The structures of the complexes of Fe²⁺ and Mn²⁺ with citric acid were investigated by infrared spectroscopy. The compounds used were [Mn (H₂O)₆] [Mn (C₆H₅O₇) H₂O]₂·2H₂O, Mn (C₆H₆O₇)·H₂O and Na₄ [Fe (C₆H₅O₇)₂]. In the IR spectra of the last complex, the strength of the band assignable to the stretching vibration of the alcoholic OH group of the citrate ion was weaker than in the free molecule. This result suggests that the OH group contributes to the chelate formation. Na₄ [Fe (C₆H₅O₇)₂] is considered to be octahedral, with the two trivalent citrate anions binding to the central iron (II) ion. Thus, two of the three carboxyl groups and one OH group within a citrate ion combine with the Fe²⁺ ion, and one carboxyl group of the citrate ion is free. On the other hand, the Mn²⁺ ion within Mn (C₆H₆O₇)·H₂O crystals is considered to take a tetrahedral configuration, and again one of the three carboxyl groups of the coordinated citrate ion remains as nonbonded and undissociated COOH. In Mn (C₆H₆O₇)·H₂O, the water molecule seems to bind to the central metal ion. The carboxyl groups of [Mn (H₂O)₆] [Mn (C₆H₅O₇)·H₂O]₂·2H₂O compound acted as either monodentate or bridging ligand groups.

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Thermal decomposition of several 1, 3-diaryl-1-nitrosoureas (Ia-e) in benzene gave denitrosated 1, 3-diarylureas (IIa-e), benzene derivatives (IIIa-e), biphenyls (IVa-e) and newly formed 1, 3-diarylureas (Va-e). Based on these results, pathways of the decomposition are proposed. Compounds Ia-e rearrange to the corresponding arylazo arylcarbamates (VIa-e), which decompose to give such intermediates as diazonium ions (VIIa-e), arylcarbamate anions (VIIIa-e) and aryl isocyanates (IXa-e). These intermediates further react with the solvent or other species to give the final products. The existence of these intermediates was confirmed by chemical and spectral studies.

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The reaction of 2, 4-dichloroquinazoline with N-methylpyrrolidine gave N-(2-chloro-4-quinazolinyl)-N-methylpyrrolidinium chloride. This product, on being heated, gave 2-chloro-4-[N-(4-chlorobutyl)-N-methylamino]-quinazoline and it reacted with water in the presence of excess N-methylpyrrolidine to give a stable betaine, 4-(1-methyl-1-pyrrolidinio)-2-quinazolinolate. By using this reaction, several new 4-[N-alkyl-N-(ω-chloroalkyl) amino]-2-chloroquinazoline derivatives were prepared from 2, 4-dichloroquinazoline and N-alkyl cyclic amines.

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Five steroidal compounds were isolated from the dried underground part of Aspidistra elatior BLUME (Liliaceae), and four of them were elucidated to be aspidistrin (diosgenin 3-O-β-lycotetraoside), proto-aspidistrin, methyl proto-aspidistrin, and 1β, 2β, 3β, 4β, 5β-pentahydroxyspirost-25 (27)-ene (Δ^{25 (27)}-pentologenin or Δ^{25 (27)}-neopentologenin), on the basis of physical and chemical investigations. The remaining steroidal compound is suggested to be a new spirostanol compound.

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A method was designed to study complex formation between saponin and cholesterol in aqueous ethanol, and was applied, with some modifications, to examine the ability of cholesterol analogues bearing various lengths of side-chain to form complexes (digitonides) with digitonin. The results indicated that all the analogues were capable of forming digitonides regardless of the length of the side-chain, but the effectiveness of digitonide formation increased as the length of the side-chain increased. A plausible structural model is proposed for the digitonide in order to interpret these results.

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The chemical structure of the chromo-and fluorophoric species χ-600 (λ_max=600nm, λ_em=615nm), which is formed in the reaction of testosterone (I) with sulfuric acid, was elucidated. The chemical species χ-600 was shown to be produced from the intermediary χ-300 (λ_max=300nm) through oxidation of its conjugate base (IV). 17-Methyl-18-norandrosta-4, 6, 8 (14), 13 (17)-tetraen-3-one (X), the conjugate base of χ-600, was isolated from the reaction of 17β-hydroxyandrosta-4, 6-dien-3-one (VIII) with a mixture of selenic acid, sulfuric acid, and ethanol. The ¹H-nuclear magnetic resonance spectrum of X in 53% deuterio sulfuric acid indicated that χ-600 is a hydroxyalkatetraenyl cation (VII). On the basis of the results described above, a mechanism is proposed for the color and fluorescence reaction.

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Two new steroidal oligoglycosides, named cynanchoside C₂ (1a) and cyanchoside C₁ (2a), were isolated from the rhizome of Cynanchum caudatum MAX. The structures of 1a and 2a were elucidated by the application of ¹³C-nuclear magnetic resonance spectroscopy and chemical reactions.

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Various aliphatic and aromatic carboxamides smoothly underwent N-acetoacetylation by means of the diketene-iodotrimethylsilane system to give the corresponding N-acetoacetyl derivatives. The diketene-bromotrimethylsilane system was found to be very efficient for N-acetoacetylation of unsaturated carboxamides such as acrylamide and methacrylamide. In addition, acyl Meldrum's acids proved effective for N-acylacetylation of carboxamides, especially heterocyclic carboxamides such as picolinamides.

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Deoxyobtusilactone A was synthesized from 1-tetradecene by a route involving [3, 3]-sigmatropic rearrangement of 1, 1-dichloro-2-(2-propenoxy)-1-hexadecene, followed by Favorskii rearrangement of the resulting γ, δ-unsaturated α, α-dichloroketone.

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Some novel compounds having a fluoromethyl group at the C₇-position on 1-alkyl-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid and on 1-alkyl-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid were prepared and their antibacterial activities were examined in vitro. In a series of quinolines, no striking difference of antibacterial activities between the 7-fluoromethyl and 7-methyl derivatives was observed. However, the activity was increased in the series of 1, 8-naphthyridines by replacement of the methyl group with the fluoromethyl group. As regards the N₁-substituents, the 2-fluoroethyl compound showed a higher activity than the others.

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Polyfluorinated derivatives of 1-alkyl-1, 4-dihydro-7-methyl-4-oxoquinoline-3-carboxylic acids were synthesized and examined for antibacterial activites in vitro. Among the N-substituents, the strength of antibacterial activity of the derivatives was in the order : CH₂CH₂F>CH₂CH₃>CH₂CF₃>CHF₂. Introduction of two fluorine atoms at the 6 and 8 positions of the skeleton (21a, b) led to high activity, but substitution of the 7-methyl group (20, 21, 25) with a fluoromethyl group (40, 41, 48) led in general to reduced activity. Thus, 6, 8-difluoro-1, 4-dihydro-1-(2-fluoroethyl)-7-methyl-4-oxoquinoline-3-carboxylic acid (21b) showed the highest activity, almost equal to that of oxolinic acid.

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By monitoring pharmacological activities, an anti-inflammatory active galactolipid [designated as M-5 (2)] and a sulfonoglycolipid [designated as M-6 (4)] which shows resistant activity against a complement fixation reaction have been isolated from the Okinawan marine sponge Phyllospongia foliascens (PALLAS). The structures of these pharmacologically active principles have been elucidated as 2 and 4, respectively, on the basis of chemical and physicochemical evidence.

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Reaction of ethyl 4-chloro (and 4-bromo) acetoacetate (1 and 2) with ammonium benzyldithiocarbamate gave ethyl 3-benzyl-4-hydroxy-2-thioxothiazolidine-4-acetate (3a), which was treated with 10% hydrochloric acid to afford ethyl 3-benzyl-2-thioxo-4-thiazoline-4-acetate (4a). Reaction of 1 (and 2) with N-substituted dithiocarbamates prepared from carbon disulfide and amines, followed by treatment with 10% hydrochloric acid gave the corresponding 4-thiazolines 4a-e. Reaction of 1 (and 2) with thioacetanilide derivatives prepared from phenyl isothiocyanate and active methylene compounds such as ethyl cyanoacetate, malononitrile, ethyl malonate, and cyanoacetamide in the presence of sodium ethoxide gave 2-substituted 4-hydroxythiazolidines 9a-c and thiophene derivative 10. Treatment of 9a-c with acid gave 4-thiazolines 8a-c, which were also prepared from compound 4e, ethyl iodide, and active methylene compounds.

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Three new chromones (8, 9, and 12), named 3'-O-angeloylhamaudol, ledebouriellol, and 4'-O-β-D-glucosyl-5-O-methylvisamminol, respectively, were isolated from the root and rhizoma of Ledebouriella seseloides WOLFF (Umbelliferae), together with five known coumarins (1-5) and six known chromones (6, 7, 10, 11, 13 and 14). The structures of 8, 9, and 12 were elucidated as (3S)-3, 4-dihydro-5-hydroxy-3-(2-methyl-2-butenyl) oxy-2, 2, 8-trimethyl-2H, 6H-benzo [1, 2-b : 5, 4-b'] dipyran-6-one, (3S)-3, 4-dihydro-2, 2-dimethyl-5-hydroxy-8-hydroxymethyl-3-(2-methyl-2-butenyl) oxy-2H, 6H-benzo [1, 2-b : 5, 4-b'] dipyran-6-one, and (2S)-2, 3-dihydro-2-(1-β-D-glucopyranosyloxy-1-methylethyl)-4-methoxy-7-methyl-5H-furo [3, 2-g] [1] benzopyran-5-one, respectively, by chemical and spectral studies.

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A series of compounds bearing the 4-(2-methyl-2-phenylpropoxy) benzyl moiety was prepared and their hypoglycemic and hypolipidemic activities were evaluated with genetically obese and diabetic mice, yellow KK. Among these compounds, 5-[4-(2-methyl-2-phenylpropoxy) benzyl] thiazolidine-2, 4-dione (18, AL-321) was found to prossess hypoglycemic and hypolipidemic activities higher than or comparable to those of ethyl 2-chloro-3-[4-(2-methyl-2-phenylpropoxy) phenyl] propionate (1a). The acidic thiazolidine-2, 4-dione ring appeared to be essential for the activities.

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Novel preparative methods for arylacetone and arylacetonitrile are described. Friedel-Crafts reactions of aromatic compounds with α-chloro-α-(methylthio) acetone (4) and α-chloro-α-(methylthio) acetonitrile (7) in the presence of Lewis acid afforded α-(methylthio)-arylacetone (5) and α-(methylthio) arylacetonitrile (8), respectively. Compounds (5) and (8) were converted into the corresponding arylacetone (6) and arylacetonitrile (9) by reduction with zinc dust in acetic acid.

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More than 100 5-substituted thiazolidine-2, 4-diones were prepared and their hypoglycemic and hypolipidemic activities were evaluated with genetically obese and diabetic mice, yellow KK. The structure-activity relationship study showed that the 5-(4-oxybenzyl) moiety is essential for substantial activity. Among these compounds, 5-(4-cyclohexylmethoxy) benzylthiazolidine-2, 4-dione (47), 5-[4-(1-methylcyclohexylmethoxy) benzyl]-thiazolidine-2, 4-dione (49, ADD-3878) and 5-{4-[2-(3-pyridyl) ethoxy] benzyl} thiazolidine-2, 4-dione (59) exhibited the most favorable properties in terms of activity and toxicity.

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Thiazolidine-2, 4-dione derivatives having one or two substituent (s) such as phenyl, heteryl and alkyl group (s) at the 5-position were synthesized and evaluated as aldose reductase inhibitors. Inhibition by the active compounds of the swelling of the lens in a rat-lens-culture assay was also measured. Among these compounds, a series of 5-(3, 4-dialkoxyphenyl) thiazolidine-2, 4-diones showed pronounced activities in both assays. Structure-activity relationships are discussed and a new approach to the synthesis of 5-arylthiazolidine-2, 4-diones is described.

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The first synthesis of the N-substituted 1, 6-dihydro-3 (2H)-pyridinones (4 and 16) is described. 1-Benzyl-1, 2, 3, 6-tetrahydropyridine (9) was treated with ethyl chloroformate to give the urethane (6), which was oxidized to the epoxide (10) with perbenzoic acid. Regioselective hydrobromination of 10 afforded the 4-bromo-3-hydroxypiperidine (11). Acetylation of 11 followed by dehydrobromination with DBU yielded the 5-acetoxy-Δ³-piperideine (13), which was hydrolyzed to the alcohol (15). Basic hydrolysis of 15 and subsequent condensation with methanesulfonyl chloride gave the sulfonamide analogue (22). The allylic alcohols (15 and 22) were oxidized to give the 1, 6-dihydro-3 (2H)-pyridinones (4 and 16), respectively.

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A synthesis of (±)-diethyl 3-benzylthio-7-oxo-1-azabicyclo [3. 2. 0] hept-3-ene-2, 2-bis-(carboxylate) (15) was accomplished.

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From the fronds of Diplazium subsinuatum (WALL.) TAGAWA, a new triterpene lactone (I) and its glycosides II, III, IV were isolated. The structure of I was established as 17, 24-dihydroxyhopan-28, 22-olide on the basis of spectral data and chemical conversions. The glycoside II was identified as 17-hydroxy-24-O-β-D-glucopyranosyl-hopan-28, 22-olide, III as 17-hydroxy-24-O-[α-L-arabinofuranosyl-(1→2)]-β-D-glucopyranosyl-hopan-28, 22-olide and IV as 17-hydroxy-24-O-[α-L-arabinofuranosyl-(1→2)]-[β-D-glucopyranosyl-(1→6)]-β-D-glucopyranosyl-hopan-28, 22-olide by spectroscopic analysis and hydrolysis reactions.

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From the fronds of Pteris bella, three new pterosin-type compounds, I, III and XI, were isolated along with pterosins B (VI), C (II), Q (VII) and T (IV), setulosopterosin (X), pterosin C 3-O-β-D-glucoside (IX) and pterosin Q 3-O-β-D-glucoside (VIII). From the fronds of Pteridium aquilinum subsp. wightianum, two new pterosin-type compounds, XVI and XVII, were isolated along with pterosins C (II), D (XVIII), F (XXII), H (XX), I (XXI) and Z (XIX) and astragalin (XXIII). The structures of the new compounds were determined on the basis of chemical and spectral data.

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The influence of triphenylphosphine, used as a ligand, on the palladium-catalyzed cross-coupling reaction of iodopyrimidines with olefins such as ethyl acrylate, acrylonitrile, and styrene was investigated. In general, the addition of triphenylphosphine was concluded to retard the reaction in the pyrimidine series. The effect of triphenylphosphine in the monoazine series is also discussed.

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A graphic program module, which can extract the pharmacophoric patterns from candidate molecules, was developed to rationalize lead generation and was added to the quantitative drug design (QDD) program. This performs molecular mechanical conformational analysis and quantum chemical calculation for a test molecule, followed by the prediction of its pharmacological features by means of retrieval of the pharmacophoric pattern data-base, which contains information on 261 pharmacophores selected according to original criteria using the atomic coordinates derived from crystallographic data. By pattern matching, as a rule, both geometry and quantum chemical indices such as electron densities (total and frontier) and frontier orbital energy are checked and molecular modelling for the test molecule is also available as an option. The example of epinephrine is shown to illustrate the use of the module. It may be useful in the evaluation process of drug activities as one of the prescreening procedures before animal tests.

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Lipid peroxidation of erythrocyte ghosts was caused by incubation in a xanthine oxidase system. Addition of superoxide dismutase to this system strongly inhibited the lipid peroxidation, implying that O₂-is an essential intermediate in the lipid peroxidation reaction. However, catalase did not inhibit but greatly promoted the lipid peroxidation, suggesting that catalase enhances net O₂-production through the stabilization of xanthine oxidase. Chemical scavengers of singlet oxygen (¹O₂) inhibited the peroxidation reaction, suggesting that the extremely reactive radical of ¹O₂ may be produced from O₂-generated by the xanthine oxidase system. Hydroxyl radical scavengers were without effect. Furthermore, the lipid peroxidation was greatly accelerated with increasing concentration of oxyHb up to 2μM. At concentrations above 2μM, however, the lipid peroxidation reaction was inhibited. In the presence of 2μM Hb, addition of superoxide dismutase or scavengers of ¹O₂ inhibited the lipid peroxidation to the same extent as in white ghosts. In the presence of 10μM Hb, however, catalase markedly prevented lipid peroxidation, whereas superoxide dismutase or chemical scavengers of ¹O₂ had little effect. These results indicate that catalse was more effective than superoxide dismutase in providing protection against lipid peroxidation induced in the presence of a relatively high concentration of Hb and that the reaction mechanism of oxygen radicals with membrane lipids was modified in the presence of Hb.

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Alterations of polypeptide backbone structure and plasminogen activator activity of human urinary urokinase (UK) denatured with 0-6 M guanidine hydrochloride (Gdn-HCl) were investigated. The fractions of helix, β-from, β-turn and unordered structure were determined by the best-curve-fitting method based on the circular dichroic (CD) spectra at 200-240 nm to be 0.14, 0.23, 0.26 and 0.37 for M.W. 55000 form (H-UK) and 0.12, 0.17, 0.32 and 0.40 for M.W. 36000 form (L-UK), respectively. In view of the variation with Gdn-HCl concentration of ellipticity at the negative extrema (204 nm for H-UK ; 202 nm for L-UK), the denaturation process was concluded not to be a two-state transition : at 2.0-3.0M Gdn-HCl, the helical and β-form fractions were immobilized within a narrow range of 0.00-0.01 for both UK forms, corresponding to almost unchanged minimal ellipticities even with the increase of Gdn-HCl concentration. This indicates that an intermediate state (I) exists besides the native (N) and denatured (D) states. At 0.75-1.25 M Gdn-HCl, an activated state (A) intervened between N and I for H-UK but not for L-UK. The N→A transition of H-UK was an exceptional transition in that the helicity steadily increased with the enhanced minimal ellipticity. This corresponded to the observation that the activity of H-UK was potentiated by 18% during this transition. At the same Gdn-HCl concentration, L-UK reduced both its activity by 27-38% and its minimal ellipticity in contrast to H-UK. These findings show that the denaturation processes consist of "four states-three transitions" for H-UK and "three states-two transitions" for L-UK.

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Encapsulation of carboquone (CQ) in liposomes was investigated by applying a reverse-phase evaporation vesicle (REV) method, and the in vitro release of CQ from the liposomes was also studied. The mean diameter of the liposomes was 0.2μm. The encapsulation efficiency in liposomes was greatly affected by the materials used for the membrane of the liposomes. The efficiency increased with a rise in the phase transition temperature of the phospholipids, the maximum encapsulation of CQ in liposomes being obtained with distearoyl phosphatidylcholine. The results of drug release showed that CQ remained in CQ-liposomes for a long time at 5°C but was released considerably faster at around the phase transition temperature (58°C) of distearoyl phosphatidylcholine.

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To clarify the cause of cracking of carbochromen hydrochloride tablets on exposure to moisture, crystal modifications of the drug were investigated in detail. At least two hydrate forms (I and II) and three anhydrate forms (I', II' and III) were found. Analyses of X-ray powder diffraction patterns, infrared spectra, the activation energy of dehydration, and other data showed that water of crystallization contained in forms I and II has different roles in the crystals. Transformation from form I to form I' or vice versa produced a mosaic structure of the crystals, whereas mutual transformation between form II and form II' did not affect the appearance of the crystal, only causing contraction or expansion of the crystal in a certain direction. These differences are believed to be closely related to phenomena occurring in tablets prepared from these crystal forms.

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The cause of cracking of tablets containing carbochromen hydrochloride was further investigated in the light of the crystal modifications described in the previous paper. In tablets, form II' crystals were transformed into dihydrates (form II) upon water absorption and this led to the occurrence of capping-like cracking of the tablet. However, tablets made of form I' crystals did not crack under the same conditions. The volume expansion of form II' tablets on exposure to moisture was larger than that of form I' tablets. Apparent density variation in the tablets was measured by the drilling load method, and it was found to be uniform in form I' tablets whereas a face of discontinuity was observed in the form II' tablets. A possible explanation of these results is that form I' crystals break down on phase transformation and the tension is dispersed in all directions. In contrast, form II' crystals expand along one of their crystal axes and create distortion in the tablet.

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Dissolution profiles of flufenamic acid (FFA) dispersed in cross-linked insoluble polyvinylpyrrolidone (polyvinylpolypyrrolidone, PVPP) were investigated by a dispersed amount method. The concentration of FFA rose very quickly and then decreased gradually, showing a typical supersaturation phenomenon. On the other hand, no supersaturation phenomenon was observed in the case of samples prepared with crystalline cellulose and potato starch as carriers in solid dispersions. In an attempt to stabilize the supersaturated state, the effects of the addition of water-soluble polymers to solid dispersions of FFA and PVPP were investigated. An adequate stabilization was obtained by the addition of methyl celluloses. Analysis of factors affecting the dissolution profiles of FFA and prediction of the dissolution behavior of FFA were carried out by a statistical technique. It was found that the penetration rate of water into sample powders, the amount of FFA adsorbed by PVPP, the cohesion tendency of sample powders the viscosity of the dissolution medium were important in the analysis of dissolution mechanisms and prediction of dissolution profiles of FFA from these systems.

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Pharmacodynamic interactions between hydralazine (HP) and phenobarbital (PB) were examined in normotensive and hypertensive rats (SHR). The hypotensive effect and the plasma concentration of HP after treatment for 7 d with the combined drugs (5mg/kg of hydralazine hydrochloride and 2.5 mg/kg of PB) or HP alone (5 mg/kg) were measured in comparison with those in a single dose group. The relationship between the hypotensive effect and plasma level of HP was analyzed on the basis of Levy's theory. In normotensive rats, the hypotensive effect was significantly decreased and the elimination of HP from plasma was markedly enhanced after the repeated treatment with the combined drugs, as compared with the results following a single dose. The decrease in the hypotensive effect and enhancement of elimination of HP in SHR, however, were less than those in normotensive rats after repeated treatment. In a single administration of the combined drugs, PB might additively contribute to the hypotensive effect of HP. An analysis of drug interaction according to Levy's theory showed a clear-cut correlation between the plasma level and hypotensive effect of HP (γ>0.968). The hypotensive effect declined linearly with time in each group. In normotensive rats, the extrapolated zerotime intercept (E₀) was decreased (77.0 to 53.6 mmHg) and the rate of decline of the hypotensive effect was enhanced after repeated treatment with the combined drugs as compared with that in the single dose group (-7.2 to -10.7 mmHg/h). The rate of decline after repeated treatment with the combined drugs in SHR was slightly smaller than that in the single dose group. The theoretical interpretation of the pharmacokinetic data obtained could account well for the pharmacological effects observed.

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DL-Polylactic acid microspheres containing dibucaine were prepared, and release patterns of dibucaine from the microspheres as well as the local anesthetic effects of the drug in the microspheres were examined. The influences of nonsolvents and dibucaine concentration at preparation on the characteristics and dibucaine contents of the microspheres were investigated. Higher pH in nonsolvents and higher dibucaine concentration at preparation resulted in increased dibucaine contents in the microspheres. The release patterns of dibucaine from microspheres varied significantly among microspheres with different dibucaine contents, and the release mechanisms of dibucaine from microspheres were greatly influenced by disintegration of the microspheres. The local anesthetic effects of 0.1 ml aliquots of dibucaine hydrochloride solutions were examined at four concentrations in vivo. Then, the local anesthetic effects of dibucaine in microspheres were compared with those of the above solutions in relation to the release rate of dibucaine from microspheres in vitro. The more the amount of dibucaine, the stronger was the local anesthetic effect. The local anesthetic effect of dibucaine in microspheres lasted much longer (300 h) than that of dibucaine hydrochloride solutions. The profile of local anesthetic effect of dibucaine in microspheres in vivo was different from the release profile in vitro.

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6-Mercaptopurine (6-MP) polymorphs were administered to rabbits as intravenous injection, oral aqueous solution, oral hard capsule and effervescent capsule. When the form III powder was given in hard capsules, the dissolution from the capsule was very slow and the plasma levels after oral administration were also lower than those obtained with form I. On the other hand, the form III effervescent capsule prepared to enhance the dissolution gave an extent of bioavailability (EBA) about 1.5 times greater than that of form I. The time course data after oral administration of each dosage form were analyzed by means of the compartment model method and the statistical moment method. It appears that the difference of EBA after oral administration as the capsule dosage forms was chiefly attributable to the difference of apparent absorption rate. These results could be explained in terms of the differences of the mean disintegration and dissolution time (MDDT) obtained by means of the moment method.

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The kinetics of hydrolysis of mechlofenoxate hydrochloride (MF-HCl) into p-chloro-phenoxyacetic acid (CPA) and dimethylaminoethanol hydrochloride (DMAE-HCl) in the solid state were studied with respect to the effect of temperature (50 to 80°C) and humidity (20 to 80%RH). The degradation ratio, χ at the initial stage could be correlated to time by the equation χ=kt_n where k and n are parameters. The degradation at the later stage was found to conform to first-order kinetics. The following mechanism is proposed : at a humidity below the CRH of MF-HCl, water vapor initiates the hydrolysis of MF-HCl into CPA and DMAEHCl on the surface of the solid by a gas-solid reaction. Once DMAE-HCl is produced, water starts to be adsorbed and forms a sorbed moisture layer, in which intact MF-HCl dissolves, diffuses and decomposes. After being completely dissolved, MF-HCl decomposes in an apparent first-order reaction. At a humidity above CRH, on the other hand, water is adsorbed rapidly on the surface of the solid and MF-HCl appears to decompose in solution from the beginning. The decomposition is not a first-order reaction because of the incompleteness of the dissolution and diffusion at the initial stage, but becomes first-order at the later stage.

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The present study was carried out to determine the effect of lipid peroxidation on renin release from renin granules of the rat. Renin granules were isolated from the kidney cortex by discontinuous sucrose density gradient centrifugation. Renin acitivity was measured by radioimmunoassay and lipid peroxidation was estimated by means of the thiobarbituric acid test. Renin release from isolated renin granules was markedly stimulated by incubation at 37°C in the presence of ascorbic acid or ferrous ions, accompanied by increased formation of lipid peroxide in renin granules. These simultaneous increases in lipid peroxidation and renin release were abolished by the addition of N, N'-diphenyl-p-phenylenediamine. On the other hand, dehydroascorbic acid or ferric ions caused no change in lipid peroxidation and renin release. In addition, the molecular weight of renin released from the granules was 40000 and its activity was not changed after acidification. From these findings, it is assumed that ascorbic acid and ferrous ions stimulate the peroxidation of endogenous lipids that form part of the membrane of renin granules, and this process results in a breakdown of renin granules.

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The in vivo and in vitro metabolism and the cytochrome P-450 substrate-binding difference spectrum of emorfazone, 4-ethoxy-2-methyl-5-morpholino-3 (2H)-pyridazinone, were studied in non-pretreated and in phenobarbital (PB)-and 3-methylcholanthrene (MC)-pretreated male guinea pigs. In non-pretreated animals, emorfazone was primarily metabolized to 5-(N-carboxymethyl-N-2-hydroxyethylamino)-4-ethoxy-2-methyl-3 (2H)-pyridazinone (M-8) and 5-[2-(carboxymethyloxy) ethylamino]-4-ethoxy-2-methyl-3 (2H)-pyridazinone (M-9), produced by oxidative cleavage of O-C or N-C bonds in the morpholino moiety. The M-8 : M-9 ratios were 10.1, 2.0 and 0.3 at doses of 20, 100 and 500 mg/kg emorfazone, respectively. In PB-pretreated animals, these ratios were 1.6, 0.7 and 0.1 ; in MC-pretreated animals they were >100, 16.9 and 5.8 at doses of 20, 100 and 500 mg/kg, respectively, indicating that PB pretreatment increased the production of M-9, whereas MC-pretreatment lead to the production of greater amounts of M-8. In in vitro experiments, the morpholino moiety was oxidatively metabolized by microsomes in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) ; metabolism involving reduced nicotinamide adenine dinucleotide (NADH) was slight. In microsomes from non-pretreated, PB-and MC-pretreated animals, respectively, the K_m values for the oxygenation of the carbon atom adjacent to the N atom were 1.1×10^-2, 3.9×10^-3 and 1.2×10^-2M ; V_max values were 0.483, 0.419 and 0.225μmol/4 nmol cyt. P-450/20 min ; these values for the oxygenation of the carbon atom adjacent to the O atom were 1.5×10^-5, 1.9×10^-4 and 1.8×10^-4M and 0.065, 0.075 and 0.338μmol/4 nmol cyt. P-450/20 min. With increasing substrate concentrations, the apparent substrate-binding difference spectrum in microsomes from the non-pretreated group gradually changed from a reverse type I to a type I spectrum. Each binding difference spectral pattern with inducerpretreated microsomes was different, i.e. the proportions of type I and reverse type I spectrum were increased in PB-and MC-pretreated microsomes, respectively. Based on these results, it may be said that the two kinds of carbon atoms of the morpholino moiety are oxidized by two species of microsomal cytochrome P-450-dependent monooxygenation systems with different affinity and capacity, and that these oxygenation mechanisms are correlated with the substrate-binding differene spectra.

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Irradiation of the 2-methylquinoline N-ethoxycarbonylimides (15a-d) having an electron-donating substituent in the 6- or 8-position gave the novel 3H-1, 3-benzodiazepines (16), together with the parent quinolines (13), whereas substituted quinoline N-imides having either an electron-donating or-withdrawing group in other positions gave no benzodiazepines. These substituent effects are discussed. A similar substituent effect was also observed in the photo-induced rearrangement of the isoquinoline N-ethoxycar-bonylimides (25) to the 1H-1, 3-benzodiazepines (28).

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The photolysis of the isoquinoline N-imides (12a-g) under basic conditions gave the corresponding 5H-2, 3-benzodiazepines (13), presumably via the 1H-2, 3-benzodiazepines (17), together with the parent isoquinolines (14), whereas irradiation of these N-imides (12) under neutral conditions gave no diazepines. Treatment of the 1-methyl-5H-diazepines (13b, f) with acetic anhydride gave the 3-acetyl-3H-2, 3-benzodiazepines (18), which reverted back to the 5H-diazepines (13) on hydrolysis. However, the 1-unsubstituted 5H-diazepines showed no such conversion. Some reactions of the 5H-diazepines (13) thus obtained were also examined.

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Ethylene-vinyl acetate (EVA) copolymer was evaluated as a carrier for controlled release of 5-fluorouracil (5-FU). In order to study the effect of comonomer ratio modifications on the drug release kinetics, the release of 5-FU dispersed in polymer matrices composed of different ratios of ethylene and vinyl acetate was investigated. The vinyl acetate content of EVA copolymer was varied from 8 to 40% w/w. An increase in vinyl acetate comonomer content increased the drug release from the polymer matrix. The release rate could be controlled by modifying the ethylene/vinyl acetate ratios in the polymer matrices. The antitumor activity of EVA copolymer matrices containing 5-FU was evaluated against Ehrlich ascites carcinoma in mice, on the basis of changes in body weight and animal survival data. Tumor cell injections were performed on Day 0 and matrix implantations on Day 4, both intraperitoneally. The suppressive effect of matrices containing 5-FU on the increase in body weight was higher than that of the free drug. A prolongation of the life-span of tumor-bearing mice following implantation of therapeutic matrices was also noted. These results indicated that EVA matrices containing 5-FU may be effective in cancer chemotherapy. Matrices composed of EVA copolymer could be useful vehicles for implanted, inserted, or surface-applied delivery systems for anticancer agents.

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The reaction of 2, 3-lutidine N-oxide (I) with phenyl isocyanate (IIa) in dimethyl-formamide at 110°C gave a 1 : 2 adduct (IIIa). Under reflux in ethanolic potassium hydroxide, IIIa readily lost a component of IIa and was converted to 5-methyl-6-N-phenylcarbamoylmethyl-3-pyridinol (IVa) in 95% yield. 2-Phenylpyridine N-oxides (V-VII) reacted with phenyl isocyanates (II) to afford 1 : 1 cycloadducts (IX-XI and XII-XIV). The reaction of 2-(p-nitrophenyl) pyridine N-oxide (VIII) with IIa directly afforded 2-anilino-6-(p-nitrophenyl) pyridine derivatives (XIVa and XVa).

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Controlled potential electrolysis of 2'-(p-chlorophenyl) amino-4'-chloro-2-nitrobenzene-sulfenanilide (4c) gave 2, 7-dichlorophenazine in good yield. This result suggested that in the electrolysis of 4'-substituted 2-nitrobenzenesulfenanilides the ring closure to form the 2, 7-disubstituted phenazines takes place through the binding of the nitrenium ion (B) to the 2'-position of the sulfenanilides. As for the 3'-and 2'-substituted 2-nitrobenzene-sulfenanilides, most of the nitrenium ions bind to the 4'-position and are oxidized further to the p-quinonediimine derivatives, and most of these are oxidized further to unidentified resinous compounds.

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Anodic pyridination of 2, 6-di-tert-butyl-4-methylphenol (1) in acetonitrile gave the corresponding 4-pyridinated cyclohexadienone and the side-chain pyridinated phenol. The yield of the former dienone decreased and that of the latter product increased with increase in the amount of added bases, pyridine and/or 2, 6-lutidine. On the other hand, the product distribution in the methoxylation of 1 in methanol or in acetonitrile containing methanol was little affected by the addition of 2, 6-lutidine, and 4-methoxylated dienone was the main product.

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Six kinds of chromone derivatives, named AH₁, AH₂, AH₃, AH₄, AH₅ and AH₆, were isolated from agarwood (Jinko) from Kalimantan. Four constituents, AH₃, AH₄, AH₆ and AH₅, were characterized as 6-hydroxy-(I), 6-methoxy-(II) and 6, 7-dimethoxy-2-(2-phenylethyl) chromone (IV) and 6-methoxy-2-[2-(3-methoxyphenyl) ethyl] chromone (III), respectively.

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A new colorimetric method for the determination of total 3α-OH bile acids in serum by means of an enzymatic cycling reaction is described. Bile acids were oxidized by 3α-hydroxysteroid dehydrogenase from Pseudomonas testosteroni, and after the destruction of the remaining nicotinamide-adenine dinucleotide (NAD)⁺, the formed NADH was determined. The cycling system consisted of two enzymes, alcohol dehydrogenase from yeast and diaphorase from Clostridium kluyverii. The formed NADH was oxidized by diaphorase in the presence of 3-(p-iodophenyl)-2-(p-nitrophenyl)-5-phenyl-2H-tetrazolium chloride and then was reduced again by alcohol dehydrogenase and ethanol. Subsequently, formazan produced as a final product was determined by rate assay. As the proposed method dose not require as extraction step, it is simpler and more accurate than the conventional methods.

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A sensitive, simple and specific method was developed for the simultaneous determination of cyanide and thiocyanate by high performance liquid chromatography with a strong base anion exchanger column. For detection, colorimetry based on the Konig reaction was employed with chloramine T, pyridine and barbituric acid as reagents. This method was applied to the determination of cyanide and thiocyanate in human urine.

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A sensitive fluorimetric method for the assay of human serum monoamine oxidase is described, in which benzaldehyde, formed enzymatically from the substrate benzylamine, is quantitated by means of the fluorimetric method for selective determination of aromatic aldehydes with 2, 2'-dithiobis (1-aminonaphthalene). The limit of detection for the benzaldehyde formed enzymatically is 100 pmol. This method is readily performed with good precision and a minimum amount of serum. Serum monoamine oxidase activity in patients with various thyroid diseases was assayed by this method.

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A simple high-performance liquid chromatographic method for the determination of nifedipine, dimethyl 1, 4-dihydro-2, 6-dimethyl-4-(2-nitrophenyl)-3, 5-pyridinedicarboxylate, in plasma is described. The method permits the accurate determination of the drug in plasma at concentrations as low as 2 ng/ml and is suitable for drug monitoring and for investigation of the bioavailabilities of drug preparations.

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The acid-base equilibrium reactions of oxazolam (10-chloro-2, 3, 5, 6, 7, 11b-hexahydro-2-methyl-11b-phenylbenzo [6, 7]-1, 4-diazepino [5, 4-b] oxazol-6-one) and thirteen other derivatives of 1, 4-benzodiazepinooxazole (BDOZ) were studied. Ultraviolet absorption and fluorescence spectroscopies were employed to obtain the equilibrium constants. In most BDOZs the protonated species were promptly cleaved at the oxazolidine ring fused to the diazepine nucleus, and equilibrated with the original species. A few exceptional compounds required an appreciable time lag for the equilibration. The effects of substituents on the pK_a value are discussed from the viewpoint of physical organic chemistry.

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Pretreatment of rats with desoxypodophyllotoxin for 4 d (day-3 to day 0) has been found to inhibit the increase of serum transaminase activities at 24 h after D-galactosamine injection (day 0) in a dose-dependent manner and to prevent histological deterioration of the liver. In the case of pretreatment with desoxypodophyllotoxin, serum transaminase activities were lower than those of the control group until 24 h after D-galactosamine injection, but rather higher than the control levels afterwards. Successive treatment with desoxypodophyllotoxin for 6 d (day-3 to day 2) markedly inhibited the increase of serum enzyme activities induced by D-galactosamine up to the end of the experiment (day 4). Concerning the mechanism of the liver-protective action of desoxypodophyl-lotoxin, it is suggested that the stabilizing effect of desoxypodophyllotoxin on the plasma membrane may play an important role in protecting the liver from lesions caused by D-galactosamine.

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The effects of some uremic toxins on the structure of normal human plasma albumin were investigated in order to cast light on the state of plasma albumin of patients with chronic renal failure. Two different ion exchange columns were prepared to isolate and purify albumin, and β-indoleacetic acid (IAA), β-indolebutyric acid (IBA), guanidinosuccinic acid (GSA) or urea as a uremic toxin was added to the normal plasma albumin. α-Helix contents as estimated from the circular dichroism spectra were found to be little affected by uremic toxins. The effect of uremic toxins on the binding of a fluorescent probe, 1-anilino-8-naphthalene sulfonate (ANS), to albumin was examined by calculating the binding parameters, the association constant and the number of binding sites. All uremic toxins decreased the association constants. GSA and urea decreased the number of binding sites, while IAA and IBA increased them. These effects increased as the concentrations of toxins added were increased, especially with IAA and IBA.

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