By the use of pyrophosphoryl chloride, 21-hydroxy-20-oxosteroids were phosphorylated in one step in quantitative yield. When the reaction was carried out on prednisolone at a higher temperature, a dienonephenol rearrangement and a simultaneous pinacolic shift took place resulting in the formation of 3, 21-diphosphate of C-nor-9, 10-secosteroidal aldehyde (A) as a by-product. This compound showed a cardioinhibitory and vasoconstricting activity and a strong toxicity to rabbits.

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Heating of 2-cyano-1-tetralones (I) with formamide and phosphoryl chloride afforded 4-amino-5, 6-dihydrobenzo [h] quinazolines (II). 4-(2-Hydroxyethylamino)-5, 6-dihydrobenzo [h] quinazolines (III) were obtained from II with ethylene chlorohydrin, and gave 1, 2, 4, 5-tetrahydrobenz [h] imidazo [1, 2-c] quinazolines (V), i.e., 11, 13, 15-triazasteroid compounds, on treatment with sodium carbonate after refluxing with phosphorus tribromide.

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The effect of N-perfluoroacyl groups and ester groups on the resolution of diastereoisomeric N-perfluoroacylprolyl-amino acid esters with respect to retention times and separation factor was investigated in detail on OV-1 column. Relation between separation factors of amino acids and CF₂ groups in N-perfluoroacylprolyl groups and CH₂ groups in primary alcohols was discussed. It was concluded that the order of elution of racemic amino acids was not influenced by N-perfluoroacyl groups or the ester groups.

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For investigation of the structure-activity relationship of xanthine derivatives, 2, 4-dioxo-1, 2, 3, 4-tetrahydropyrrolo [2, 3-d] pyrimidines (A), which belong to 7-deazaxanthine derivatives, were prepared from the corresponding 6-aminouracils and chloroacetaldehyde, and then were catalytically reduced to give 2, 4-dioxo-1, 2, 3, 4, 5, 6-hexahydropyrrolo [2, 3-d]-pyrimidines (B). A new method for synthesis of compounds (A) was found by heating 6-hydrazinouracil derivatives with aldehydes or ketones. Diuretic, cardiac, and central nervous system stimulating activities of compounds (A and B) were tested to be compared with those of caffeine. Compounds (A and B) showed caffeine-like activities.

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The reaction of epoxides with several conjugated C-N double bond compounds was attempted. Aromatic aldazines were found to undergo criss-cross cycloaddition toward epoxides. On the other hand, aromatic ketazines gave the oxazolidines formed by the cycloaddition of one molecule of epoxides to one of the C-N double bond of the ketazines. Moreover, in the reaction with N, N'-bis-benzylidene-p-phenylenediamine and N, N'-p-phenylene-bis-methylidenaniline, cycloaddition of two molecules of epoxides to two C-N double bonds of these compounds occurred to give the corresponding p-phenylenebis-oxazolidines.

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The roles of the rat liver cytoplasmic Y and Z binding proteins and T binder on the hepato-biliary transport of some organic anionic compounds, four non-metabolizing sulfonic acid dyes, bromphenol blue (BPB), bromthymol blue (BTB), amaranth (AM) and tartrazine (TZ) and a non-metabolizing carboxylic acid, p-acetylaminohippuric acid (PAAH) which are excreted into bile by an active transport system were investigated. No free form of these compounds was detected in the rat liver cytoplasmic fraction by means of the gel filtration of the liver 100000 g (av.) supernatant using a column of Sephadex G-75 following the intravenous administration of these compounds, and these compounds were in common bound to Y binding protein. In addition BPB and BTB of which the liver/plasma concentration ratios were greater than one were bound to Z binding protein but AM, TZ and PAAH of which the liver/plasma concentration ratios were equal or less than one were not bound to Z binding protein. When sulfobromophthalein, 5 times molar ratio to BPB, was pre-administered to rats, the binding of BPB to Y binding protein was decreased 65% but the binding to Z binding protein was reversely increased 27%. Kinetical experiment showed that the binding of BPB to Y binding protein followed a hyperbolic curve and reached maximum at 15 min after the administration whereas the binding to Z binding protein was more slowly increased.

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Two flavonol glycosides, I and IIf, were isolated from the fresh leaves of Saxifraga stolonifera MEERBURG (Saxifragaceae). I is a new flavonol glucoside, C₂₁H₂₀O₁₂·H₂O, mp 264°, and was named saxifragin. The structure of saxifragin (I) has been determined as quercetin-5-β-D-glucoside by chemical and spectral means. II, pale yellow needles, mp 186-190°, was identified as quercitrin by direct comparison with an authentic sample.

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In order to find pharmacologically active azetidine derivatives, convenient procedures for the synthesis of 3-substituted azetidines have been investigated. 3-Azetidinyl mesylates (IV), prepared by treatment of azetidin-3-ols (I) with sulfenes, were shown to be useful intermediates for the synthesis of 3-substituted azetidines, 3-amino-, 3-cyano-, 3-guanidinoazetidines (V, VI and VIII) and azetidine-3-carboxylic acids (VII) via VI. 1-Cyclohexyl-3-guanidinoazetidine showed an excellent antihypertensive activity.

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The stereochemical course of diastereomeric 1-cyclohexyl-2-phenyl-3-azetidinyl mesylates (IVa and Va) was investigated with nucleophilic reagents. The retention of the configuration in these reactions and ring contracted products in some cases of reactions of IVa were observed. The presence of 1-azabicyclobutonium ions (VII and VIII) as intermediates in these reactions has been proposed from these results. The stereochemistry of 3-substituted azetidines obtained by nucleophilic reactions via IVa and Va was established by chemical evidence and nuclear magnetic resonance studies with a shift reagent, Eu (DPM)₃.

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Reactions of various substituted quinoline 1-oxides with cyanogen bromide in ethanol were investigated. The corresponding ethyl N-(8-quinolyl) carbamates were formed in most cases, but their yields were rather low except reactions of N-oxides of 4-quinolinol (If), 4-aminoquinoline (Ig), 2-quinolinol (IXf), 5-nitroquinoline (XXVI) and 6-chloroquinoline (XXX). In addition to 8-quinolylcarbamates, 2-quinolylcarbamates (VIc and VIe) were obtained from reactions of 4-ethoxyquinoline 1-oxide (Ic) and lepidine 1-oxide (Ie), and further the 6-quinolylcarbamate (VII) was also isolated in the latter case. The reaction of 4-quinolinol 1-oxide (If) gave the 3-quinolylcarbamate (VIII) as the main product besides 8-quinolyl derivatives, IIf and IIi. 2-Imino-1, 2, 4-oxadiazolo [2, 3-α] quinoline hydrobromide (XVI) was produced without the participation of ethanol in a good yield of 65% from the reaction of 2-aminoquinoline 1-oxide (IXg). From 8-ethoxycarbonylaminoquinoline 1-oxide (XX), a small amount of 2, 8-bis (ethoxycarbonylamino)-quinoline (XXI) was obtained. The features and mechanisms of some reactions were also discussed.

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Δ¹-Tetrahydrocannabinol (Δ¹-THC, Ia) was oxidized with selenium dioxide to yield 7-hydroxy-(VI), 6α-hydroxy-(VIIa), 6β-hydroxy-(VIIIa) and 6-oxo-Δ¹-THC (IX) together with cannabinol (CBN, III), 7-hydroxy-(X), 6-hydroxy-(XI) and 7-oxo-CBN (XII). Δ⁶-THC (IIa) was transformed merely to 7-hydroxy-(IVa) and 7-oxo-Δ⁶-THC (Va) in a similar manner. Individual products isolated are well defined mainly on the spectroscopic evidences. The oxidation of Ia favors the endocyclic allyl methylene rather than the exocyclic allyl methyl while the reverse is the case with IIa. Such a sharp contrast shown in their reactivities as mentioned above must be interpreted in terms of the steric interference at the reactive center.

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Reaction of Oxazolium salts (IX) with dialkyl acylphosphonates (IV) in the presence of triethylamine afforded 1, 4-oxazin-3-one (XII) and/or azetidin-2-one derivatives (XIII). In the reaction of IXa-b with IVa, stable reaction intermediates (Xa-b) were isolated. Some of the products were confirmed to be identical with authentic samples synthesized by an independent pathway. The mechanism of this novel reaction involving ring expansion and ring contraction, substituent effects on the reactivity, and stereochemistry of XIII are discussed.

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2-Pyridylisocyanate (IIa) reacted with diketene to give 3-acetyl-2-hydroxy-4H-pyrido [1, 2-α] pyrimidin-4-one (IIIa), 3-acetyl-4-hydroxy-6-methyl-1-(2-pyridyl)-2-pyridone (IVa), and 2-methyl-4H-pyrido [1, 2-α] pyrimidin-4-one (Va). On the other hand, reaction of diketene with 2-pyridylisothiocyanate (IIb) afforded only 3-acetyl-2-mercapto-4H-pyrido-[1, 2-α] pyrimidin-4-one (IIIb). Reaction of ketene with IIa and IIb gave rise to 2-acetoxy-4H-pyrido [1, 2-α] pyrimidin-4-one (VIa) and 2-acetylthio-4H-pyrido [1, 2-α] pyrimidin-4-one (VIb), respectively.

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The nitration of 11 gave 14-nitro (12) and 13-nitro ester (10), in ca. 1 : 1 ratio. Next, some methyl 7-oxo-derivatives having a substituent in 12 position (18, 19, 21, and 23) were smoothly nitrated to give selectively the corresponding 13-nitro-deisopropyl ester, and the nitration of the corresponding 14-substituted ester (26) gave a mixture consisting of three compounds. On the contrary, a nitration of 39 gave only 14-nitro product (40). Finally, a nitration of 41 gave an addition product (42) to the double bond.

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The nitration of methyl dehydroabietate derivatives having a hydroxyl and methoxyl group as in methyl 12-hydroxy-dehydroabietate and methyl 12-methoxy-dehydroabietate gave only 11-substituted compound. However, methyl 12-bromo-dehydroabietate was nitrated in different behavior and gave more complex result.

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According to the relationship between the rate constant of bond-scission in the quasiequilibrium theory of mass spectra and the heat of reaction, the molecular orbital theories for all valence electrons were examined in the mass spectra of aliphatic amines, alcohols, an aldehyde, and a ketone. Among those theories, the MINDO/2 and its unrestricted methods were shown to be best fitted for the purpose. It was shown that the scissionprobability can be predicted from the calculated heat of reaction in an almost quantitative exact.

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Two new aloesin esters were isolated from the fresh leaves of Aloe arborescens MILL. var. natalensis BERGER and their structures were established to be 2"-O-p-coumaroylaloesin and 2"-O-feruloylaloesin on the basis of chemical and spectral evidences. These esters are the first naturally occurring 2"-O-acylated C-glucosyl compounds.

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A fluorescent probe specific for sulfhydryl group was synthesized. Conformational change in HSA was observed by fluorescence spectral shift on binding. From the experimental evidences of urea denaturation and fluorometric pH titration, phenylbutazone or secobarbital binding was concluded to induce the conformational change of HSA from the native state to a more expanded form.

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Carbon-13 nuclear magnetic resonance spectra of thirty-two kinds of 5, 5-disubstituted barbituric acid derivatives were measured. Two conclusions were obtained from analyses of these spectra. (1) The additive law is applicable to chemical shifts of sp³-hybridized carbons. (2) Hammett's constant σ in Hansch analysis can be replaced by a quantity A expressed by the value related to chemical shifts of the 5-position carbon.

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The crystal structure of a 1 : 1 complex of aminopyrine and cyclobarbital was determined from X-ray diffraction data. The triclinic unit cell dimensions are a=12.877, b=14.357, c=7.199Å, α=91.49°, β=104.42°, and γ=100.05°. The space group is P1 ; Z=2. The intensity data were collected on a single crystal diffractometer and the structure was solved directly by the symbolic addition procedure. Molecules in the crystals were arranged in the series of aminopyrine-cyclobarbital-cyclobarbital-aminopyrine linked by hydrogen bonds. A partially disordered structure was observed of the cyclobarbital molecule.

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Action patterns of dextranase from P. funiculosum on the substrate were investigated. Isomaltodextrins and their reduced derivatives (isomaltodextrinols) were used as the substrate. Comparison of the enzymatic digestion products did lead the conclusion that the attack points of the dextranase on isomaltodextrin were primarily at second and third glucosidic linkage from the non-reducing end of the substrate. On the increase of polymerization degree of substrate, the enzyme hydrolyzed also at fourth or fifth glucosidic linkage from the non-reducing end. The inhibition of dextranase hydrolysis reaction by some mono-and disaccharides was also investigated. It was found that C-2 and C-6 positions of glucosidic residue were primary positions to effect the binding to active center of the enzyme ; C-2 position was likely to effect the binding affinity and C-6 position was to exert the binding site.

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The phlogistic activity of secalonic acid A (S.A.A) was examined, isolation of which has recently been completed from Aspergillus ochraceus. S.A.A. gave rise to a biphasic increase of vascular permeability in the abdominal cavity of mice by intraperitoneal application in the dye-leakage test. The peak of this biphasic increase was at about 1 hr and about 18 hr respectively. Exudation of leucocyte in the abdominal fluid was remarkable in the delayed phase. S.A.A also induced intensive sustained edema in a rat paw by a single local application, making the edema last more than 10 days. Pus-like thick fluid and a scab developed around the injected position 3-4 days after the injection of S.A.A and lasted as similarly as edema did. The increased vascular permeability and the rat paw edema were inhibited by aspirin, hydrocortisone and indomethacin in appropriate doses. The phlogistic activity of S.A.A considerably decreased when its chemical structure was changed. The effect of the abdominal fluid exuded by intraperitoneal application of S.A.A was examined on the isolated preparation of guinea pig ileum, rat duodenum and rat estrous uterus, respectively. The fluid contracted the ileum but this activity was supposed not to be due to S.A.A itself.

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Benzyne reaction of 1-(2-bromo-4, 5-dimethoxybenzyl)-1, 2, 3, 4-tetrahydro-6, 7-dimethoxy-2-methylisoquinoline (6) using sodium methylsulfinylmethanide afforded 5, 6, 12, -12a-tetrahydro-2, 3, 9, 10-tetramethoxy-12a-methyldibenzo [b, g] indolizine (7). 1-(3-Bromo-4-methoxybenzyl)-1, 2, 3, 4-tetrahydro-7-hydroxy-6-methoxy-2-methylisoquinoline (9) also gave 5, 6, 12, 12a-tetrahydro-2-hydroxy-3, 9-dimethoxy-12a-methyldibenzo [b, g] indolizine (11) under the similar conditions.

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The reaction of 3-picoline 1-oxide (VI) with phenyl isocyanate (I) in dimethylformamide at 110° gave the cycloadducts VII and VIII in 33.7 and 24.1% yield, respectively. The reaction at 150° gave 2-anilino-3-methylpyridine (IX) and 2-anilino-5-methylpyridine (X), along with a small amount of VII. Hydrolysis of VII and VIII in alcoholic potassium hydroxide affords IX and X, respectively. The structures of VII and VIII were discussed in the light of spectroscopic data. IX and X were identified by comparison with the authentic samples prepared by an alternative route.

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Three kinds of analogues of glycyrrhezin (ester-, ether-and ester-ether-type glycosides) were synthesized by coupling gentio oligosachacrides to the carboxyl group, the hydroxyl group and both of its aglycone, and their hydrophilic properties were compared. The solubilities in water as well as water-oil partition coefficients increased with the increasing number of the D-glucose unit, and the introduction of sugars to the hydroxyl group was more effective to the solubilization of the aglycone than to the carboxyl group.

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Crystalline coriose which forms α-furanose yielded a product (III) at the initial stage of the trimethylsilylation, and other two products (IV and V) upon prolonged trimethylsilylation. Increase of IV and V at the expense of III was observed in gas-liquid chromatography. These products were isolated by distillation and chromatography, and the structures of III, IV, and V were elucidated to be 1, 2, 4, 5, 7-pentakis-O-trimethylsilyl-α-coriofuranose, 1, 2, 3, 4, 5, 7-hexakis-O-trimethylsilyl-α-coriofuranose, and 1, 2, 4, 5, 6, 7-hexakis-O-trimethylsilylcoriose of keto-form, respectively.

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15α-Hydroxy-ent-kaur-16-en-19-oic acid (IX) (=grandifloric acid) and a new diterpene acid, 17-hydroxy-ent-kaur-15-en-19-oic acid (X) were isolated as the minor constituents from the roots of Aralia cordata THUNB. The final identification of IX and the structural elucidation of X were accomplished by preparation of IX and the methyl ester of X (XI) from methyl ent-kaurenoate (XII) by means of the double bond isomerization and the dye-sensitized photooxidation.

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Identification of the radioactive metabolite of PaS³⁵SO₃H in B. bifidum N4 was undertaken. The strain was incubated with (PaS³⁵SO₃)₂ Ca for 60 min at 37° in CySS (-) MGM, and after removal of the bacteria, the medium which showed a new radioactive peak on a chromatogram was neutralized and reacted with NEM or HCHO and PABA. By this treatment, the peak disappeared and in turn a new peak emerged in both cases. They were identified as NEM-³⁵SO₃H and SMPABA-³⁵S by PEP (1 M HCOOH, pH 2) and radiochemical crystallizations. In the absence of the bacteria, the peak of the radioactive metabolite was not produced by the incubation of (PaS³⁵SO₃)₂ Ca with CySS (-) MGM, neither produced NEM-³⁵SO₃H from (PaS³⁵SO₃)₂ Ca by NEM treatment. Furthermore, transformation of ³⁵SO₄^2- to H³⁵SO₃^- by the strain was not observed. These results demonstrate the production of HSO₃^- from PaSSO₃H by B. bifidum N4.

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Propranolol concentrations in the blood was determined after rapid femoral vein and 50 min portal vein infusion of several doses to rats. No propranolol appeared in the systemic circulation after intraportal infusion of doses less than approximately 2 mg/kg. The mean bioavailability of propranolol was 42% in a dose of 5 mg/kg and increased progressively with increasing dose. However, the area under the blood concentration-time curve after portal vein infusion of propranolol was found to vary with infusion rate. The hepatic elimination of the drug during the first pass through the liver after portal vein infusion was highly dose-dependent in lower doses, and highly rate-dependent in higher doses. Therefore, the bioavailability of the drug was dose and rate-dependent. However, in higher doses, it remained almost constant at a constant infusion rate.

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α, β-Unsaturated esters were made to react with N, N-dibromobenzenesulfonamide and formic acid in chloroform to give bromo-formyloxyesters. Methyl acrylate (1a), ethyl crotonate (2a), ethyl trans-cinnamate (3a), methyl tiglate (4a), methyl methacrylate (5a), and methyl phenylacrylate (6a) gave methyl 2-bromo-3-formyloxypropionate (1b), ethyl erythro-2-bromo-3-formyloxybutyrate (2b), ethyl erythro-2-bromo-3-formyloxy-3-phenylpropionate (3b), methyl erythro-2-bromo-3-formyloxy-2-methylbutyrate (4b), a mixture of methyl 3-bromo-2-formyloxy-2-methylpropionate (5b) and methyl 2-bromo-3-formyloxy-2-methylpropionate (5c), and methyl 3-bromo-2-formyloxy-2-phenylpropionate (6b) respectively in good yields.

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