In a research programme for the synthesis and development of non-narcotic analgesics, synthesis of 5, 5-disubstituted 1 2, 3, 4-tetrahydro-5H-2-benzazepines was attempted. 2, 5, 5-Trisubstituted 7-hydroxy-1, 2, 3, 4-tetrahydro-5H-2-benzazepines were prepared by the Bischler-Napieralski reaction of 3, 3-disubstituted 3-(3-methoxyphenyl) propylamines. The analgesic activity of the compounds tested indicated that 2-cyclopropylmethyl-5, 5-dimethyl-7-hydroxy-1, 2, 3, 4-tetrahydro-5H-2-benzazepine had the most potent activity.

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As fundamental studies on the crystallization of thiabenzenes, new aromatic ring compounds with a decet quadri-covalent sulfur bonding, and for the application of thiabenzenes as medical pharmaceutics, synthesis of thiaanthracenes with an amino group was examined. Several kinds of thioxanthones with an amino group were synthesized and, taking these as a model compound, reaction conditions that could be used for thiabenzene synthesis were examined. Thiaanthracenes synthesized under conditions thereby established were three kinds with a cyclic amino group in 1-position, five kinds with (N, N-dialkylamino) alkylamino group, and four kinds with a sulfonamido group.

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Regeneration of free amino acids from dinitrophenylated (DNP) amino acids was carried out by the use of hydroxylamine as the nucleophilic reagent. For this reaction, ca. 1 mg of DNP-amino acid is dissolved in 1 drop of 2-methoxyethanol, 1 drop each of 20% NH₂OH·HCl and 20% KOH are added, and the mixture is shaken for a few minutes at room temperature. One drop each of 20% AcOH and acetone are then added, and the mixture is submitted to thin-layer chromatography for the detection free amino acids. Good results were obtained with dinitrophenylated glycine, L-alanine, L-leucine, L-valine, L-phenylalanine, L-proline, L-serine, DL-threonine, L-tyrosine, L-glutamic acid, L-aspartic acid, L-cysteine, DL-methionine, L-lysine, and L-arginine. In the reaction of DNP-DL-methionine, a minute amount of Ninhydrin-positive substance was produced by the action of NH₂OH on methionine. A good result was not obtained with DNP-L-histidine. This reaction requires an excess of alkali hydroxide and a good result is obtained when the molar ratio of NH₂OH·HCl to KOH is 1 : 2. This is not merely a substitution reaction of hydroxylamine and amino acid but, considering the formation of 3-amino-4-nitro-benzoquinone 1, 2-dioxime (II), substitution of -NHCH₂COOH with -NHOH is followed by dehydrative cyclization of -NHOH with the neighboring -NO₂ to form a benzofuroxane derivative (VII) which undergoes reduction to an o-quinone dioxime derivative, and introduction of an NH₂ group into the 3-position at about the same time.

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Several isopropylantipyrine (IA) derivatives were synthesized in order to develop their new biological activities and depress the side effects of IA. Among these compounds, especially, ephedrine-IA (EIA) possessed much stronger inhibitory actions to histamine and anaphylactic shocks of isolated guinea pig ileum, rat erythrocyte hemolysis, and polymorphonuclear leukocyte (PMN) chemotaxis than the mixture of IA and ephedrine, other IA derivatives and aminopyrine, but EIA was similar to IA in analgetic and antipyretic actions. LD₅₀ (oral) of EIA is 3.48±0.39 g/kg in mice, and EIA did not show the toxic behavior of ephedrine and any side effects in mice treated for 8 weeks. When ³H-EIA was administered orally to rats, about 30% of the given ³H was absorbed from digestive system in 30 min and about 42% in 6 hr, more than 85% of it was excreted in the feces and urine during 3 days, and about 15% was also excreted in the bile. The highest concentration of ³H in most organs was found 3 hr after oral administration and ³H was concentrated in the small intestine, stomach and liver. About 15% of ³H excreted in urine within 24 hr after the administration was identified as an unaltered ³H-EIA.

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The components of shoot oils of Magnolia Kobus DC. obtained from various localities in Japan were examined. The yield of oil was 0.05-0.23% and the composition of the oils was slightly defferent in each case. The characteristic constituents of these oils are d-limonene, p-cymene, 1, 8-cineole, d-nerolidol, and l-camphor.

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A new trisaccharide was found in Polygala senega L.var. latifolia TORAY et TGRAY (Polygalaceae), and its structure was determined as 1, 5-anhydro-[O-α-D-galactopyranosyl (1→2)-O-α-D-galactopyranosyl-(1→2)]-D-glucitol. Another trisacchride was assumed to be arabinosyl-α-D-galactosyl-D-glucose.

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The cleavage reactions of methylenedioxy group in erythrinan alkaloids by metallic sodium in liquid ammonia were examined. The reactions for cis- (16) and trans-15, 16-methylenedioxyerythrinanes (17), which were synthesized, were found to proceed in two directions and the corresponding 15-(20) and 16-hydroxyerythrinanes (21), characterized as their O-methyl ethers (22 and 23), were obtained. On the other hand, tetrahydroerythraline (30) was cleaved under the same condition to afford only the 15-oxygenated compound whose O-methyl ether was identical with 16-deoxytetrahydrocrysodine (27) derived from erysodine (24).

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Isolation and some properties of a new acidic amino acid, named quisqualic acid, along with arginine, trigonelline and γ-amino butyric acid from Quisqualis Fructus (Japanese name "Shikunshi") are described. Also, aspartic acid, glutamic acid, serine, glycine, proline, leucine, valine, alanine, threonine, asparagine, histidine, and lysine were detected by paper chromatography and paper electrophoresis.

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A new catechin dimer (II), (-)-epiafzelechin-(-)-epicatechin-4, 8 (or 6)-dimer, was isolated from the roots of Boehmeria tricuspis MAKINO (Urticaceae) together with (-)-epicatechin (I) and (-)-epicatechin-(-)-epicatechin-4, 8-(or 6)-dimer (III).

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The selective acetylation of 17α, 20, 20, 21-BMD-pregnan-5α, 6β, 11β-triol-3-one (IV), derived from cortisone, was led to its 6β-acetate (V). A solution of V in CHCl₃ containing EtOH (0.7%) was treated with HCI gas to give 17α, 20, 20, 21-BMD-4-pregnene-6α, 11β-diol-3-one-6-acetate (VIa) and in pure CHCl₃ to give 6β-derivative (VIb). The hydrolysis of 6-O-acetate of VIa with K₂CO₃ followed by succinylation with succinic anhydride gave 17α, 20, 20, 21-BMD-4-pregnene-6α, 11β-diol-3-one 6-hemisuccinate (VIIIa). 6α-Hydroxy- cortisol 6-hemisuccinate (IXa) was obtained by the hydrolysis of the bismethylenedioxy protecting group in VIIIa with 50% AcOH. 6β-Hydroxycortisol 6-hemisuccinate (IXb) was also obtained from VIb by the same procedure.

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α-Diphenylmethylene-(1a) and β-diphenylmethylene-γ-butyrolactone (2a) were synthesized by the reduction of 1-ethyl 4-hydrogen 2-diphenylmethylenesuccinate (4a), 2-diphenylmethylenesuccinic acid (5a), 2-diphenylmethylenesuccinic anhydride (6a), and 4-ethyl 1-hydrogen 2-diphenylmethylenesuccinate (7a) under controlled conditions. α-Diphenylmethylene-β-methyl-(1b) and β-diphenylmethylene-α-methyl-γ-butyrolactone (2b) were also synthesized by a similar method. 1-Benzyl-4-benzylamino-4-diphenylmethyl-2-pyrrolidone (11) and 1-benzyl-4-diphenylmethyl-3-methyl-Δ³-pyrrolin-2-one (15) were obtained as major products by the reaction of corresponding lactones (2a ana 2b) with benzylamine.

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A new method for determining effective surface area of organic drug substances was developed by measureing the initial dissolution rate. The principle is based on comparison of the initial rate of the sample powder with those in the calibration curve predetermined with disks of the same powder which has a constant surface area. The procedure and apparatus used were similar to those previously reported. The method was tested with phenacetin and sulfanilamide powder, and its results were satisfactory to prove that the method is accurate, simple, and widely applicable. Also, goodness of the method that directly gives the effective surface area for dissolution was verified by comparing the results with those by conventional methods for particle size determination, such as sieve analysis and gas adsorption measurement.

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Syntheses of non-symmetric 2, 2'-dipyridyl, 2, 2'-pyridylquinoline, and pyridylphenanthroline derivatives were attempted by the use of N-oxides of pyridine, quinoline derivatives, and phenanthroline, and phatinated palladium-carbon catalyst. It was considered from its results that examinations should be made on the relative values of A and B routes in order to obtain the objective compound (I).

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A phenolic glucoside was isolated from the acetone extract of a chinese crude drug, Heshouwu ( ?? ?? ?? ), the roots of Polygonum multiflorum THUNB. (polygonaceae), and it was elucidated as 2, 3, 5, 4'-tetrahydroxystilbene 2-O-β-D-glucoside (I).

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Determination of conjugated bile acids in bear gall by thin-layer chromatography was examined, using an apparatus equipped with a flame ionization detector. Neutral lipid-free methanolic extract from bear gall was spotted on a chromatographic rod, a fine rod of quartz coated with silica gel, and developed, Acids were separated quantitatively by means of multiple development with toluene : acetic acid : water (10 : 10 : 1) and hexane : diisopropyl ether : acetic acid (2 : 1 : 1). The calibration curve was constructed with the use of taurolithocholic acid as an internal standard.

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Three kinds of novel 3, 4-bis(4-substituted phenyl)-2-furaldehydes were obtained by formylation of 3, 4-bis (4-substituted phenyl) furans (R=H, OCH₃, CH₃) with phosphorus trichloride in dimethylformamide. Novel methyl 3, 4-diphenyl-5-formyl-2-furancarboxylate was synthesized from methyl 5-chloromethyl-3, 4-diphenyl-2-furancarboxylate by the Kronke-Borner method. Condensation of 3, 4-diphenyl-2-furaldehyde and acetaldehyde resulted in the formation of a novel 3-(3, 4-diphenyl-2-furyl) acrolein. 3, 4-Diphenyl-2-furaldehyde was submitted to the Cannizzaro, Perkin, Wittig, reduction reactions, and condensation with amines. The corresponding Schiff's bases were obtained by the reaction of 3, 4-bis (4-methoxyphenyl)-2-furaldehyde and amines. The Schiff's base-type compounds and vinylene-type compounds thereby obtained were tested for their antibacterial activity and a wide antibacterial spectrum was found in some of the Schiff's base-type compounds of 3, 4-bis (4-substituted phenyl)-2-furaldehydes and aminoguanidines.

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An improved method for microassay of lipase activity is described. The method is an application of fluorometric titration to fatty acids. Fatty acids liberated from an olive oil emulsion on treatment with lipase at 37° for 5-20 min are extracted with Dole's extraction mixture and an aliquot of the heptane solution of the acids, containing at least 0.1-2.0μeq, is titrated with 0.01_N isopropanolic sodium hydroxide using isopropanol solution of umbelliferone as a fluorescent indicator. Constancy of the reaction rate is obtained by 40-min incubation. Short incubation time, precision, and sensitivity make this method suitable for the assay of lipase in body fluid. Preliminary application of this method to some samples of serum, bile, and pharmaceutical preparations is mentioned.

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A general method for synthesis of L-α-amino acid choline ester was devised by way of (a) condensation of L-α-benzyloxycarbonyl-amino acids (I) with β-dimethylaminoethyl chloride (II), followed by methylation with methyl bromide or methyl p-toluenesulfonate, and (b) condensation of L-α-benzyloxycarbonyl-amino acids (I) with choline p-toluenesulfonate (VI) by dicyclohexyl carbodiimide. Resulting L-α-benzyloxycarbonyl-amino acid choline esters (IV) were treated with 25% solution of hydrogen bromide in glacial acetic acid to give the desired L-α-amino acid choline dibromides (VII).

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Examinations on the essential oils of Magnolia Kobus DC. were begun in order to compare with that of M. salicifolia MAXIM. from the viewpoint of chemical systematics. Examinations were made on the constituents of the essential oils of the plants cultivated in the garden of Ikeda from the seeds obtained from the Takarazuka Botanical Garden. The yield of the shoot oil was 0.08-0.14% for the fresh materials. The characteristics of this oil are abundant presence of d-limonene, p-cymene, l-camphor, and d-nerolidol. The absence of phenol ethers was also noted.

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The reactions of 2, 2, 6, 6-tetrachlorocyclohexanone (1) with bases were examined. The uses of sodium alkoxide in dimethylformamide and formate salts in formic acid were found to afford 2-alkoxy-3-chlorophenols and 2, 2, 6, 6-tetrachlorocyclohexanol, respectively, in excellent yields. A facile synthetic route for 2-chlorocyclopentanone was also proposed.

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The essential oil of Magnolia Kobus DC. var. borealis SARG. from Sapporo, Hokkaido, was examined. The yield of shoot oil was about 0.2% and that of branchets was 0.03%. The characteristic constituents of these oils are limonene, 1, 8-cineole, p-cymene, l-camphor, and α-terpineol.

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In the survey of the root constituents of a Japanese valerian indigenous to Tobishima Is., west of northern Honshu, a number of sesquiterpenoids have been isolated or detected. This valerian is characterized by containing sesquiterpenoids of the valerane skeleton (in particular, valeranone) in large quantities, but those of the kessane skeleton in minute amounts. The absence of kessyl glycol is especially noteworthy.

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Hydrolysis of Ginseng saponins with crude preparations of hesperidinase, naringinase, pectinase, cellulase, amylase, and emulsin was examined. Among these crude enzymes, crude hesperidinase, naringinase, and pectinase showed rather high activities. Crude hesperidinase hydrolyzed ginsenoside-Rg₁ to give its genuine sapogenin, 20(S)-proto-panaxatriol (II) and glucose in almost quantitative yield. Whereas, a mixture of ginsenosides-Rb₁, -Rb₂, and -Rc gave compound K (=20-O-β-glucosyl-20(S)-protopanaxadiol) (III) as a main product with this crude enzyme preparation. Since the purified hesperidinase could not hydrolyze these saponins, the hydrolysis took place with the other glycosidase present in this crude preparation. The crude hesperidinase also hydrolyzed the saponins of Ginseng leaves, and the saponins of the roots of Panax japonicus (excepting chikusetsu saponin-III) to yield the corresponding sapogenins. The diterpene glucoside, stevioside (V), yielded its genuine aglycone, steviol (VI), in almost a quantitative yield with this enzyme preparation.

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