It was found that the water-soluble fraction of royal jelly contained a factor which had a vasodilating activity on dog femoral artery. This activity was transitory, was present in 100- to 200-fold of that in honey, and the activity was rapidly lost in alkaline aqueous solution. This active factor was partially purified by Sephadex G-25 chromatography, and various examinations were made to elucidate its principle. It was thereby found that this factor was inactivated by the protease treatment, was antagonized by atropine, and was inactivated by the true cholinesterase. Consequently, this vasodilating factor was considered to be a cholinergic substance, and was determined as acetylcholine by paper chromatography.

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2-(6-Methoxy-2-naphthyl) propanoic acid (1), with a potent anti-inflammatory and analgesic activity, was prepared by two convenient methods. These procedures were found to be extremely useful for the synthesis of 1 from the industrial point of view. The structures of E and Z isomers of 2-butenoic acid and oxiranecarboxylic acid derivatives, synthetic intermediates, were studied. Among the derivatives prepared, 3-(6-methoxy-2-naphthyl)-2-oxo-butanamide (9) showed a potent anti-inflammatory activity comparable to phenylbutazone in the first screening of carrageenin-induced rat paw edema.

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From the ethanolic solution obtained by the browning reaction of N-p-tolyl-D-glucosylamine (I) and p-toluidine, 3-deoxy-D-glucosone (XI) was isolated and identified by gasliquid chromatography. Formation of intermediate reductones, including enediol, enaminol, and enediamine, was indicated by the determination of reducing substances using 1, 1-diphenyl-2-picrylhydrazil and 2, 6-dichlorophenolindophenol. It was suggested that XI and these reductones were important intermediates in the browning reaction of D-glucose with p-toluidine. D-Arabinose, D-erythrose, D-glyceraldehyde, D-arabonic acid, D-erythronic acid, D-glyceric acid, and glycolic acid were also identified by paper chromatography as the nitrogen-free decomposition products in the browning reaction. It was assumed that these products undergo further degradation through free radical reaction.

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The apogalanthamine analogs, 10, 11-methylenedioxy-(1) and 10, 11-dimethoxy-5, 6, 7, 8-tetrahydrodibenz [c, e] azocine (2), as α-adrenergic blocking agents were synthesized by photolysis of N-benzyl-2-bromo-4, 5-methylenedioxy-(9) and N-benzyl-2-bromo-4, 5-dimethoxy-β-phenethylamine (10). 2, 3-Methylenedioxy-(3) and 2, 3-dimethoxy-5, 6, 7, 8-tetrahydrodibenz [c, e] azocine (4), were also prepared by photolysis of N-(2-bromo-4, 5-methylenedioxybenzyl)-(11) and N-(2-bromo-4, 5-dimethoxybenzyl)-β-phenethylamine (12).

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Heating of 3, 5-disubstituted 1-(2-hydroxyethyl) pyrazoles with 47% hydrogen bromide afforded 3, 5-disubstituted 1-(2-bromoethyl) pyrazoles. 3, 5-Dimethyl-, 3, 5-diphenyl-, 5-chloro-3-methyl-and 5-chloro-3-phenyl-1-vinylpyrazoles were synthesized by dehydrohalogenation of the corresponding 1-(2-haloethyl) pyrazoles with potassium hydroxide in ethanol. However, treatment of 1-(2-bromoethyl)-5-hydroxy-3-methyl-and-3-phenylpyrazoles under the same reaction condition afforded cyclized products ; 2, 3-dihydro-6-methyl- and-6-phenylpyrazolo [3, 2-b] oxazoles, respectively. Treatment of 5-benzoyloxy-1-(2-bromoethyl)-3-methyl-and-3-phenylpyrazoles with sodium t-butoxide in butanol furnished 5-hydroxy-3-methyl-and-3-phenyl-1-vinylpyrazoles.

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Tortuosity was measured by the water permeation method (qw) and the electrical conductivity method q (qv, vertical ; qw, horizontal) on the sedimentation beds of monodispersed particles of glass sphere and sea sand, and aggregated particles of calcium carbonate. Water and aqueous solutions of potassium chloride, sodium dodecyl sulfate, and sodium polyacrylate were used as the suspending medium. The values of qw thus obtained were in the range of 1.4-1.5 which was nearly equal to Carman's value of qw=√(2), while the values of q were in the range of 1.05-1.20. From the result that qw>q, it was considered that water and ion flow through different voids in the sedimentation beds, and a theoretical equation (Eq. (15)) was derived, which gives the values of q as a function of the porosity of sedimentation beds ε, porosity between secondary particles, ε_ext, and conductivity ratio inside the secondary particles, f_in. For the sedimentation beds of monodispersed particles, Eq. (15) can be reduced to a simple equation ; q=√(ε²+(1-ε) qw) Eq. (16). Values of q calculated by this equation were in good agreement with the experimental values of qv for monodispersed particles of glass sphere and sea sand. For the aggregated suspension of calcium carbonate, it was concluded that ions go through inside the secondary particles.

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An X-ray diffraction method for quantitative representation of the degree of orientation of aspirin crystals within a tablet was considered, and the effect of the shape of aspirin crystals on the degree of their orientation and the breaking strength of tablet was studied. Since, as reported previously, (100) faces of aspirin crystals aligned themselves parallel to the upper flat punch during compression, X-ray diffraction intensities, I, of (100) for the upper surface and faces parallel to it were strong, and those for oblique and normal faces were weak. Therefore, the degree of orientation was represented by the ratio of I of (100) for parallel face vs. that for normal face. As the shape of aspirin crystals became more flat, the degree of their orientation increased. Consequently, the tendency to laminate, that is, the ratio of breaking strength of a tablet in normal direction to upper surface vs. that in parallel direction, increased.

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Drug disposition of chlormezanone-¹⁴C and its interaction with aspirin were studied in mice. Chlormezanone-¹⁴C was well and rapidly absorbed from the gastrointestinal tract after oral administration of 24mg/kg. Blood levels of radioactivity reached a peak 60 min later. Tissue concentration became lower in the order of the adrenal gland, kidney, liver, pituitary, lung, brain and muscle. The high affinity of chlormezanone-¹⁴C for the tissues was deduced from the fact that the concentration ratio of tissue to blood was larger than 1.0. Urinary excretion of radioactivity was approximately 21% of the administered dose within 120min. Examination of metabolites in the plasma, liver, kidneys and brain indicated that chlormezanone-¹⁴C was mainly found in the tissues in an unchanged form but its metabolites such as p-chlorobenzoic acid, p-chlorohippuric acid, N-methyl-p-chlorobenzamide, 2-[N-methyl-N-(p-chlorobenzoyl)] carbamoylethylsulfonic acid and p-chlorobenzoic acid glucuronides showed a low concentration. Aspirin administered concomitantly had no effect on the absorption, distribution and metabolism of chlormezanone-¹⁴C, but significantly inhibited urinary excretion of chlormezanone-¹⁴C and its metabolites. These results suggest that chlormezanone-¹⁴C is well and rapidly absorbed and is distributed highly into tissues without the effect of combination of aspirin and exerts its pharmacological effect in an unchanged form.

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The reaction of dimethylsulfonium acetylmethoxycarbonylmethylide (Ia) with isoquinoline 2-oxide (II) in the presence of benzoyl chloride gave 2-hydroxy-1-(1-isoquinolyl)-3-methoxycarbonylpyrrolo [2, 1-a] isoquinoline (III). Dimethylsulfonium diacetyl-and acetyl-benzoylmethylides (Ib and Ic) gave 4-methyl-and phenyl-3-methylthio-2-oxo-2H-pyrido [2, 1-a] isoquinolines (VII and X). Compounds VII and X were desulfurized by treatment with Raney nickel to the corresponding 4-methyl-and 4-phenyl-2-oxo-2H-pyrido [2, 1-a] isoquinolines (VIII and XI). When excess Raney nickel was used, 4-methyl- and 4-phenyl-6, 7-dihydro-2-oxo-2H-pyrido [2, 1-a] isoquinolines (IX and XII) were obtained.

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Bromination of 1, 3-diphenylfuro [3, 2-c] pyrazole (I) by equimolar bromine occurred preferentially in the 5-position of the furo [3, 2-c] pyrazole ring, as do Vilsmeier formylation and Friedel-Crafts acyaltion of I. However, nitration of I by acetyl (nitric acid-acetic anhydride) at 0° occurred preferentially in the para and ortho positions of 1-phenyl group to yield 1-(p-nitrophenyl)-3-phenylfuro [3, 2-c] pyrazole and 1-(o-nitrophenyl)-3-phenylfuro-[3, 2-c] pyrazole.

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A new prenyl chalcone, xanthoangelol (II), was isolated from the roots of Angelica keiskei KOIDZUMI (Umbelliferae), together with a known prenyl chalcone, 4-hydroxyderricin (I). The structure of II was elucidated as 2', 4, 4'-trihydroxy-3'-[(E)-3, 7-dimethyl-2, 6-octadienyl] chalcone.

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A rearranged steroidal olefin was obtained from the urinary hydrolysate. The structure was determined as 17α-ethyl-17β-methyl-18-nor-5β-androst-13 (14)-en-3α-ol (I), which was completely identical with the one derived from 20α-tosyloxy-steroid (X). This urinary product was found to be formed from urinary pregnanediol 20-sulfate (XI) by hot acid hydrolysis.

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Acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, caproyl, enanthoyl, caprylyl, pelargonoyl, caprinoyl, lauroyl, myristoyl, palmitoyl, and benzoyl esters of 4-methylumbelliferone were synthesized and a method was developed for the determination of these esters by the use of a high-speed liquid chromatography. Separation can be achieved by using a 1-m column of Permaphase ODS, using gradient from H₂O to MeOH as an eluant with a Du Pont 830 liquid chromatograph. By this method, satisfactory separation was obtained for 12 normal aliphatic acyl esters of 4-methylumbelliferone. Accuracy in this method was about ±2%.

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A method was developed for microdetermination of fatty acids in serum, based on the use of an improved copper reagent, without the addition of sodium chloride, for the lower phase and the extraction solvent as the upper phase for extraction of free fatty acid-copper complex. The improved copper reagent contains 10% (w/v) Cu (NO₃)₂·3H₂O, 2M triethanolamine, and 2M acetic acid in 10 : 9 : 1 (v/v) ratio in water and adjusted to pH 8.1. The extraction solvent is a 61 : 37 : 2 (v/v) mixture of heptane, chloroform, and methanol. After extraction, the upper phase containing the free fatty acid-copper soap is rapidly separated from the aqueous phase and free fatty acid is determined as a copper soap by colorimetry with 0.8% ethanol solution of diphenylcarbazide. This method was found to be about 3 times more sensitive than the conventional diethyldithiocarbamate method. It was also found that the color development is not affected by chain length of fatty acids in the range of C₁₂ to C₁₈, but increases to some extent in the presence of lecithin. Sera from 29 patients were examined by this and the conventional method, and the correlation coefficient for the two methods was good.

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Microbiological transformation of α-santonin analogs with culture broths of Aspergillus ochraceus, Fusarium nivale, and F. solani is described. 4α-Oxide (II) and 4β-oxide (III) were transformed to the corresponding 1, 2-dihydro-3β-hydroxy derivatives (VII), (VIII), and IX, respectively). 3α-Acetoxy derivative (V) was hydrolysed to the 3α-hydroxy derivative (X) in a good yield. 3β-Chloro derivative (VI) was stereoselectively transformed to the compound (X) with inversion of the C₃-configuration. Benzoquinone (XV) was reduced to hydroquinone by Asp. ochraceus, while microbiological transformation of compounds XI, XII, XIII, and XIV was not observed.

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Reaction of 1-phenyl-1H-pyrazolo [3, 4-d] pyrimidine 5-oxide (I) with methanesulfonyl chloride and potassium cyanide in acetone-water afforded 1-(1-phenyl-1H-pyrazolo-[3, 4-d] pyrimidn-4-yl)-2-propanone (III) instead of the expected 4-(methylsulfonyl)-1-phenyl-1H-pyrazolo [3, 4-d] pyrimidine (II). II was not formed in the same reaction carried out in dioxan-water and the product was 1-phenyl-1H-pyrazolo [3, 4-d] pyrimidine-4-carbonitrile (IV).

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Stability of seven diuretics in aqueous solution was examined under the condition of equilibrium dialysis study. It was found that furosemide, ethacrynic acid, and bumetanide were not decomposed and that benzothiadiazine derivatives except hydrochlorothiazide were slightly decomposed in pH 7.4 buffer solution within 120 hr at 5° or 6 hr at 30° or 37°. The hydrolysis of hydrochlorothiazide could not be disregarded. The binding of these diuretics by bovine serum albumin (BSA) was investigated using equilibrium dialysis technique at pH 7.4 and 30°. The mathematical analysis of binding data described by Scatchard was applied, and the binding data of hydrochlorothiazide were corrected using its hydrolysis rate. All the compounds were found to interact with BSA, but a large difference in BSA. binding was recognized among them. Physicochemical properties such as ionic form ratio and hydrophilicity of benzothiadiazine derivatives were found to be related to their BSA binding ability.

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Conformation of the ketyl radical of 10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5-one (heptenone), produced by reduction with calcium amalgam, was evaluated from ESR hfs and MO calculations based on McLachlan's method. The rotational angle about the C-C bond connecting the aromatic group and carbonyl group was found to be 18-26°.

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Flavanone glycosides in the peels of Citrus and Poncirus were examined by thin-layer chromatography. The results obtained from the analysis of eleven Citrus species and one Poncirus species show that each species has an ability of synthesizing both flavanone neohesperidosides and flavanone rutinosides. This fact is out of accordance with the proposals made by Horowitz and Nakabayashi. In all the species of subgenus Metacitrus examined, hesperidin is present as a main flavanone component. On the other hand, the results obtained from Archicitrus species are complicated.

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