A series of 4-substituted phenyl-(A, B) and 5-substituted 2-thienyl-(C) acetic acid derivatives were synthesized. Inhibitory activity of collagen-induced rabbit platelet aggregation of 29 compounds including A, B, C and the intermediate compounds of them was studied. Compounds (A-18, B-21 and -27) were inhibitory against platelet aggregation and the most potent compound (B-21) was more effective than aspirin.

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The distribution of mercury and selenium in subcellular fractions was examined to see effects of selenium on metabolism of mercuric chloride in rats. The subcellular distribution of mercury and selenium was changed greatly with the concurrent administration of them and decreased in soluble fraction and increased in nuclei and debris fractions. We found an interesting result that 56% of mercury existed in soluble fraction with the administration of mercury alone and only 1% of mercury with the concurrent administration of mercury and selenium. In this point, the molar ratio of mercury to selenium was about 1 : 1 in nuclei and debris, mitochondria and microsomes fractions, respectively. Amount of mercury in nuclear fraction prepared by the method of Chanda and others with the concurrent administration of mercury and selenium, was 9 times that with the administration of mercury alone. Furthermore, insoluble nonhistone protein fraction from nuclear fraction had 60% of mercury and in this fraction, amount of mercury per mg protein with the concurrent administration of mercury and selenium was about 13 times that with the administration of mercury alone. The behavior of mercury and selenium was also examined in the plasma. It was considered that mercury and selenium accumulated with the ratio of 1 : 1 in the plasma. We found that the gel filtration pattern of mercury in plasma protein on Sephadex G-200 chromatography was changed greatly and most of mercury was accumulated in some protein of high molecular fraction with the concurrent administration of mercury and selenium.

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The effects of frog heart inotropic substances on beating phenomena in cultured myocardial cells of neonatal rats were investigated. The beating rate and percentage of trypsin-dissociated cells were determined in Eagle minimum essential medium (MEM) supplemented with 10% bovine serum at 2 days in culture. The attachment and the spreading of cells were observed in Eagle MEM supplemented with 0.5% bovine albumin. The positive inotropic glycoprotein, Fr. A from calf heart, and its cyanogen bromide peptide, Fr. A-1, significantly increased the beating rate and percentage of single cells in their dosages to be effective on frog heart assay as well as epinephrine. Another positive inotropic lipoprotein, Fr. I-B from calf thymus, also increased the rate, but did not effect on the percentage like acetylcholine. Negative inotropic dipeptide, anserine, decreased the rate but not the percentage of single cells. In the beating rate of cell-cluster, Fr. A, Fr. A-1 and Fr. I-B showed accelerating effects in their concentrations of 10^-8M, 10^-7M and 10^-9M, respectively. The effect of Fr. I-B on cell-cluster was transitory 5 to 20 min after sample addition, and those of Fr. A and Fr. A-1 were relatively continuous up to 40 min. The chronotropic actions on cell-cluster by these three samples were not affected by the addition of propranolol. Fr. A significantly increased the attached cells and Fr. I-B greatly decreased the spreading cells, but both of them did not promote the spreading process of myocardial cells in their doses of improving the beating properties.

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Glycerol dehydrogenase was purified from Erwinia aroideae IFO 3830 by precipitation of acetone and ammonium sulfate, and chromatographies on diethylaminoethyl (DEAE)-cellulose, Sephadex G-200 and DEAE-Sephadex A-50. The purified enzyme was demonstrated to be homogeneous by disc electrophoresis. Optimum pH and temperature of this enzyme for glycerol oxidation was 10.5 and 50°, respectively. The glycerol dehydrogenase was stable over a pH between 6 and 9 at 5°for 15 hr, and showed more than 90% activity of the original under the conditions of pH 7.0 and 70°for 20 min. It was clarified that glycerol, glycerol-α-monochlorohydrin, 1, 2-propanediol and 2, 3-butanediol were good substrates for glycerol dehydrogenase from Erwinia aroideae. From the result of effect of sulfhydryl agents, it is suggested that this enzyme has a catalytic sulfhydryl group.

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On treatment of 2-p-chlorophenylthiazinothiamine (Ib) with hydrogen peroxide, 2-hydroxy-2-p-chlorophenylthiazinothiamine (IIb) was obtained. Similar reaction products of phenyl-and methylthiazinothiamine (Ia and Ie) were reinvestigated and found to be IIb analogues (IIa and IIe, respectively). Reactions of IIa, IIb or IIe with acetic anhydride afforded the corresponding N-(2-methyl-4-aminopyrimidin-5-yl) methyl-N-(2-acetylthio-4-amino-1-methyl-1-butenyl) aryl (or methyl) oxalamide (IIIa, IIIb or IIIe, respectively). Treatment of 2-o-tolylthiazinothiamine (Ic) with hydrogen peroxide gave N-[1-(2-oxido-1, 2-oxathiolan-3-ylidene) ethyl]-N-[(2-methyl-4-aminopyrimidin-5-yl) methyl]-o-tolyloxalamide (VIIIc) as a major product and similar treatment of o-methoxyphenylthiazinothiamine (Id) with hydrogen peroxide gave 1-(2-methyl-4-aminopyrimidin-5-yl) methyl-2-methyl-3-(2-hydroxyethyl)-4-hydroxy-4-(2-methoxyphenyl)-⊿²-pyrrolin-5-one (XV). Oxidations of Ia, Ic and Id with m-chloroperbenzoic acid also gave VIIIc and the corresponding VIIIc analogues (VIIIa and VIIId, respectively). The mechanisms of these reactions are discussed as shown in Chart 2.

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The biosynthetic origins of pyrindicin, a metabolite of Streptomyces griseoflavus var. pyrindicus, have been investigated by the use of ¹³C nuclear magnetic resonance spectroscopy. It has been established that pyrindicin is derived from five acetates and one propionate.

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In order to analyze the renal handling of drugs under more suitable conditions to enable clinical application, renal clearance method based on computer analysis after administering a single dose of a drug was developed in rabbits. Phenolsulfonphthalein, sulfamethoxazole, sulfanilamide, and sulfamethizole which present characteristically different renal handling were studied, and it had been demonstrated that the results of analysis of our proposed model agreed well with the data obtained by combining the clearance experiments of constant-infusion technique with inhibitory experiments using iodopyracet. The order of reabsorption fraction was similar to that of the partition coefficient of these drugs. The renal tubular reabsorption of these drugs was dependent upon nonionic diffusion which could be explained by lipoid solubility of the drug, while tubular secretion could be explained by active transport that conformed to the Michaelis-Menten equation. Further, it was presumed that the tubular secretion of these drugs was dependent upon the unbound drug concentration in plasma. From these results, a comprehensive scheme which elucidated the renal handling of these four drugs was proposed. In this method as neither constant infusion nor massive dose loading of secretion inhibitors were used, the experiment was conducted under comparatively less harsh conditions than the standard renal clearance and inhibitory experiments. Thus, it is felt that this method can be safely applied to humans.

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Electrocorticograms in restrained rats and in restrained and water (35°)-immersed rats showed a series of cycles fluctuating between low voltage rhythmical waves and high voltage irregular waves including spindles and spikes during a 6-hr stress period, whereas those in restrained and water (25°)-immersed rats showed a succession of low voltage rhythmical waves whose initial increased frequency gradually decreased below the original levels as the stress period was prolonged. Hippocampal electrical activities fluctuated in parallel with the cortical activities. A specific gastric motility, a severe gastric ulceration, and a marked hypothermia were observed only in the restrained and water (25°)-immersed rats. Acute adrenalectomy in the restrained and water (25°)-immersed group more decreased frequencies of the rhythmical low voltage waves and induced abnormal waves such as discharges and wave flattening with high mortality. These changes could be retarded by epinephrine or corticosterone administration but not by ACTH administration.

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The microscopic distribution of ¹⁴C-diltiazem in the dog kidney after renal arterial injection was studied by means of microautoradiographic technique. The highest silver grain density existed in the proximal and distal tubules, and the ascending loop of Henle. The definite accumulation of the radioactivity in the distal tubule and the ascending loop of Henle, which are involved in Na-transport, seems to be compatible with the observation that diltiazem affects directly on these segments, thus causing the diuretic action. The presence of radioactivity in the proximal tubule may also suggest that diltiazem has an influence on this tubule and increases the urinary volume.

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In order to clarify the steric mechanism for biotransformation of ⊿⁵-3β-hydroxysteroid into ⊿⁴-3-ketosteroid the metabolic fate of hydrogen at C-4 during conversion of cholesterol into cholestenone by 3β-hydroxysteroid oxidase has been investigated. Of three substrates required for this purpose 4α-d₁-cholesterol was prepared through 4-d₁-cholest-4-en-3β-ol tert-butyldimethylsilyl ether as a key intermediate. The substrate was incubated with the enzyme, and the content and locality of deuterium in resulting cholestenone were determined by inspection of the mass, nuclear magnetic resonance, and infrared spectra. The transformation products formed from 4α-and 6-deuterated cholesterols retained the label almost intact, while that derived from 4β-d₁-cholesterol showed ca. 50% retention of the heavy isotope at 6β. Incubation studies using 6β-d₁-cholestenone as a substrate implied that a 50% loss of the label would be ascribable in part to the exchange with the incubation medium under the enzymatic control. These results led to a definite conclusion that 4β-hydrogen was transferred stereospecifically to the 6β-position during biotransformation of cholesterol into cholestenone.

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The condensation of 5-amino-1, 3-dimethylbarbituric acid (I) with aromatic aldehydes gave 5-benzylideneamino-1, 3-dimethylbarbituric acids (II). Treatment of (II) with thionyl chloride afforded 2-aryl-5, 7-dimethyloxazolo [5, 4-d] pyrimidine-4, 6 (5H, 7H)-diones (IV) in good yields. The reaction of (IV) with phosphorus pentasulfide in pyridine provided 2-aryl-5, 7-dimethylthiazolo [5, 4-d] pyrimidine-4 (5H)-one-6 (7H)-thiones (VI), which were then converted to 2-aryl-5, 7-dimethylthiazolo [5, 4-d] pyrimidine-4, 6 (5H, 7H)-diones (VII) by the action of 30% hydrogen peroxide in acetic acid or thionyl chloride.

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Experiments were carried out in an attempt to elucidate the effects of various amino acids and their related agents in association with neurotransmitter substances on the morphine-induced Straub tail reaction (STR) in mice, using intracerebral injection technique. γ-Aminobutyric acid (GABA) and aminooxyacetic acid yielded significant decrement of the STR. Bicuculline provided the significant increment of the STR. DL-γ-Amino-β-hydroxybutyric acid and γ-guanidinobutyric acid had no influence on the STR. Glycine and taurine inhibited the STR significantly. L-Glutamic acid, L-aspartic acid, L-tyrosine and L-tryptophan had no influence on the STR. These results suggested the possibility that GABA, glycine and taurine may prevent the morphine-induced STR by means of an inhibitory action on the central nervous system in mice.

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Metabolites (XVIIa, b, c) of ubiquinone, phylloquinone and α-tocopherol, and their 2', 3'-dihydro (XXa, b, c), dicarboxy (XVIa, b, XXIIIa, b, c, XXIVa, b and XXVa, b) and 3'-demethyl (XXIa, b) derivatives were synthesized. During the synthetic studies of these compounds, we found that cis-4-acetoxy-1-bromo-2-methyl-2-butene (cis-III) was more reactive to nucleophiles than the corresponding trans isomer. γ-Vinyl-γ-butyrolactone (XII), which was a useful starting material for the synthesis of XXIa, b, was synthesized in one step from 1, 3-butadiene. The 3'-methyl group of XVIIa, b was not essential for the membrane-stabilizing activity in the rat-liver lysosome. Introduction of a carboxyl but not a carboxyl ester group into XVIIa, b resulted in a loss of the stabilizing activity.

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p-Toluenesulfonylethene reacted with iodine azide (IN₃) to give 2-azido-1-iodo-1-p-toluenesulfonylethane which was treated with 1, 4-diazabicyclo [2. 2. 2] octane (Dabco) to afford trans-2-azido-1-p-toluenesulfonylethene (3a). Similarly benzenesulfonylethene was converted to trans-2-azido-1-benzenesulfonylethene (3b). cis-and trans-2-Benzenesulfonyl-styrenes also reacted with IN₃ to give threo-(10) and erythro-2-azido-1-iodo-2-phenyl-1-benzenesulfonylethanes (6), respectively. Treatment of 10 with Dabco gave α-azido-β-benzenesulfonylstyrene (11), whereas 6 yielded β-iodo-β-benzenesulfonylstyrene (7). Heating 3 in ethanol at 50°produced dimeric compounds 13. Refluxing 11 in methanol or irradiation of 11 in a Pyrex tube gave 3-benzenesulfonyl-2-phenyl-1-azirine (14).

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Activated cyclophosphamide analogues having a 4-hydroperoxy-1, 3, 2-diazaphos-phorinane-2-oxide ring were synthesized by ozonolytic cyclization reaction of N-3-butenyl-phosphorodiamidates. Stereochemistries of the 1, 3, 2-diazaphosphorinane derivatives were investigated by proton magnetic resonance (PMR) spectroscopy. Both the chemical and PMR properties of these derivatives were similar to those of the corresponding 1, 3, 2-oxazaphosphorinane derivatives. The 1, 3, 2-diazaphosphorinane derivatives practically had no antileukemic activity against L1210-BDF₁ mice, providing a further evidence that the 1, 3, 2-oxazaphosphorinane ring of cyclophosphamide-related compounds is not replaceable by other ring systems for promoting antitumor activity.

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Two macroreticular polystyrene resins containing 8-hydroxyquinoline (oxine) groups were prepared. Resin I with oxine group attached to polystyrene via thioureido linkage was prepared by treating aminopolystyrene with 8-hydroxy-5-quinolyl isothiocyanate in a mixed solution of triethylamine and dioxane. Resin II was prepared by the reaction of chloromethylpolystyrene with zinc-oxine chelate in nitrobenzene. Resin I was highly selective for Hg (II) and Cu (II), but resin II was selective only for Hg (II) in the pH range below 5.

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An efficient asymmetric synthesis of D-α-amino acid derivatives (VI) has been achieved by alkylation of the Schiff base (III), prepared from glycine tert-butyl ester and (1S, 2S, 5S)-2-hydroxypinan-3-one (II), followed by hydrolytic cleavage of the alkylated Schiff base (V). The chiral source (II) was also recovered in good yield, allowing the proliferation of the asymmetry according to the cycle of the amino acid asymmetric synthesis shown in Chart 1.

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N-Acetylcytisine (2) was formed by an enzyme in Sophora seedlings from cytisine (5) in the presence of acetyl-coenzyme A. An acetyl-coenzyme A : cytisine N-acetyltransferase was reasonably stable upon a heat treatment at 90°for 15 min. Some other properties of the enzyme are described.

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Effect of particle size on absorption rate of rabbit and in vitro rate of dissolution was examined using sulfonamide powder drugs with the solubility ranging from 0.1 to 1mg/ml at 37°in suspension, and the following results were obtained. 1) The dependence of particle size on absorption rate constants and dissolution rate constants obtained with in vitro test under sink conditions showed the strongest correlation in the case of the lowest solubility drug of sulfadiazine and this relation decreased with an increase in solubility. 2) Blood level showed that the peak time of the aqueous solution was the fastest of all other samples for each sulfonamide as to the relative order of peak time after the administration of different dosage forms. This fact indicated that the dissolution rate was the rate-limiting step on the absorption of these sulfonamides. Effect of particle size on absorption rate was marked but its effect on the extent of bioavailability was almost constant irrespective of particle size. 3) Plot of percentage unabsorbed vs. time for each sulfonamide was linear and the lines for larger particle size had an inflexion about 3 hr after administration of the drug. This fact indicated that absorption of these sulfonamides was apparently first order and an inflexion for larger particle size was considered due to that passage of the drug in the gastrointestinal tract resulted in the change of dissolution environment. It was further considered that the time of an inflexion appearing at 3 hr corresponded to the gastric emptying time.

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A intracellular cytolytic substance, named monopodialysin was isolated from the mycelium of a Streptomyces strain designated as Streptomyces aureomonopodiales. The cytolytic substance was purified by extraction with acetone, followed by column chromatography on silica gel and gel filtration on a column of Sephadex LH-20. Monopodialysin was obtained as colorless plate (M. W. <1000) and contained C, H, and O as elements. It showed very high hemolytic activity for several kinds of mammalian erythrocytes and its activity was inhibited by soy bean lecithin or cholesterol but no sucrose. Protoplasts of Bacillus subtilis and lysosomes from ratliver were also lysed but monopodialysin displayed no antimicrobial activity.

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(±)-erythro-1-(2, 5-Dimethoxyphenyl)-3-diethylamino-n-butanol was resolved with d-and l-10-camphorsulfonic acid to (+)-and (-)-enantiomers. The optically active threo-enantiomers were synthesized from the optically active erythro-enantiomers. Their absolute configurations were determined by chemical interrelation.

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A theoretical model is introduced to describe the permeation of drug through membranes from systems containing micelles. Taking distribution of drug between aqueous and micellar phases into account, an equation is derived which describes the permeation profile of drug from the system. Applicability of the model was experimentally tested employing local anesthetics, one of five surfactants, and silicone or ethylene-vinyl acetate copolymer membrane.

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While nitrosation of 6-substituted 2, 4-dimethylpyrimidines with ethyl nitrite in liquid ammonia occurred preferentially at the 4-methyl group to give the corresponding pyrimidine-4-aldoximes, the same reaction of 1, 2, 4-trimethyl-6-oxo-1, 6-dihydropyrimidine (IV) afforded 1, 4-dimethyl-6-oxo-1, 6-dihydropyrimidine-2-aldoxime. Acylation of IV with ethyl benzoate and diethyl oxalate under basic conditions also gave α-(1, 4-dimethyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) acetophenone and ethyl 3-(1, 4-dimethyl-6-oxo-1, 6-dihydro-2-pyrimidinyl) pyruvate, respectively.

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The present paper describes the 1, 1-dichlorocyclopropane formation from highly electron-deficient carbon-carbon double bonds conjugated, in the main, with two cyano groups by allowing to react with trichloroacetic acid. β-Trichloromethylation was indicated in some cases. Path of the 1, 1-dichlorocyclopropane formation is presumed not to involve dichlorocarbene, but β-trichloromethylated intermediate.

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Amphetamine inhibited (E. C. 2. 6. 1. 7) kynurenine aminotransferase and (E. C. 3. 7. 1. 3) kynurenine hydrolase in mouse liver homogenates. It has been suggested that the inhibitory effect of amphetamine was due to formation of Schiff's base with pyridoxal phosphate, causing a reduction in the level of free pyridoxal phosphate, which is a co-factor for both enzymes. The inhibitory effect of amphetamine for both enzymes is of the competitive type.

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Role of intestinal mucus in the absorption of quinine and four water-soluble dyes, methylene blue, bromthymol blue, bromphenol blue, and phenol red, from the rat small intestine was investigated. Immediately after pretreatment with pH 6.5 buffer solution for 10 min and recovery period of 15 min after the pretreatment, absorption experiments were carried out at pH 6.5 using the in situ perfusion technique and in vitro uptake method by the everted sacs. Considering from the results of determination of protein and neutral sugar, it seems likely that mucus was secreted during the recovery period of 15 min after the pretreatment with pH 6.5 buffer solution. All drugs examined bound to mucus prepared from intestinal washings after the recovery period of 15 min. It is suggested that the mucosal surface of the small intestine, mucus layer, has an important role in the absorptive process of quinine and four water-soluble dyes.

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The structure of chelirubine (1c), one of the fully aromatized O₅-benzo [c] phenanthridine alkaloiks, was unequivocally established by total synthesis using photocyclization of the enamide (27). On this basis, the formulae (36), (37), and (38) were proposed for chelilutine, sanguirubine, and sanguilutine, respectively.

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The permeation patterns of iodine through a dimethylpolysiloxane membrane were studied using an all-glass permeation cell. The permeability of iodine was greater from solvents in which iodine is less soluble. In the presence of polyvinylpyrrolidone (PVP), the permeability decreased with storage period and with increasing amount of PVP. The permeability of iodine from a solution containing PVP decreased with increasing storage temperature prior to permeation studies. When iodide ions were added to the PVP-iodine system, the permeability of iodine became less than that in the absence of iodide ions. Further, the storage-time dependent decrease in permeability of iodine was much less in the presence of iodide ions. These observations suggest the decrease in the amount of permeable iodine in the system with time. This phenomenon is attributed to the acceleration of the hydrolysis of iodine in the presence of PVP.

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Two analogs of porcine motilin altered at position 8, [L-Ala⁸]-motilin and [D-Ala⁸]-motilin, were prepared by the conventional solution method via the corresponding sulfoxides (Met¹³) and evaluated in vitro for the ability to contract the duodenal muscle of rabbit. The D-Ala analog exhibited a higher potency than synthetic motilin, whereas substitution of glycine at position 8 with L-alanine decreased the biological activity to approximately 30% relative to the synthetic motilin.

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The effective production of streptothricin antibiotics by the addition of various amino acids (chemistry defined medium C) and the incorporation of ¹⁴C-labeled amino acids into streptothricin-C molecule (organic medium E) were studied with a strain of Streptomyces lavendulae OP-2. It was confirmed that proline, alanine, leucine, and arginine stimulated the production of antibiotics, and arginine and glycine promoted the mycelial growth. Of the amino acids tested, arginine was incorporated preferentially into streptothricin-C, but not tartaric acid or streptolidine itself. Approximately a one-half of radioactivity from arginine incorporated into the antibiotic was located in the streptolidine moiety. Furthermore, from the localization of ¹⁴C from arginine in the antibiotic molecule from four strains, a different pattern from that described above was observed. Localization of radioactivity in streptolidine moiety of racemomycin-A from S. lavendulae ISP-5069 was lower than that of β-lysine moiety, suggesting that biogenesis of streptolidine in streptothricins from S. lavendulae strains follows two pathways.

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Series of 3-alkylthio-5-(2-pyridyl)-1, 2, 4-triazoles and 1-picolinoyl-S-alkylisothiosemi-carbazides were prepared and their antimicrobial activities were tested. Of the twenty-two compounds synthesized and screened in vitro, 3-pentylthio-5-(2-pyridyl)-1, 2, 4-triazole, 1-picolinoyl-S-butylisothiosemicarbazide, 1-picolinoyl-S-pentylisothiosemicarbazide, and 1-picolinoyl-S-hexylisothiosemicarbazide were the most active against M. tuberculosis H₃₇Rv.

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3-Phenyl-4-(β-and-α-D-ribofuranosyl) pyrazoles (1a) and (2a) have been synthesized from 2, 3, 5-tri-O-benzoyl-D-ribofuranosyl bromide (3) by the substitution of 3 with bisphenylethynyl) mercury (4a) into 1-phenyl-2-(2, 3, 5-tri-O-benzoyl-β- and -α-D-ribofuranosyl) ethynes (5a) and (6a) and subsequent addition reaction with diazomethane. Ethynylation of 3 with 4a have furnished a mixture of 5a and 6a, however, with phenylethynylcopper (4b) the ketal (7a) was formed together with 5a. The configuration of the anomeric carbon of the major product (5a) was proved by its permanganate oxidation into the known tri-O-benzoylallonic acid (5d). The nuclear magnetic resonance spectra of the 2, 3-O-isopropylidene ribofuranosyl derivatives (9a-d) and (10a-d) have shown that the coupling constant of the proton at the anomeric carbon is approximately 4 Hz in the 1-α-substituted anomer, and, on the other hand, almost negligible in the 1-β-substituted anomer. Both acetylenic compounds (5a) and (6a) were converted into ribosyl pyrazole (5f) and (6c) by 1, 3-dipolar addition reaction with diazomethane, which were finally debenzoylated with ammonia into the triols (1a) and (2a), respectively.

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The radioimmunoassay of hen egg-white lysozyme (hen lysozyme) was investigated and evaluated in order to examine the biotransformation of the enzyme in men. ¹²⁵I-labeled hen lysozyme was prepared and separation of the free from the bound form of the enzyme was performed by dextran-treated charcoal method in comparison with two-antibody method. From the result, it was idnicated that dextran-treated charcoal method was useful from the viewpoint of precision, reproducibility and simplicity. The stability of hen lysozyme labeled was determined by the degree of radioactivity bound to antibody. The recovery of radioactivity bound to antibody decreased with the time lapse after labeling and it was found that the recovery rate was restored by dialysis. In this radioimmunoassay system, the competitive binding of labeled and unlabeled hen lysozyme to antibody was examined, and 0.3 to 5.0ng/ml of the enzyme were detectable. It was found that human lysozyme had an influence on the radioimmunoassay system with over 2μg/ml. But, the influence did not disturb the assay of hen lysozyme in human serum. Additionally, since it was found that the ratio of the bound form to the free increased with human serum, the assay of hen lysozyme in human serum was carried out using a calibration curve of the enzyme added to untreated human serum. Thus, human serum levels after oral administration of hen lysozyme were measured by the radioimmunoassay in comparison with the determination method by lytic activity. This radioimmunoassay system was found to be appropriate for the determination of hen lysozyme in human serum.

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The generality in effects of transmucosal fluid movement and glucose on drug absorption from the rat small intestine was investigated using twenty three drugs having different charges in the physiological pH of the intestine of the animal with the in situ recirculating perfusion method. All of the regression lines representing the relation between ratio of the transmucosal fluid movement on the vertical axis and intestinal absorption of respective drugs on the horizontal axis were not perpendicular to the horizontal axis but have some inclinations without exception. These evidences did support the concept that intestinal drug absorption was subtly affected by the transmucosal fluid movement and thus the generality in effect of the movement was apparently demonstrated. Concerning the glucose effect, two regression lines, one was of sodium chloride and another was of glucose in the perfusate, were obtained in all of the drugs. However, these two regression lines were overlapped in the cases of unionized drugs. On the other hand, in the cases of cationic drugs the regression lines of glucose were always shifted significantly to the right hand side of those of sodium chloride and in the cases of anionic drugs the regression lines of glucose were shifted to the left hand side without any exception. These evidences demonstrated that glucose increased the absorption of cationic drugs and decreased that of anionic drugs and, moreover, these findings were supported by investigating blood level of respective drugs in the subjected animal. Thus the generality in the glucose effect was apparently demonstrated. Moreover, the glucose effect was also recognized when two drugs were coexisted simultaneously in the perfusate. The glucose effect in drug absorption might be one of mechanisms of drug interactions which have been observed in clinical medicine.

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As the part of the studies to clarify the interaction between 11-cis retinal and apoprotein opsin in the rhodopsin molecule, the retro-γ-retinal, possessing the dissected diene and trienal groups, has been investigated as a new chromophore in rhodopsin analogues. The syntheses, spectral properties of three retro-γ-retinal isomers [all-trans (VIIa), 11-cis (VIIa') and 9-cis (VIIb)] and some chemical behaviours of VIIb have been described. Of these three isomers, VIIb has given a new artificial visual pigment.

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The cyclodehydration of β-(p-toluidino)-acrolein (I) in sulfuric acid was studied kinetically in relation of that of 4-(p-toluidino)-3-penten-2-one (VII). Reversible sulfonation of I at α-position and cyclodehydration to 6-methylquinoline (II) proceeded in parallel. The difference in reactivity between β-arylaminoacrolein and 4-arylamino-3-penten-2-one was discussed.

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3-Hydroxy-2-naphthoates of lidocaine (I), mepivacine (II), and bupivacaine (III) were prepared as a potential means of prolonging the action of these local anesthetic amines through their sparingly soluble salt forms. The molar ratio of the local anesthetic base to 3-hydroxy-2-naphthoic acid (IV) was 1 : 1 and the hydroxynaphthoates contained no solvent of crystallization. Dissolution characteristics of these hydroxynaphthoates were determined in water and 0.7M phosphate buffer, pH 7.46 at 37°and compared with those of the corresponding bases. The hydroxynaphthoates of I and II exhibited lower equilibrium solubilities but their dissolution rates were greater than the corresponding bases in these media. As for III, the hydroxynaphthoate showed higher solubility than the base in water.

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An improved method for the synthesis of 1, 1a, 6, 10b-tetrahydrodibenzo [b, f] cycloprop-[d] azepine (3) was described. Thus, 5H-dibenz [b, f] azepine (1) was formylated and dichloro-cyclopropanated with dichloromethylene generated from chloroform and aqueous sodium hydroxide in the presence of a phase-transfer catalyst to yield 1, 1-dichloro-1a, 10b-dihydrodibenzo [b, f] cycloprop [d] azepine-6 (1H)-carbaldehyde (2). The latter compound and its deformylated product, 1, 1-dichloro-1, 1a, 6, 10b-tetrahydrodibenzo [b, f] cycloprop [d] azepine (5), were reduced to 3 with sodium in liquid ammonia. 5-Acetyl-, 5-carbamoyl, 5-methyl- and 5-(3-chloropropyl)-5H-dibenz [b, f] azepines (6, 8, 11 and 14), when treated with the dichloromethylene, gave the corresponding dichloro-cyclopropanation products and some other products, in which the substituents had reacted simultaneously with dichloromethylene in several fashions. The reduction of 5 under drastic conditions yielded 5, 6, 7, 12-tetrahydrodibenz [b, g]-azocine (20) and 10H-indolo [1, 2-a] indole (21). cis-and trans-1-Chloro-1, 1a, 6, 10b-tetra-hydrodibenzo [b, f] cycloprop [d] azepines (23, R=H and 24, R=H), on the other hand, were the main products of catalytic hydrogenation of 5. Conformational aspects of the N-methyl derivatives 23 (R=CH₃) and 24 (R=CH₃) were discussed.

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The chemical properties of the epoxy ring in 1a, 10b-dihydro-6H-dibenz [b, f] oxireno-[d] azepines (1) are dependent on the nature of the substituents on the nitrogen at the 6-position. Treatment with acids or alkalis led to either the normal cleavage of the epoxy ring or the rearrangement to the acridine ring.

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The tissue distribution and excretion of perfluorochemicals (PFCs) in the mixed PFC emulsion, which were a mixture of 7 parts Perfluorodecalin (FDC) and 3 parts Perfluoro-tripropylamine (FTPA), were studied in rats and dogs hemodiluted to a hematocrit of 5% and monkeys to 1%. The half life of both PFCs in rats given 4g/kg body weight were calculated from their expiratory excretion rate to be about 7 days for FDC and 63 days for FTPA. Both PFCs in the mixed PFC emulsion were excreted according to respective excretion rate, indicating no mutual effect of combined use on respective excretion rate. Both PFCs were taken up into the liver, spleen and bone marrow in the majority and eliminated through expiration as the main route and bile as the minor route, the maximum deposition occurring in 4 days after infusion. FDC localized in the tissues was rapidly eliminated and no longer detected both in dogs at 6 months after hemodilution and in monkeys at 4 months. On the other hand, FTPA was also fairly rapidly eliminated from the tissues, but at a slower rate and it was retained only in the liver and spleen in both of dogs at 6 months and monkeys at 4 months in a very small amount. The absence of excess fluoride ion in urine and the coincidence of mass spectra of FDC and FTPA retained in the liver with those of the standard suggested that both of them were not catabolized in vivo.

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Measurements of the moisture sorption and the volume expansion of amorphous lactose tablets, as well as measurements of the formation of crystalline lactose, were carried out under controlled relative humidities. At high relative humidity, it was suggested that the supersaturated solution of lactose was formed on some parts of the surface of amorphous lactose particles and the crystallization occured in an autocatalytic manner, which led to a rapid expansion of tablets. On the other hand, at low relative humidity, it appeared that the hygroscopic swelling owing to the physical adsorption of moisture on the inner surface of tablets occured without crystallization.

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The cyclization of N-acrylyl-trans-and-cis-octahydro-7 (1H)-quinolones (IXa and IXb) was examined under both acidic and basic conditions. Under kinetic conditions, the trans-isomer (IXa) gave two isomeric tricyclic lactams (X and XI) while the cis-isomer (IXb) gave no cyclized compounds. Under thermodynamic conditions, the cis-isomer (IXb) as well as the trans-isomer (IXa) gave the same lactams (X and XI). In the former case with kinetic conditions, the difference in behavior toward cyclization between IXa and IXb was interpreted by taking a stereoelectronic requirement for the Michael addition into consideration, and in the latter case with thermodynamic ones, unexpected formation of the lactams (X and XI) from the cis-isomer (IXb) was rationalized by assuming a reaction pathway via the intermediate enone (XXII) of which we succeeded in isolation from the reaction mixture.

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In order to obtain 1-β-D-arabinofuranosylcytosine derivatives with better antitumor effect, 12 kinds of saturated fatty acyl groups were introduced at the N⁴-position of 1-β-D-arabinofuranosylcytosine. The presence of a great excess of water and about two-fold equivalents of carboxylic anhydride was found to be most desirable for selective N⁴-acylation. This simple method of one-step N⁴-acylation should be generally applicable to cytosine nucleosides and a variety of carboxylic anhydrides.

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Starting from 2'-azido-2'-deoxyadenosine (1), sugar-acetylated 6-chloro compound (5) was synthesized by successive deamination, acetylation and chlorination. Using the compound 5 as intermediate 6-monomethylamino-, dimethylamino-, mercapto- and methylthio 2'-azido nucleosides (6, 8, 11 and 12) were obtained. Palladium-catalyzed hydrogenation of compound 6 and 8 afforded 2'-amino nucleosides (7 and 9) respectively.

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Photolysis of N-methylencbisphthalimides (6) gave the intramolecularly cyclized compounds (7), products of recombination of ketyl-like intermediates which are not obtained in usual intermolecular reactions.

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Three analogues of somatostatin, in which the tryptophan residue in position 8 was replaced by 3-(1-naphthyl)-L-alanine, 3-(2-naphthyl)-L-alanine and 1, 2, 3, 4-tetrahydro-β-carboline-3-carboxylic acid, were synthesized by the solid-phase method. All of these analogues showed diminished biological activity compared to synthetic somatostatin. The results suggest strongly that the indolyl NH group in the tryptophan residue of somatostatin plays an important role to elicit full hormonal activity and that the function accomplished by the tryptophan residue in somatostatin is different from that in luteinizing hormone-releasing hormone.

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Gastric juice inhibitory substance (GIS) produced by Streptomyces bottropensis F4708 suppressed carrageenin-induced edema but did not show analgesic effect or influence the circulation system. Effect of adrenergic antagonists on the gastric juice inhibition and lowering of body temperature by GIS was examined. The gastric juice inhibitory activity of GIS was not affected by premedication with Dibenamine or Propranolol. However, the lowering of body temperature by GIS was markedly reinforced by premedication with the antagonists. The dark brown pigment component from GIS was presumed to be a melanin-like substance by comparing its chemical properties with those of DOPA-melanin which exhibited a significant reduction of gastric secretion in rats. Therefore, the gastric juice inhibitory activity of GIS was found to depend on this pigment component in its molecule. Lowering of body temperature of rats was not observed by the administration of DOPA-melanin.

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The structure of ketodihydrocampholenolactone (II), which had been obtained by oxidation of dihydrocampholenolactone (I) (1, 8, 8-trimethyl-2-oxabicyclo [3, 3, 0] octan-3-one) and called by Fujita, was established to be the formula of 1, 8, 8-trimethyl-2-oxabicyclo [3, 3, 0] octan-3, 6-dione (III).

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The structure-activity relationship of tuftsin, a phagocytosis-stimulating peptide, has been investigated using its analogs newly synthesized. Two basic amino acids on tuftsin could be replaced with each other without activity loss.

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