-2-(1-cyclohexenyl)cyclohexanone (III), which was prepared from II by cyanoethylation. Further, 7-(1-cyclohexenyl)hexamethylenimin-2-one (IX), the Beckmann rearrangement product of II, was successfully converted to 2-(1-cyclohexenyl)-1-[2-(N-propionylanilino)propyl]hexamethylenimine (XVII) according to Wright's procedure.

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Reaction of quinoline 1-oxides having substituents in 2- and 4-positions with benzoyl chloride and potassium cyanide in aqueous solution was attempted. The N-oxides used were 2, 4-dimethyl-(Ia), 4-methyl-2-phenyl-(Ib), and 2-methyl-4-phenyl-quinoline 1-oxide (Ic), methyl 1, 2, 3, 4-tetrahydro-9-acridinecarboxylate 10-oxide (Id), and methyl 2-ethyl-3-methyl-4-quinolinecarboxylate 1-oxide (Ie). Results of the reaction were as follows : 1) Ia and Ie afforded 1, 2, 3, 4-tetrahydroquinoline derivatives; 3-benzoyloxy-4-methyl-2-methylene-1, 2, 3, 4-tetrahydroquinoline-4-carbonitrile (IIa) from Ia and methyl 3-benzoyloxy-4-carbamoyl-2-ethyl-2-hydroxy-3-methyl-1, 2, 3, 4-tetrahydroquinoline-4-carboxylate (IIe) from Ie. 2) A product (III) in which a benzoyloxy group was introduced into the α-carbon in the side-chain at 2-position of the quinoline ring, accompanied with liberation of oxygen from the N→O group, was formed; IIId in a good yield from Id and IIIa from Ia. 3) Similar product with introduction of a benzoyloxy group into the quinoline ring, accompanied with liberation of oxygen from the N-O group, was formed; 6-substituted compound (IVa, b) from Ia, 3- and 8-substituted compounds (IVb, 3 and IVb, 8) from Ib, 3- and 8-substituted compounds (IVc, 3 and IVc, 8) from Ic, and 8-substituted compound (IVb, 8) from Ie.

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2', 5'-Dihydroxy-2-(2-methoxy-5-nitrophenyl) acetophenone (III) and 6-hydroxy-2'-methoxy-5'-nitroisoflavone (IV) were synthesized.

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The takatonine-type compounds, (±)-1-(4-methoxybenzyl)-2-methyl-5-hydroxy-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline and its derivatives were synthesized via the Bischler-Napieralski ring-closure reaction. Correlation between the chemical Shift in NMR spectra and the conformation of these compounds and related compounds was examined. There are two stereochemical forms, called "s-cis" type and "s-trans" type conformation in the benzyl -benzene rings. It was concluded that the benzyl-benzene ring of tetrahydrotakatonine-type alkaloids takes the "s-cis" type conformation with respect to the benzene ring of isoquinoline moiety, while that of takatonine, papaverine, and N-methylpapaverine-type alkaloids take the "s-trans".

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