The elimination of seven barbiturates from plasma was studied in rabbits after intravenous administration at a dose of 20-80 mg/kg. The elimination rate constant, elimination half-life, and apparent volume of distribution of barbiturates did not depend on the dose. The area under the plasma concentration-time curve (AUC) of each barbiturate increased in proportion to the dose. Therefore, the distribution and elimination of barbiturates were considered to follow linear kinetics in rabbits. The elimination rate constant of barbiturates at a given dose was linearly related to the lipid solubility (measured as the partition coefficient between chloroform and pH 7.4 phosphate buffer). To investigate the effect of lipid solubility on the metabolism of barbiturates, the in vitro rate of metabolism in rabbit liver microsomes was determined. Only barbital (having low lipid solubility) was hardly metabolized during incubation for 60 min. A linear relationship was obtained for six barbiturates (not barbital) in a logarithmic plot of the in vitro metabolic rate constant vs. the partition coefficient. Furthermore, the in vivo elimination rate constant of the six barbiturates showed a good correlation with the in vitro metabolic rate constant in a logarithmic plot (r=0.9670). These results indicate that barbital was mainly eliminated by renal excretion, while other barbiturates were mainly eliminated metabolically in the liver, depending on their lipid solubilities.

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In order to elucidate the interactions of the components of an aminopyrine (28.9 mg)-phenacetin (57.8 mg)-phenobarbital (13.3 mg) preparation on repeated administration (100 mg/kg of body weight) to mice, the analgesic activity of the preparation, the hepatic drug-metabolizing enzyme activities and the plasma concentrations of phenobarbital, phenacetin and acetaminophen in mice dosed repeatedly for 7 days were estimated in comparison with a single dose group. The analgesic activity was significantly decreased and the liver drug-metabolizing enzyme activities were markedly enhanced after the repeated treatment as compared with the results obtained following a single dose. The plasma levels of phenacetin were markedly lower at both 45 and 90 min in the repeated dose group, while the levels of acetaminophen and its glucuronide were higher in mice dosed repeatedly than in the single dose group 45 min after intraperitoneal injection, but lower after 90 min. The plasma concentrations of phenobarbital 45 and 90 min after the combined drug were not significantly different in the single and repeated dose groups. When the induction rate of the drug-metabolizing enzymes by the combined drug was compared with that by phenobarbital alone, there was a clear-cut correlation (r=0.986 for repeated dosing and r=0.985 for a single dose). This strongly suggests that phenobarbital in the combined analgesic induced metabolic inactivation of the other component drugs without significant enhancement of its own metabolism, while aminopyrine and phenacetin had no such effect.

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Addition of methanol or water to the N-cyano group in 3-cyano-1, 1-dichloro-2-methoxy-1a, 2, 3, 7b-tetrahydro-1H-cyclopropa [c] quinoline (1a) afforded the corresponding N-imino ester or N-carboxamide compounds under alkaline (sodium hydroxide) conditions. Hitherto unknown N-unsubstituted 2-alkyl (or aryl)-1a, 2, 3, 7b-tetrahydro-1H-cyclopropa [c] quinolines were obtained in excellent yields by the reaction of 1a with Grignard reagents (RMgX : R=Me, Et, n-Pr, iso-Pr, n-Bu, PhCH₂, Ph, X=Cl, Br, I) in an ethereal medium. Ring expansion to produce benzazepine derivatives did not take place.

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α-Chymotrypsin, trypsin, elastase and acyl-α-chymotrypsin contain a charge relay structure composed of aspartate, histidine and serine or water ; in trypsin and elastase, histidine forms a bifurcated hydrogen bond with aspartic acid, while on the other hand, histidine of α-chymotrypsin forms a linear hydrogen bond. First, in order to determine the origin of the charge relay structure, the interaction energy between histidine and aspartate was calculated by the ab initio method. Since the bifurcated structure was much less stable than the linear one, it was suggested that reactions of enzymes containing the bifurcated hydrogen bond structure will occur via a linear hydrogen bond. The main contributors to the stability difference were the differences of electrostatic interaction energy and charge transfer energy. Moreover, the position of the proton between histidine and aspartate was determined by geometry optimization. Since the proton took a position midway between N of histidine and O of aspartate, the complex was named "hispartic acid." The interaction energy between water and hispartic acid was more stable than that between water and the histidine anion ; this was due to the differences of electrostatic interaction energy and exchange repulsion energy. Secondly, the interaction energies between water and histidine were calculated in detail ; the linear hydrogen bond structure was more stable than the bifurcated one. These energies were also decomposed in order to elucidate their origins.

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The reactions of 4, 6-phenanthroline (I) and its N-oxides, 6-oxide (II) and 4, 6-dioxide (IV), with dimethyl sulfoxide were carried out in the presence of sodium hydride (or potassium tert-butoxide), and 3-monomethyl compounds (V, VI, and IX) were obtained from all the compounds. This reaction of the 4-oxide (III) resulted in deoxygenation of the N-oxide group to afford the 3, 5-dimethyl compound (VII) and 5-(methylsulfinyl)-methyl-4, 6-phenanthroline (VIII). The same reaction of 1, 10-, 1, 7-, and 4, 7-phenanthrolines (X, XI, XII) gave the 4-methyl compound (XVI) and 4, 7-dimethyl compound (XVII) from X, and the 4-methyl compound (XVII) and 7-(methylsulfinyl) methyl compound (XIX) from XI, while XII gave a polymer. The reaction of their N-oxides, 1, 10-phenanthroline 1-oxide (XIII), 1, 7-phenanthroline 1-oxide (XIV), and 4, 7-phenanthroline 7-oxide (XV), for 30 min resulted in liberation of the N-oxide group to form benzo [h] quinoline (XX) in the former two cases and benzo [f] quinoline (XXIII) in the latter case. Reaction of XIII for 4 hr resulted in the formation of compounds of XX methylated at the 6- or 5-position (XXI and XXII). The same reaction was carried out in an NMR sample tube, and it was shown that N-oxide liberation occurred in the reaction mixture ; the previously proposed reaction mechanism had to be corrected. Calculation of the reaction indices of 4, 6-phenanthrolines by Huckel's molecular orbital method gave values agreeing well with the experimental results.

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The metabolic fate of 1, 4-dimorpholino-7-phenylpyrido [3, 4-d] pyridazine (DS-511) was studied in the rat and the dog. Urine and bile were extracted with ethyl acetate before and after enzymatic hydrolysis and separated into lipophilic and hydrophilic fractions. The structures of seven lipophilic and two hydrophilic metabolites obtained on thin-layer chromatograms were investigated by comparing their ultraviolet, infrared and nuclear magnetic resonance spectra, Rf values on thin-layer chromatograms and other physicochemical properties with those of synthetic samples. The main metabolites were 7-(4-hydroxyphenyl)-1, 4-dimorpholinopyrido [3, 4-d] pyridazine and 4-[N-carboxymethyl-N-(2-hydroxyethyl) amino]-1-morpholino-7-phenylpyrido [3, 4-d] pyridazine. In addition, 7-(4-hydroxy-3-methoxyphenyl)-1, 4-dimorpholinopyrido [3, 4-d] pyridazine and 7-(4-hydroxy-3-methoxyphenyl)-4-morpholinopyrido [3, 4-d] pyridazin-1 (2H)-one were observed as minor metabolites in the dog and the rat, respectively.

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The stability of vitamin A (VA) acetate in ethanolic solutions with various water contents and the formation and disappearance of its major decomposition products were studied quantitatively by high performance liquid chromatography (HPLC) using Li-Chrosorb Alox T (basic alumina). Three major decomposition products were fractionated by HPLC and identified as anhydro VA, 4-ethoxy anhydro VA, and VA ethyl ether. VA ethyl ether has an ultraviolet (UV) spectrum similar to that of VA acetate and caused interference with the estimation of VA acetate in these test solutions by UV spectrophotometry. The structure of 4-ethoxy anhydro VA, which has a UV spectrum similar to that of the retro VA analog, was assigned by mass spectroscopy, nuclear magnetic resonance, UV, and infrared analyses. This substance was largely converted into anhydro VA in aqueous ethanolic solution and is thus considered to be a precursor of anhydro VA.

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The complex of 1-anilinonaphthalene-8-sulfonate (ANS) and chlorpromazine was studied by chemical and spectroscopic methods. Elemental analysis indicated that the complex is composed of equimolecular quantities of ANS and chlorpromazine. Spectral data suggested that there is a strong interaction of the anilino hydrogen with the sulfonate group, and that hydrophobic stacking between the phenothiazine ring of chlorpromazine and the aromatic ring of ANS may occur. The fluorescence intensity of ANS in the presence of chlorpromazine was more markedly enhanced in chloroform than in water. Thus, it is likely that molecular rigidity and coplanarity of the aromatic rings of ANS are the dominant factors influencing the quantum yield of fluorescence of ANS. Finally, the enhancement in fluorescence of ANS in the presence of serum albumin and chlorpromazine is interpretable in terms of complex formation on the binding sites of albumin.

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Lysergic acid diethylamide (LSD) was biotransformed by various species of microorganisms to give four metabolites ; lysergic acid ethylamide (LAE), and norlysergic acid diethylamide (norLSD) are already known, but lysergic acid ethyl-2-hydroxyethylamide (LEO) and lysergic acid ethylvinylamide (LEV) have not been reported previously. Characteristic features of Streptomyces roseochromogenes and S. lavendulae were noted in biotransformation experiments with LSD and isoLSD. The latter has an enzyme system for the demethylation of LSD and isoLSD, but the former does not. Using the technique of reincubation of metabolites, the metabolic pathway from LSD to LEV or LEO in S. roseochromogenes was studied, and the pathway of biotransformation from LEV to LEO was established.

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Four new dibenzocyclooctadiene lignans, angeloyl-(1), tigloyl-(2) and benzoyl-gomisin H (3) and gomisin H (4), were isolated from the fruits of Schizandra chinensis BAILL. (Schizandraceae). Their structures were elucidated by chemical and spectral techniques.

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Two new lignans named pre-gomisin (1) and gomisin J (2) were isolated from the fruits of Schizandra chinensis BAILL. (Schizandraceae). The structure of the former was elucidated as (2S, 3R)-1, 4-bis (3´-hydroxy-4´, 5´-dimethoxyphenyl)-2, 3-dimethylbutane (1) by its preparation from guaiaretic acid. The structure and conformation of the latter were elucidated by chemical and spectral studies.

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The desired compound (10) was synthesized from crude stachyose (1). Compound 1, separated from tubers of Stachys sieboldi MIQ., was heated with aqueous acetic acid to yield manninotriose, which was isolated as a crystalline β-undecaacetate (2). Treatment of 2 with saturated hydrogen bromide in acetic acid afforded a crystalline acetobromomanninotriose (3). Methyl glycosidation of 3 followed by deacetylation gave methyl β-manninotrioside (4) as a white powder. Selective tritylation and subsequent acetylation of 4 afforded a crystalline methyl nona-O-acetyl-6"-O-trityl-β-manninotrioside (6). Stirring of 6 with acetobromogalactose in nitromethane in the presence of silver perchlorate and Drierite yielded the acetate (9) in 42% yield. Deacetylation of 9 gave 10 as a white powder. Methylation of 10 by Hakomori's method gave a crystalline fully methyl ether (11). The structure of 10 was confirmed by GC and GC-MS analyses of acid hydrolysates of 11. β-Galactosidase from jack bean meal hydrolyzed 10 to D-galactose and methyl β-manninotrioside.

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The hypoglycemic activity and physico-chemical properties (pK_a, log P) of cyclic guanidines were measured. Qualitative structure-activity relationships were investigated in various mono-, bi-, and tricyclic guanidines and it became apparent that compounds which have a bulky group and a pK_a value between 8-11 showed potent activity. It was possible to correlate hypoglycemic activity with the pK_a values and partition coefficients of cyclic guanidines.

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During the course of re-investigation of the cardiac glycosides of Nerium, new cardenolides with a novel aglycone moiety were isolated and named oleasides A-F. The structure of the aglycone, oleagenin, was established as 3β-hydroxy-15 (14→8) abeo-5β-(8R)-14-oxo-card-20 (22)-enolide, and the sugar moieties were identified as D-diginose (oleaside A), D-digitalose (-B), β-D-glucosyl-D-diginose (-C), 4-O-β-D-glucosyl-D-digitalose (-D), β-gentiobiosyl-D-diginose (-E) and 4-O-β-gentiobiosyl-D-digitalose (-F).

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The structures of tryptoquivaline L, M and N, which were newly isolated from the fungus, Aspergillus fumigatus, have been elucidated as 1, 3 and 11, respectively. Concomitantly, the previously proposed structures of tryptoquivaline C (9) and D (4) have been revised to 10 and 8. The exchange of the hydrogen on C-12 during epimerization of the dextrorotatory tryptoquivalines was demonstrated by means of a deuterium NMR spectral study.

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A potent kinin-inactivating enzyme, Shimeji kininase, may have applications in research on the kallikrein-kinin system in the body. In order to test its suitability, the effects of this enzyme, in addition to kinin destruction, on substances related to the kallikrein-kinin system were investigated. This enzyme hardly affected the esterase activities of the glandular kallikreins. It destroyed the heat-denatured kininogens of various species, but did not attack the native rat low molecular weight kininogen molecule. The vasodilative activity of this enzyme assayed in the dog was almost negligible, and no kinin activity could be detected in incubation mixtures of this enzyme and heatdenatured kininogens of various species by the Magnus method. Therefore, this enzyme does not have kininogenase activity, and its destruction of the heat-denatured kininogens was not due to kinin liberation from the kininogens. Intravenous injection of this enzyme in the rat caused the depletion of plasma high molecular weight kininogen, presumably due to plasma prekallikrein activation, while the low molecular weight kininogen level in plasma was not significantly changed.

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The origin of the borazane complex, which is composed of NH₃ (C_3V) and BH₃ (C_3V), was studied from a quantum-chemical point of view. Calculations were carried out by the ab initio method. A double zeta basis set with polarization functions (4-31G^**) and a single zeta basis set (STO-3G) were used. In order to identify the origin of the complex, energy decomposition analyses were carried out at the molecular orbital level. Among the MO-MO interactions which contribute to charge transfer (CT) in the complex formation, the following are significant in the order indicated. [numerical formula] As for the repulsion energy, A₁-A₁ and valence-valence MO interactions were significant. HOMO-HOMO interaction was dominant in exchange repulsion. Moreover, valence-core MO interaction and E-E MO interaction could not be neglected. On the other hand, it appeared that the internal rotation barrier of the complex might originate from le-le MO interaction. Therefore the same analysis was applied to ethane, disilane, methylsilane, H₃B-CH₃^-and H₃N-CH₃⁺. These quantitative analyses showed that the le-le MO interaction is the most important component in the internal rotation barrier of these compounds and complexes.

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The thiocarbamoylaminophosphonium salt (3) obtained from an amine (1) and TPPT (2) has been shown to be a useful synthetic intermediate for the preparation of thioureas (4), amides (10) and acylthioureas (11) by treatment with water and a carboxylic acid (9). The reaction mechanism is discussed.

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Both enantiomers of methyl (or ethyl) phenyl phosphoramidate (8, 13) were prepared from the corresponding diastereomeric amidates of L-phenylalanine ester (5, 10), via a transaminative reaction involving the following sequence : N-chlorination, treatment with sodium methoxide, and mild acid-catalyzed hydrolysis of the resulting amino acetal (7, 12). Stereochemical studies of H⁺- and BF₃-catalyzed alcoholyses of 8 and 13 indicated that the nature of the acid catalyst had a profound effect on the steric course of the reaction. Complete stereospecificity observed in H⁺ catalysis was ascribed to direct displacement with inversion of configuration at phosphorus (A-2 mechanism). On the other hand, BF₃ catalysis, which produced both inversion (70%) and retention product (30%), was explained in terms of (1) a pentacoordinate intermediate mechanism for retention product formation and (2) a dual mechanism, pentacoordinate intermediate and direct displacement A-2 mechanisms, for inversion product formation.

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Partial acid hydrolysis of Abelmoschus-mucilage M, a representative mucilage isolated from the roots of Abelmoschus manihot MEDICUS, led to the isolation of three oligosaccharides. Analysis of components, reduction and methylation, and partial degradation studies showed that these oligosaccharides are O-α-(D-galactopyranosyluronic acid)-(1→2)-L-rhamnopyranose, O-β-(D-glucopyranosyluronic acid)-(1→3)-O-α-(D-galactopyranosyluronic acid)-(1→2)-L-rhamnopyranose, and O-β-(D-glucopyranosyluronic acid)-(1→3)-O-α-(D-galactopyranosyluronic acid)-(1→2)-O-α-L-rhamnopyranosyl-(1→4)-[O-β-(D-glucopyranosyluronic acid)-(1→3)]-O-α-(D-galactopyranosyluronic acid)-(1→2)-L-rhamnopyranose. The structural features of the polysaccharide moiety in the mucilage are discussed.

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Sterility tests of distilled water obtained through faucets in hospitals revealed that all of the samples were contaminated with microbes. Once the faucets became contaminated with airborne microbes, all distilled water obtained subsequently was contaminated. Two types of microbial barrier faucets were manufactured and tested by a method for microbial contamination testing using air artificially loaded with bacteria, as reported in the previous paper. One of the faucet was reasonably effective in preventing airborne microbial contamination, but further improvement is required for practical purposes.

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Hydrolytic reactions of 5, 5-disubstituted 1-methylbarbituric acid derivatives at 30°, 40°, and 50° in alkaline solutions of various concentrations were investigated, and the rate constants and thermodynamic parameters of all of the compounds tested were determined. As physico-chemical parameters which might reflect the substituent effect on the hydrolytic rate, the acid dissociation constant (pK_a), the value of ¹³C chemical shift (δ_c) at the 5-position, the "six number" (Six No.), and the molecular connectivity index (χ) were selected. An extrathermodynamic linear equation was then derived using these parameters. The correlation between log k'OH and the combined parameters pK_a and δ_c (5) was largest, as determined by multiple regression analyses.

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The effects of porcine calcitonin (CT), salmon CT, or synthetic eel CT ( [Asu^{1, 7}] ECT) on the calcium concentrations in the bile and serum have been examined after a single intraperitoneal administration of calcium chloride to thyroparathyroidectomized rats. The administration of these hormones (80 MRC mU/100 g body weight, respectively) markedly increased calcium excretion into the bile within 1 hr after the injection of calcium chloride (4.0 mg Ca/100 g). The effect of synthetic eel CT was more prolonged than that of any other hormone (up to 3 hr after administration). The administration of porcine CT, salmon CT, or synthetic eel CT significantly inhibited the elevation of serum calcium concentration within 1 hr after the injection of calcium. The serum calcium concentration was slightly decreased at 3 hr after the administration of salmon CT or synthetic eel CT. These results suggest that the lowering effect of CT on the serum calcium level results partly from the stimulation of calcium excretion into the bile.

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N-Methyl-3-methyl-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid (MDTI), a new chemical compound, was prepared by cyclization of α-methyl-α-(3, 4-methylenedioxybenzyl)-α-aminoacetonitrile with formaldehyde and formic acid, followed by hydrolysis with hydrochloric acid. The compound (MDTI) showed extremely high electron-donating activity and was found to have excellent antioxidant properties.

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Exposure of 11β, 17α-dihydroxy-21-methylpregna-1, 4-diene-3, 20, 21-trione 17-acetate (Ia) and 17α-hydroxy-21-methylpregn-4-ene-3, 20, 21-trione 17-acetate (Ib) in EtOH to sunlight gave products having a new ring system in excellent yields, i.e., 3´, 4´, 16α, 17α-tetrahydro-4´ξ, 11β, 17α-trihydroxy-4´ξ-methylcyclobut [16, 17] androsta-1, 4, 16-triene-3, 3´-dione 17-acetate (IIa) and 3´, 4´, 16α, 17α-tetrahydro-4´, 17α-dihydroxy-4´ξ-methylcyclobut [16, 17] androsta-4, 16-diene-3, 3´-dione 17-acetate (IIb). The structures of the products were assigned on the basis of spectral data.

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N-Acylaminorhodanine (II) reacted with hydrazine hydrate to afford the mesoionic 4-amino-1, 2, 4-triazolium-3-thiolate (I). Reactions of I with methyl iodide, sodium nitrite, and acylating agents were investigated. Acylation of I gave diacyl derivatives (VII and VIII), and alkaline hydrolysis of these compounds afforded monoacyl derivatives (IX and X). The monoacyl compounds (IX-XI) were derivatived to aminimides (XII-XIV) by treatment with methyl iodide and alkali.

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Reaction of the mesoionic 4-amino-1, 2, 4-triazolium-3-thiolates (I) with cyanogen bromide gave bicyclic mesoionic compounds (III) related to the product (II) obtained on treatment of I with phosgene. Benzoylation, tosylation, and nitrosation at the exocyclic nitrogen of III were also investigated.

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New types of methylene compounds, N-alkylthiomethyl derivatives of N-alkyl (or aryl) hydroxylamines and N, N-bis (alkylthiomethyl) hydroxylamines, have been obtained by Mannich-type condensation using thiols, formaldehyde and hydroxylamines.

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A method for separation and determination of optical isomers of 2, 2´-(4, 4´-cyclohexylidenediphenoxy)-2, 2´-dimethyldibutyric acid (clinofibrate) by high-performance liquid chromatography was developed. meso, d- and l-isomers of clinofibrate were derivatized with D-(+)-α-methylbenzylamine to the corresponding diastereomer amides, which were separated from one another by high-performance liquid chromatography. Each isomer in clinofibrate was determined. The chromatographic conditions were as follows : column, stainless-steel two connecting columns (150 mm in length and 4 mm in i.d.) packed with LiChrosorb SI-60 (5 μm) ; mobile phase, n-hexane/isopropanol (500/3, v/v) ; flow rate, 1.6 ml/min ; detector, UV photometer at 254 nm.

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A novel 2, 3-pyrrolidinedione ring closure has been found to be induced on heating 1, 1, 1, 5, 5, 5-hexachloro-4-dimethylamino-3, 3-dimethyl-2-pentanone in ethanol in competition with the formation of α-chloro-γ-ketoacylamine.

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Trialkylphosphates, (RO)₂P(O)OR', were prepared from dialkyl hydrogen phosphites, (RO)₂PHO, and lithium chloride in R'OH by constant current electrolysis at a glassy carbon anode. Electrolysis at an anode having a larger area and at a lower current density gives better yields of the products. The electrolytic phosphorylation was also performed in acetone and in acetonitrile.

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Cholesterol esterase was purified about 85 times from the broth filtrate of Streptomyces lavendulae by procedures involving precipitation with ammonium sulfate, reprecipitation with acetone, affinity chromatography on palmitoyl cellulose, and ion exchange chromatography on DEAE-cellulose. The purified enzyme showed a single band on polyacrylamide disc gel electrophoresis and SDS-polyacrylamide gel electrophoresis, and the specific activity of the enzyme was 36.3 U/mg. The molecular weight of the enzyme was 12000 as determined by SDS-polyacrylamide gel electrophoresis. The enzyme showed different properties from other cholesterol esterases as regards its affinity for cholesterol.

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Carbocyclic analogs of captopril (SQ-14225, I), an angiotensin-converting enzyme (ACE) inhibitor, were synthesized starting from methyl cyclopentenoate (III) in order to examine their inhibitory activity of ACE.

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An ATP-independent phosphotransferase was newly found to be widely distributed in higher plants. This novel enzyme catalyzes the synthesis of O-phospho-L-homoserine from O-succinyl-L-homoserine and K-phosphate. About 1/15-1/18-fold activity was observed when O-acetyl-L-homoserine replaces O-succinyl-L-homoserine, but L-homoserine itself could not serve as a donor of the 3-amino-3-carboxypropyl-moiety. Some other properties of the enzyme are also described.

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