Some amidinothiocholine derivatives have been prepared and tested for the ganglion blocking activity, as compared with that of hexamethonium. Among them, most potent ganglionic blocking compound was S-(2-trimethylaminoethyl)-1'-ethylisothiuronium which was more potent than hexamethonium on the cat superior cervical ganglion, the guineapig hypogastric nerve-vas deferens preparation and the cat and rat blood pressure. Other compounds, also, had the ganglionic blocking action, but were not so potent as hexamethonium.

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An unusual reaction where an allylic methylene is converted into an ethyl ester by means of Wohl-Ziegler's reagents is presented : The reaction of 4-acetyl-1-methyl-2-phenyl-1, 2, 3, 10-tetrahydro-4H-pyrazolo [3, 4-c] [1, 5] benzothiazepin-3-one (7) with N-bromosuccinimide or N-bromoacetamide in commercial (ethanol-containing) chloroform gave ethyl 3-acetyl-5'-oxo-1'-phenyl-spiro [benzothiazoline-2, 4'-[2] pyrazoline]-3'-carboxylate (8). Similarly ethyl 3, 5'-dioxo-1'-phenyl-spiro [benzo [b] thiophene-2 (3H), 4'-[2] pyrazoline]-3'-carboxylate (11) was obtained from 1-methyl-2-phenyl-1, 2, 3, 10-tetrahydro-4H-pyrazolo [3, 4-c] [1] benzothiepin-3, 4-dione (10).

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In every mass spectrum of the metal thiooxinates, the peak being attributable to the molecular ion was observed, and the mass units correspond to a 2 : 1 molar ratio chelate (ligand : metal). The loss of 160 mass units from the molecular ion was observed. This indicates that a cleavage of one molecule of the coordinated thiooxine from the molecular ions affords the fragment ion of a 1 : 1 ratio chelate. In the following fragmentation process, the group of Mn, Co, Ni, Cu, and Pd chelates and the group of Zn, Cd, Hg, and Pb chelates showed different pathway. In order to examine the stabilities of these metal thiooxinates under electron impact, the intensity ratio of a fragment ion peak of a 1 : 1 molar ratio chelate to a molecular ion peak was calculated and the following decreasing stability order in the central metal atom was observed ; Cd>Zn>Ni>Pd∼Co>Mn>Cu>Hg>Pb. This order is found to be quite similar to that of metal oxinates, reported in a previous paper. A definite correlation between these intensity ratios and the chargeradius ratio, e/r, and the ionization potential of the central metal atoms was shown.

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A new colorimetric method for the determination of non-and mono-substituted guanidine compounds was established, by using 0.04% 9, 10-phenanthraquinone in dioxane-EtOH (1 : 4) and 2% 3, 5-dihydroxybenzoic acid in EtOH with the addition of 2 N KOH aqueous solution, and measuring the absorbance at 615 nm. The color intensity becomes constant after standing for 90 min in the case of guanidine, and for more than 100 min in the case of mono-substituted guanidine at room temperature. This method is recommended for the determination of non-and mono-substituted guanidines. Beer's law holds in the range of 2.5×10^-3 to 6×10^-2 μmol/ml in the final solution of various guanidine compounds such as salts of guanidine (25-28), glycocyamine (32), agmatine (33), and arginine (34). Guanidines with a large substituent or with an electronegative group, showed less color intensity than methylguanidine (29), or did not show any coloration. On the other hand, 1-naphthol method can be used only for the detection of monosubstituted guanidines. Limit of identification of these compounds was in the range from 0.3 to 2 μg.

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1-Deaza-(I) and 3-deazaadenosine 3', 5'-cyclic phosphate (II) (analogs of adenosine 3', 5'-cyclic phosphate) were synthesized from N⁶-acetyl-1-deazaadenosine (III) and 3-deazaadenosine (VI), respectively. In addition, a number of 1-and 3-deazaadenosine phosphates including 1-(XII) and 3-deazaadenosine 2', 3'-cyclic phosphate (XIII) were also prepared. Both VII and XIII were found to be hydrolyzed to the corresponding nucleoside 3'-phosphate by ribonuclease M. Both 1-deaza-(V) and 3-deazaadenosine 5'-phosphate (XI) were hydrolyzed by snake venom 5'-nucleotidase to the respective deazaadenosine and inorganic phosphate; the latter, however, was found to be hydrolyzed with much reduced rate.

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Autoxidation of cysteine catalyzed by Cu (II) in glycylglycine buffer was examined spectrophotometrically. Upon mixing the Cu (II) and cysteine solutions was produced a transient purple color, due to a Cu (II)-cysteine complex, giving a broad electronic spectrum with λ_max=530 nm. The purple Cu (II) complex, which is decomposed fleetingly to Cu (I) species, is stabilized relatively as pH increases. The autoxidation of cysteine does not exhibit Michaelis-Menten kinetic behaviors, and appears to be half order in concentration of cysteine over pH 7.3. Increasing concentrations of oxygen in the medium promote the autoxidation. As cysteine is autoxidized, hydrogen peroxide is produced and partially accumulated. The plot of the reciprocal of the rate as a function of the reciprocal of the oxygen concentration gives a straight line. One molar oxygen participates probably in a step of the reoxidation of the Cu (I) species. A pH-rate profile of the autoxidation displays a bell-shaped curve with a maximum at pH 7.4.

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The kinetics of ligand exchange reaction of mercury-aminopolycarboxylates (Hg-Y) with monothiodibenzoylmethane (SBB) is studied by solvent extraction method. EDDA, NTA, EDTA-OH, DPTA-OH, EDTA, methyl-EDTA, GEDTA and DTPA are used as aminopolycarboxylic acid. The reaction rate is determined by the measurements of the radioactivity of ²⁰³Hg in the aqueous phase. From the respective dependencies of the rate constant on the concentrations of hydrogen ion, SBB and Y, the formation of the mixed ligand complex was approved in the reaction mechanism. The values of the rate constants and stability constants of Hg-Y are found to be correlated each other with a few exceptions such as the cases of EDTA-OH and DPTA-OH, and the rate determining step is considered to be involved in the step of the dissociation of aminopolycarboxylic acid. The usefulness of the solvent extraction method for the kinetic study of complex formation was proved through the result presented here.

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The kinetics of ligand exchange reaction of mercury-monothiodibenzoylmethane complex with various thiol compounds (THIOL) is studied by stripping solvent extraction method. Mercaptoethylamine (MEA), penicillamine (Pen), cysteine (Cys), glutathione (GSH), α-mercaptopropionic acid (α-MPA), β-mercaptopropionic acid (β-MPA), N-acetylcysteine (NAC) and thiomalic acid (TMA) are used as thiol compounds. The reaction rate is determined by the measurements of the radioactivity of ²⁰³Hg in the aqueous phase. Thiol compounds were classified into two types based on their reaction rates, and in these reactions the formations of the mixed ligand complexes are considered to be involved. The observed reaction rates at physiological pH are distinctly higher in the thiols with amino group than in other thiols.

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Several 3-ylideneaminoimidazo [4, 5-c] pyridazines (IV and VI) were synthesized for the investigation of the ring isomerization reaction. The reactions of IVa, IVb, IVc, and IVd with 5% or 50% acetic acid gave VIII as the ring isomerization product. Similarly IVe afforded X. In the case of IVd, intermediate product (IXd) was obtained by the reaction with 50% acetic acid. This compound (IXd) was converted to VIII by the treatment with 70% acetic acid. The possible reaction mechanism was proposed.

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Cyclization reactions of 8-(β-haloethylthio) adenine, 8-(β-haloethylamino) adenines and 8-(γ-halopropylamino) adenine occurred at both of N⁷ and N⁹ of purine ring and pairs of cyclized compounds, 4-aminodihydrothiazolo [2, 3-f]-and 4-aminodihydrothiazolo [3, 2-e] purine, 4-aminodihydroimidazo [2, 1-f]-and 4-aminodihydroimidazo [1, 2-e] purines, and 4-aminotetrahydropyrimido [2, 1-f]-and 4-aminotetrahydropyrimido [1, 2-e] purine were obtained. Structures of 4-aminodihydrothiazolopurines were determined by desulfurization with Rany Ni and those of 4-aminodihydroimidazopurines and 4-aminotetrahydropyrimidopurines were determined by comparison of spectral data with those of N-cyclonucleosides.

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The anodic oxidation of N, O-dialkyl- and N, N, O-trialkylhydroxylamines in acetonitrile was studied. These hydroxylamines generally showed two waves at a glassy-carbon electrode and the Ep values were larger than those of N-alkyl- and N, N-dialkylhydroxylamines. N, O-Diethyl and N-ethyl-O-t-butylhydroxylamine gave O-ethylacetaldoxime and O-t-butylacetaldoxime, respectively, as the major oxidation product, which suggests that N-alkoxy-N-alkylamino radical was a transient intermediate in the anodic oxidation.

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Reaction of 6-cyano-1, 3-dimethyluracil (1) with some nucleophilic reagents such as sodium hydroxide, sodium methoxide, alcohols, butylamine, and hydrazines gave 5-cyano- (2 ; cine-substitution product), 6-methoxy- (3), 6-butylamino- (10a), 6-hydrazino-1, 3-dimethyluracil (10b) and imidates of 1. Reaction of 5-bromo-6-cyano-1, 3-dimethyluracil (5) with hydrazine hydrate gave 6-amino-1, 3-dimethyluracil (11), which was also obtained by reaction of 5-bromo-6-chloro-1, 3-dimethyluracil (12) with hydrazine hydrate.

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Synthesis of viral-specific neuraminidase (NAase), one of the structural proteins of influenza virus, was inhibited by addition of 2-mercapto-1-(β-4-pyridethyl) benzimidazole (MPB), at a concentration of 50 μg/ml, to culture medium of infected HeLa cells during the first 1 hr post infection, and this inhibition was easily released by changing medium containing the drug to the drug free medium. Addition of MPB later than 5 hr, however, showed little inhibition of viral NAase induction in infected cells. Moreover, this drug as well as actinomycin D did not prevent the synthesis of NAase in infected HeLa cells with Newcastle disease virus. The mode of inhibitory action of MPB was very similar to that of actinomycin D excepting that MPB acted reversibly.

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Uptake and accumulation of alkoxyethylmercury compounds in several organs of mice, in comparison with alkylmercury compounds, were studied. Diets containing various organic mercury compounds were continuously fed to mice, and organic mercury in the organs was extracted with dithizone-carbon tetrachloride and determined by gas chromatography. Histological studies in mice poisoned by methoxyethylmercury chloride showed a prominent damage of the kidney, and proliferation of glial cells and atrophy of nervous cells in the cerebrum. In all of the compounds administered, the organic mercury was found in the liver and kidney. The ratio of the mercury contents in blood to plasma was higher in ethylmercury chloride than in alkoxyethylmercury compounds. Ethylmercury chloride was highly incorpolated into the brain, while alkoxyethylmercury compounds were at much slower rates. The mercury contents in the brain at onset of the neural symptoms were much lower in methoxyethylmercury than in ethylmercury. In the brain after administration of alkoxyethylmercury compounds, it appeared to be present as an inorganic mercury for the most part, in contrast with significant amounts of the organic mercury in the case of the alkylmercury. It may be presumed that manifestation of the symptoms after exposure of organic mercury compounds is not merely related to mercury levels and not always in need of organic forms in the brain.

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Metabolism and excretion of alkoxyethylmercury compounds in mice were studied, and their gastrointestinal absorption was discussed. The total mercury and the organic mercury in blood, liver, kidney, and excreta at time intervals after a single subcutaneous injection of methoxyethylmercury chloride (MEMC) and n-propoxyethylmercury chloride (n-PEMC) were determined. Initially, the greater part of mercury in the blood, liver, and kidney was found as organic forms, but thereafter the organic mercury rapidly decreased with decrease of the total mercury. During 120 hr, the ratio of excretion of mercury in urine/feces was 2/1 after injection of MEMC and 1/2 after injection of n-PEMC, and more than half of the mercury in urine were in organic forms. Mercury in the feces was not determined as the organic form and was a chemically stable compound. It is most likely that the fecal mercury is mercuric sulfide, since it was formed from inorganic mercury ion in the cecum. Inorganic mercury was found in the gastric contents initially after oral administration of MEMC. The release of inorganic mercury in the stomach indicates a reason for the poorer gastrointestinal absorption of alkoxyethylmercury compounds.

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Using 1α- and 2β-hydroxy derivatives of 3β-hydroxy-17, 17-ethylenedioxyandrosta-5, 7-diene obtained in our previous work as starting materials, 1α- and 2β-hydroxylated analogues of 17-nor-17, 17-ethylenedioxyvitamin D have been prepared via (i) photochemical conrotatory opening of the B-ring and (ii) the subsequent thermal 1, 7-antarafacial hydrogen shifts. 1α-Hydroxy-17, 17-ethylenedioxyvitamin D showed no significant antirachitic activity in rats. This fact seems to suggest that, in addition to the 1α-hydroxy function, the presence of the side chain in the vitamin D system plays also an important role in the biological action of the D analogues.

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A modified Curtius reaction of N-benzyloxycarbonyl-L-proline (I) with diphenyl phosphorazidate (DPPA) in the presence of triethylamine in tert-butyl alcohol afforded the allophanate (III) as the major product but the expected carbamate (II) as a minor product. Similar result was obtained in the case of the ordinary Curtius reaction of I. However, the use of tert-butyl carbamate (X) as an additive changed the reaction course and the desired carbamate (II), though accompanied by racemization, was obtained in good yield.

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1) The present research has been planed to demonstrate the importance of tryptophan residues on enzyme activity of papain by means of NBS oxidation. 2) About 2 tryptophan residues were oxidized and the first oxidizable tryptophan was important for enzyme activity. 3) The relationship between tryptophan oxidation and enzyme activity for acetylpapain and mercuripapain are quite similar to that for papain. 4) About 1 tryptophan and 3 tyrosine residues in papain were modified by NBS oxidation. However, only 1 tryptophan residue and no tyrosine residue in acetylpapain were oxidized at complete inactivation. 5) The acetylation of tyrosine in papain prevented the tyrosine from oxidizing by NBS. 6) SH group and histidine residues in papain were not affected by NBS oxidation. 7) These results indicate that the modification of a tryptophan residue by NBS oxidation causes loss of the enzyme activity.

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The metabolic fate of octopamine has been investigated in the rat and rabbit, using octopamine-2-³H. Urinary metabolites after oral administration were separated and identified by direct comparison with the authentic samples. The principal metabolite of the drug in both animals was the aliphatic dehydroxylated compound, p-hydroxyphenylacetic acid. Pretreatment with antibiotics (streptomycin and penicillin G potassium) did not cause to change the metabolic pattern of octopamine, suggesting that gut flora did not participate in the aliphatic dehydroxylation of octopamine.

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Major water-soluble extracellular polysaccharides of A. solani obtained by DEAE-cellulose column fractionation, ASP-1 and ASP-2 were heteroglycans which were composed of D-galactose, D-glucose and D-mannose. The molar ratios of ASP-1 and ASP-2 were 2.2 : 3.1 : 1.0 and 1.0 : 1.7 : 2.0, respectively. FSP-1 obtained from F. solani was a heteroglycan composed of D-galactose, D-glucose, D-mannose, and small amounts of glucuronic acid and rhamnose (approximate molar ratio : 10.5 : 10.6 : 7.6 : 1.8 : 1.0). Optical rotations of these glycans were [α]²⁵_D+66.0°(ASP-1), [α]²⁵_D+38.0°(ASP-2), and [α]²⁵_D+25°(FSP-1), respectively. The results of periodate oxidation, Smith-degradation, methylation studies, and Gas-liquid Chromatography-Mass Spectrum spectra showed that these polysaccharides have highly branched structure and 1, 2-, 1, 3-, and 1, 6-linked glucopyranosyl (ASP-1), 1, 2-linked mannopyranosyl and 1, 6-linked glucopyranosyl (ASP-1), and 1, 2-linked glucopyranosyl and 1, 3, 6-linked mannopyranosyl residues (FSP-1), and 1, 2, 6-linked galactofuranosyl residues are present as main linkages of each glycan. The terminal groups are glucopyranosyl and small amount of mannopyranosyl residues. Probable structures are proposed.

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I and II were synthesized as their barium salts. Methyl (1-bromo-tri-O-acetyl-α-D-glucoside) uronate was condensed with haloindolyl acetate in dry methanol containing sodium methoxide. Acetylation of crude methyl (haloindol-3-yl-β-D-glucoside) uronate thus obtained, followed by deacetylation and demethylation with aq. alkali acetone, afford the desired haloindol-3-yl-β-D-glucuronides. The hydrolysis of I and II by rabbit liver β-glucuronidase was investigated. The rate of hydrolysis depends on the nature of the buffer, and decreases in the following order : acetate>citrate-phosphate>phosphate. The optimum pH was 4.75 in acetate buffer and 5.0 in both citrate-phosphate and phosphate buffer. K_m for I and II is 8×10^-4M and 5×10^-3 M, respectively. I was applied to the demonstration of β-glucuronidase in disk electrophoresis.

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2, 4-Benzothiazepin-5 (1H)-one were usually the predominant products in reactions of o-chloromethylbenzoyl chloride with 1, 3-disubstituted thioureas ; but with methyl, benzyl or allyl substituted thioureas, 2, 4-benzodiazepin-1-ones were obtained together with 2, 4-benzothiazepin-5 (1H)-ones. These structures were elucidated from infrared, ultraviolet and nuclear magnetic resonance spectra. We also found that nature of the base and solvent as well as thiourea substituents affected the course of the reactions affording 2, 4-benzothiazepin-5 (1H)-ones or 2, 4-benzodiazepin-1-ones. Several 2, 4-benzothiazepin-5 (1H)-ones and 2, 4-benzodiazepin-1-ones possessed weak pharmacological activities, such as coronary vasodilating and local anesthetic activity.

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Solvolysis of 3-keto-23-tosyloxy (A) and 3-keto-24-tosyloxy (B) derivatives of triterpenoid with t-butoxide proceeded in stereospecific manner to yield rearranged bicyclo [3, 2, 0] heptanones (C) and (D), being antipodal to one another with respect to the ketonic chromophor, whose structures were respectively established by spectral and chemical means. Reinvestigation of solvolysis for the simplest keto-tosylate (13) confirmed the formation of two bicyclo [3, 1, 1]- (14) and bicyclo [3, 2, 0]-(15) heptanones. The former rearranged by acid to a new bicyclo [3, 2, 0] heptanone (20), while the latter was stable to acid. Based on these evidences a plausible mechanism (Chart 4) of the homo-Favorskii rearrangement (13→15) was proposed. A new method of selectively converting a cyclobutanone to a γ-lactone in high yield was described.

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Lyclavatol, a constituent of L. clavatum, was elucidated as a novel type of bisnortriterpenoid, 3α, 8β, 14α, 21β-tetrahydroxy-26, 27-bisnoronocerane (1a).

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The effect of a single intraperitoneal administration of lead acetate on acid hydrolases activity in bone tissues of rat was studied. The administration of lead to rats produced a persistent increase in acid phosphatase activity, while alkaline phosphatase activity decreased. There was a significant increase in β-glucuronidase, β-N-acetylglucosaminidase, and β-galactosidase activities in bone tissues as early as 1 day after lead administration. These enzymes activity, at three dose levels (5, 10, and 20 mg lead per 100 g body weight), significantly increased when compared with the values obtained from rats received control injection with distilled water. In the present study, it is demonstrated that the administration of lead could cause an increase in lysosomal acid hydrolases activity in the bone tissues of rat.

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The catalytic alkylation of xylenes with methanol over alumina activated with hydrofluoric acid was examined using a flow reactor under the atmospheric pressure. The methylation takes place from 300°to 500°in the presence of an excess amount of methanol. At temperatures from 300°to 350°isomerization and disproportionation are not observed. The selectivity of the methylating position was correlated with the nature of the catalyst such as acidity, acid strength, and the structure of fluorinated alumina catalysts. The activity showed a maximum for 12.7% fluorinated alumina catalyst and conversion increased with the acidity of catalysts. The acid strength determined by the indicator method falls in the range of +1.5≤H₀≤3.3, which suggests that the acid sites have a uniform structure on its surface. From the X-ray powder patterns of the catalysts used the active species were proposed to be AlF (OH)₂ and AlF₂ (OH).

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Pueraria root was extracted consecutively with acetone, methanol, and water, and 13 fractions (PA1-PA5, PM1-PM5, PW1-PW3) were prepared for basic pharmacological examinations. Many pharmacological actions were separated as fractionation of the extract progressed. Coexistence of substances having a mutually reverse pharmacological effect was found in the crude drug. Acute toxicity of each fraction was very weak. PA4, PA5, PM2, PW2, and PW3 decreased body temperature of mice, while PM4, PM5, and PW2 increased it. PA3, PA4, PA5, PM2, and PM4 exerted a papaverine-like action on the isolated guinea pig ileum, while PM1, PM3, and PM5 contracted this organ. PA5 and PM2 relaxed while PM3 contracted, the isolated guinea pig taenia coli. PA3, PA5, and PM2 showed a papaverine-like action on the isolated rat uterus. PA3, PA5, and all PM fractions contracted the isolated guinea pig vas deferens. PM2, PM3, and PG1 which was regarded as the component of PM2 potentiated the noradrenaline-induced contraction in this organ. PA3, PA5, all PM fractions, and PW2 inhibited electrically induced muscle contraction in the isolated frog sciatic nerve-sartorius muscle preparation. PA3, PA5, PM1, PM2, and PM4 contracted the isolated frog rectus abdominis muscle. PA3, PA5, PM1, PM3, PM4, PM5, and PW2 decreased blood pressure in anesthetized dogs, while PM2 elevated it. PA3, PA5, PM1, PM3, PM4, PM5, and PW2 increased femoral arterial blood flow in anesthetized dogs. Some discussions were made on the pharmacological actions of each fraction.

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The concentration of trans-4-aminomethylcyclohexanecarboxylic acid (tranexamic acid) in human serum was determined by peak matching operation. N-Heptafluorobutyryl amide derivative of tranexamic acid n-butyl ester was found to be the most suitable derivative for this purpose. The present operation enabled to confirm that peak due to tranexamic acid had no contaminants at all. Deuterium labeled tranexamic acid was used as an internal standard for quantiation of tranexamic acid in human serum. It was also found that proteins in human serum were precipitated completely with heptafluorobutyric acid which was readily removed by evaporation. On the oral administration of 250 mg of tranexamic acid, the serum level concentration reached maximum at 3-4 hour post-dose period.

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Rate of excretion and metabolites in urine and feces of mice after intravenous or oral administration of ¹⁴C-cyclocytidine and ¹⁴C-aracytidine were examined. Furthermore, absorption from gastrointestinal tract was examined. After intravenous injection, about 80% of cyclocytidine was excreted in urine within 24 hours and not in feces. Main radioactive compound in urine was intact cyclocytidine and small amount of aracytidine and arauridine were detected, while two-thirds of ¹⁴C-aracytidine administered were excreted after metabolized to arauridine. A half of cyclocytidine was excreted in feces as intact when administered orally. Very small amount of cyclocytidine was excreted in expired air as CO₂. However, one-fourth of radioactivity was excreted in expired air after oral administration of ¹⁴C-aracytidine. Cyclocytidine was mainly absorbed from stomach and slightly from large intestine.

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Three reactants, aminomethylpyridine, α-keto acid and divalent metal ion were mixed in methanol and formation of metal chelate of aldimine was followed by changes of electronic absorption spectra. Aminomethylpyridines used were pyridoxamine and 3-hydroxy-4-aminomethylpyridine ; α-keto acids were Na pyruvate, Na α-ketobutyrate, K α-ketoisovalerate, ethyl pyruvate and ethyl α-ketobutyrate ; metal ions were Zn (II), Ni (II) and Cu (II). Every combination of the substances were examined. Analyses of spectral changes showed that the reactions consisted of two slow steps, ketimine metal chelate formation from the three reactants and its isomerization to aldimine metal chelate. In reactions with Zn (II) ion, the isomerization step was rate determining, while in reactions with Ni (II) ion ketimine chelate formation became slower step. By chelation with Cu (II). ketimine chelate formation was retarded but the isomerization was accelerated. Ketimine formation was faster with esters of keto acid than with anions. In the anions rate of ketimine formation was pyruvate>α-ketobutyrate>α-ketoisovalerate in the presence and in the absence of the metal ions. None of the combination of the reactants in the present study produced an intermediate absorbing in the 500-nm region.

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A rapid, specific and highly sensitive electron-capture gas chromatographic method for the determination of flurazepam and its four metabolites in human urine, serum and plasma was developed. The metabolites in blood specimens and in β-glucuronidase treated urines were cleaned up using porous polymer resin and selective extraction, and were derivatized to trimethyl silylate (TMS), methyl derivatives and methyl ester, respectively. The recoveries were almost quantitative and the sensitivity was enough for therapeutic dose levels (15-30 mg). The sensitivity limits were 0.3-2.0 ng/ml of each metabolites in serum and plasma. The method was applied to urine and serum specimens of single dose of chronic dose of 30 mg of flurazepam, and the metabolic properties of the drug were also discussed.

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In order to obtain the key intermediates leading to the D-homo cardenolide analogs, the preparation of the C-17a epimeric D-homo-5α, 14β-pregnan-20-ones (VIII, IX) has been undertaken. Upon catalytic hydrogenation the Δ^{14, 16}-dien-17a-one (IV), derivable from D-homo-5α-androstan-17a-one (I) by repeated unsaturation, provided the desired 14β-steroid (V) as a main product. Introduction of a C₂ unit into C-17a was attained by the Grignard reaction with ethynylmagnesium bromide, followed by hydration with mercury resin to yield D-homo-5α, 14β, 17a-pregn-17-en-20-one (VII). Subsequent hydrogenation over palladium-on-charcoal afforded IX and VIII in a ratio of ca. 5 to 1. Configurational assignment of the side chain in IX was accomplished by transforming the 20-oxime (XIV) into the 17aα-acetamido derivative (XV) by the Beckmann rearrangement.

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Conclusive evidence was obtained for the position of chiral alkyl groups in the esters of 3-nitrophthalic and 4-nitrohemimellitic acid, which are key substances demonstrating interesting chiroptical property due to twisting of the nitrobenzene chromophore controlled by the remote chiral groups through in phase twisting of the intervening substituents. Diphenylphosphorylazide (DPPA) was used as the reagent for modified Curtius rearrangement with good success. Since it acts specifically on carboxylic acid but not on ester function, only the former is converted to amine function. The amino compounds so derived were proved to be identical with the known substances. The method seems useful generally for determining the free carboxylic position in some partial esters of polycarboxylic acids.

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(a) Partial acetylation of sarcostin (1) gave two diacetates ; 3, 12-O-acetate (4) and 3, 20-di-O-acetate (3) in 3 : 1 ratio, besides 3-mono-O-acetate (5) and 3, 12, 20-tri-O-acetate (2). On the other hand, benzoylation of 5 with equimolar amount of benzoyl chloride gave its 20-O-benzoate (6). (b) Treatment of 1 with paraldehyde under acid catalytic conditions afforded 14, 17-12, 20-di-O-ethylidene-sarcostin (14). (c) The configuration at C-20 position of 1 is S on the basis of the X-ray analysis of 3-O-p-bromobenzoate (16). The o-nitrobenzoate (17) showed a negative Cotton effect contrary to the expectation from Nagai's data but the 14, 17-O-ethylidene derivative (18) of 17 showed a positive Cotton effect. (d) The configuration of the C-20 carbinol derived from sodium borohydride reduction of the corresponding ketone is ascribable to the stereochemistry at C-17 of the ketone. The 20-O-o-nitrobenzoate (24) derived from the sodium borohydride reduction product of lineolon diacetate (25) shows a positive Cotton effect while the o-nitrobenzoate (26) from isolineolon diacetate (27) shows a negative effect.

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To know the absorption spectra associated with species protonated and nonprotonated on the pyridine nitrogen of pyridoxamine and its analogs, spectra of methanol solutions of the following four compounds were examined ; pyridoxamine (I), 3-hydroxy-4-aminomethylpyridine (II), 1-methylpyridoxamine chloride (III), and 1-methyl-3-hydroxy-4-aminomethylpyridinium chloride (IV). Assignments of the absorption bands to molecular species present in methanol solutions are summarized in Table I. Similarities of spectral characteristics of N-protonated and N-methylated species were shown by comparison of the spectra of the compounds. On the basis of the absorption bands assigned to Zn (II), Cu (II) and Ni (II) chelate of III and IV (Table II), the presence of N-protonated species of metal chelates of I and II in acidic methanol and their spectra are discussed (Table III).

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The effect of transmucosal fluid movement on drug absorption from rat small intestine was studied, using in situ recirculation of perfusion method. Transmucosal fluid movement was obtained by using perfusion solutions of various tonicities of sodium chloride or glucose, and drugs emploved were sulfanilamide, sulfisoxazole and metoclopramide. The results obtained revealed that the drug absorption was increased with increasing the transmucosal fluid movement from lumen to blood, and in the case when the fluid was secreted, that is, counter directional fluid movement was obtained, the absorption was found to be decreased. These relations became apparent from figures in which the absorption on the horizontal axis and the ratio of the fluid movement on the vertical axis. Using the method of the illustration of figure, the effect of glucose on drug absorption had become occasionally apparent.

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The thermal behavior of the δ form of chloramphenicol palmitate was examined by differential scanning calorimetry. The previous prediction that by very rapid quenching the melted chloramphenicol palmitate would crystallize to the δ form was realized on cooling at 80°/min using helium as a purge gas in the Perkin-Elmer DSC 1B. The heat of crystallization from the melt to the δ form (-2.8±0.2 kcal/mole) and the heat of transition from the δ form to the sub-α form (-2.7±0.2 kcal/mole) coincided with the predicted values (-2.9±0.5 and -2.2±0.7 kcal/mole), respectively. The area under the broad exothermal peak (P₂) corresponding to the change from the sub-α form to the α form could not be determined directly in this experiment and was calculated from the equation (1).

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Polymethylene bis-amines, with heterocycle as a carrier moiety, and their sulfonamides were synthesized and tested against S. aureus, E. coli and M. tuberculosis (H37Rv strain). Structure-activity relationship has been discussed.

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Reaction of 6-methyl-2-phenyl-4H-1, 3-oxazin-4-one (I) with active methylene compounds, such as diethyl malonate (IIIa), acetylacetone (IIIb), cyclohexane-1, 3-dione (IIIc), malononitrile (IIId), ethyl acetoacetate (IIIe), ethyl cyanoacetoacetate (IIIf), and cyanoacetophenone (IIIg) afforded pyridone derivatives, such as 3-acetyl-5-ethoxy-carbonyl-4-hydroxy-6-phenyl-2 (1H)-pyridone (IVa), 3, 5-diacetyl-4-methyl-6-phenyl-2 (1H)-pyridone (IVb), 4-acetyl-1-phenyl-6, 7-dihydro-3, 8-(2H, 5H)-isoquinolinedione (IVc), 3-acetyl-4-amino-5-cyano-6-phenyl-2 (1H)-pyridone (IVd), 3-acetyl-5-ethoxycarbonyl-4-methyl 6-phenyl-2 (1H)-pyridone (IVe), 3-acetyl-5-cyano-4-hydroxy-6-phenyl-2 (1H)-pyridone (IVf), and 3-acetyl-5-cyano-4, 6-diphenyl-2 (1H)-pyridone (IVg), respectively. Similarly, 2-ethoxy-2, 6-dimethyl-2H-1, 3-oxazin-4 (3H)-one (II) reacted with IIIa-t under the same conditions to give the corresponding pyridone derivatives (Va-f).

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1-Alkoxy-3, 6-dimethyl-5-nitro-4 (1H)-pyridazinones (VIIa, b) were synthesized by the nitration of 3, 6-dimethyl-4-hydroxypyridazine 1-oxide (IV), followed by alkylation with alkyl halides. The catalytic hydrogenation of the nitro compound VIIa gave 1-methoxy-3, 6-dimethyl-5-amino-4(1H)-pyridazinone (IX). 1-Methoxy-3, 6-dimethyl-5-bromo-4 (1H)-pyridazinone (XI) was similarly synthesized by the bromination of IV, followed by alkylation.

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The effect of thyroparathyroidectomy and thyrocalcitonin on the bone acid phosphatase activity and the serum calcium level in lead-treated rats was studied. Lead administration to intact rats produced a significant increase in bone acid phosphatase activity and serum calcium level. Thyroparathyroidectomy significantly decreased the bone acid phosphatase activity and the serum calcium level in intact normal rats. However, lead administration prevented this reduction. Thyrocalcitonin injection significantly depressed the bone acid phosphatase activity and the serum calcium level elevated by the administration of lead to thyroparathyroidectomized rats and intact normal rats. The present results suggest that the increase in the bone acid phosphatase activity and the serum calcium level caused by lead administration is independent upon the action by parathyroid hormone.

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The treatment of 6-(benzylidene-1'-methylhydrazino)-3-methyl-5-nitrouracil (I) with sulfuric acid in acetic acid gave a mixture of 1, 6-dimethyl-5, 7-dioxo-8-nitro-3-phenyl-1, 5, 6, 7-tetrahydro-s-triazolo [4, 3-c] pyrimidine (III) and 1, 5-dimethyl-3-phenylpyrazolo-[3, 4-d] pyrimidine-4, 6 (5H, 7H) dione. The reaction in the presence of potassium nitrate under the same conditions gave exclusively III. The reaction of 6-(benzylidene-1'-methylhydrazino)-3-methyluracil with potassium nitrate in acetic acid in the presence of sulfuric acid gave a mixture of 3-phenyltoxoflavin and 3-phenyl-1-demethyltoxoflavin. The treatment of 6-benzylidenehydrazino-3-methyl-5-nitrouracil with potassium nitrate in acetic acid (with or without sulfuric acid) gave 5, 7-dioxo-6-methyl-8-nitro-3-phenyl-1, 5, 6, 7-tetrahydro-s-triazolo [4, 3-c] pyrimidine. The treatment of 6-benzylidenehydrazino-3-methyluracil with sodium nitrite in acetic acid at low temperature gave the corresponding 5-nitroso derivative, which was converted into 3, 6-dimethyl-2, 4, 5, 7 (1H, 3H, 6H, 8H)-pyrimido [5, 4-g] pteridinetetrone by treatment with a mixture of acetic acid and sulfuric acid.

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As an extention of the studies on metabolism and excretion of aminopyrine, 4-formylaminoantipyrine which has been already reported as a new metabolite in man's urine was detected also in the urine of rabbits, guinea pigs and rats by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS).

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Aus den oberirdischen Teilen von Pteris oshimensis HIERON wurden zwei weitere Pterosinglykoside isoliert und als Pterosin Q-3-β-L-Arabinopyranosid und Pterosin C-3-β-L-Arabinopyranosid identifiziert.

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E-and Z-forms of 10, 11-dihydroatlantone and its 6-oxo-compound were newly isolated in optically inactive form from heart wood of Ginkgo biloba L. These structures were confirmed by synthesis stating from limonene.

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Two new neutral cannabinoids, cannabichromevarin and cannabigerovarin, were isolated from the "Meao variant, "Thailand Cannabis and their structures were determined to be the homologues of cannabichromene and cannabigerol which have a propyl sidechain, respectively, on the basis of spectral and chemical evidences.

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The structure and absolute stereochemistry of dihydroflorilenalin, a new guaianolide isolated from Helenium autumnale L., have been determined on the basis of physicochemical data, chemical transformation, and X-ray crystallographic analysis.

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