The reaction of heteroaromatic nitriles with trace of sodium borohydride in alcohol was examined.Cyano group substituted at α-position of heteroatoms was easily converted to the corresponding imidate.It was also possible to convert selectively one cyano group to the ester group without any change of the other cyano groups.

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The reaction of 6-amino-1, 3-dimethyluracil (I) with phenacyl bromide in DMF gave 1, 3-dimethyl-6-phenylpyrrolo [2, 3-d] pyrimidine-2, 4 (1H, 3H)-dione (II) in high yield. The reaction of I and phenacyl bromide in acetic acid afforded the isomeric 1, 3-dimethy1-5-phenylpyrrolo [2, 3-d] pyrimidine-2, 4 (1H, 3H)-dione as a byproduct besides II. Nitrosation of II gave 1, 3-dimethy1-5-nitroso-6-phenylpyrrolo [2, 3-d] pyrimidine-2, 4 (1H, 3H)-dione (III) along with the corresponding 5-nitro derivative. Ring expansion of III by the Beckmann rearrangement was carried out to give 1, 3-dimethy 1-5-hydroxy-6-phenylpyrimido [4, 5-d]-pyrimidine-2, 4 (1H, 3H)-dione. Denitrosation of III by the action of sulfuric acid was observed.

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N-Amidino-O-alkylisourea was allowed to react with acetylacetone and benzoylacetone. Heating of N-amidino-O-alkylisourea with acetylacetone in boiling ethanol gave 2-alkoxy-4-amino-6-methyl-sym-triazine. On the other hand, the same reaction at room temperature gave 2-alkoxyamidino-4, 6-dimethylpyrimidine. The reaction of N amidino-O-alkylisourea with benzoylacetone in boiling ethanol afforded 2-amino-6-methyl-4-phenylpyrimidine. Difference of the reactivity in these reactions was also discussed.

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A skeletal transformation of XI, drived from l-abietic acid (I), was tried by the cleavage of B/C-ring juncture and successive condensation. The ether bridge suppresses the condensation direction as in the synthesis (VII→VIIIa) previously reported, and then, the cyclization gives XVIa regarded as a mother skeleton of aconitine.

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Autoxidation is important phenomenon in the resin acid field. Styrene (III and VIII) and homostyrene (VII) compounds were autoxidized to the corresponding benzonili denederivatives (IV and IX), which are expected to have interesting reactivity.

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Catalytic hydrogenations of 5-acylamido-2, 3-disubstituted quinoxalines (IIa-e) with palladized carbon in carboxylic acid afforded 4, 5-disubstituted 5, 6-dihydro-4Himidazo [1, 5, 4-d, e] quinoxalines (IIIa-e). Conformations of the substituents at 4- and 5-position of the products were also investigated.

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Aus den Blättern von Forsythia viridissima (Oleaceae) wurden Forsythid (1), ein neues Iridoidglucosid, und sein Methylester (2) isoliert und ihre Strukturen aufgeklärt. Beim Ester handelt es sich aber wahrscheinlich urn einen Artefakt. Glucosid (1) wurde auch in F. japonica sowie F. europaea nachgewiesen. Es war dagegen nicht nachweisbar in F. suspensa und F. koreana.

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A method for microdetermination of cortisol and corticosterone in blood by the isotope derivative dilution analysis was established by the use of thiosemicarbazide-³⁵S as the labeled reagent and ³H-labeled corticosteroid for correcting the loss during extraction and separation procedures.
Cortisol and corticosterone are reacted with thiosemicarbazide-³⁵S in acetic acidmethanol at 65° for 90min, and the thiosemicarbazones-³⁵S formed are extracted with dichloroethane. After addition of the carrier to the extract, it is submitted to repeated thin-layer chromatography at a low temperature of 10°, using solvent systems of chloroform-ethanol (9:1, v/v) and benzene-acetone (1:1), by which corticosteroids are separated from each other and from substances present in blood. The amount of isolated cortisol and corticosterone thiosemicarbazones are estimated from the radioactivity of ³H and ³⁵S.
According to this method, the values of cortisol and corticosterone are in the range of 0.001-10.0μg, recovery rate is ca.100%, and relative standard deviation is 1.0-6.7%. The determination can be made with good accuracy and precision. Comparative examination of the same sample by this method and by fluorometry gave a slightly higher values from this method, and the relative standard deviation showed a large dispersion of 6.0-18.0%. However, the analytical precision and sensitivity of this method are better than fluorometry. Determination of 0.1-5.0ml of sample plasma by this method showed. relative standard deviation of 0.8-3.4%, with small dispersion, and accuracy of determination was found to be satisfactory.

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In order to clarify in more detail the cyclization mechanism of thioanilide to benzothiazole under the modified Willgerodt-Kindler reaction conditions, 2-picoline (III) was heated with meta-substituted anilines (IV) in the presence of sulfur and the reaction also gave thioanilides and one of the two possible benzothiazoles. The latter was proved tohave the structure of 5-substituted 2-(2-pyridyl) benzothiazoles (VI) by independent synthesis.
On the other hand, the expected two isomeric benzothiazoles (VI and VII) were obtained from the oxidative cyclization of thioanilides by the modified Jacobson reaction.

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The roots of Angelica longeradiata (MAXIM.) KITAGAWA afforded two new ester coumarins, angeladin (III) and isoedultin (IV) together with known coumarins, archangelicin (I) and umbelliferone (II). The structures of III and IV were established as 2'(S), 3'(R)-O-angeloy1-3'-p-coumaroyloxy-2', 3'-dihydrooroselol and 2'(S), 3'(R)-O-angeloy1-3'-acetoxy-2', 3'-dihydrooroselol, respectively.

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Isomaltose and isomatoltriose were synthesized unequivocally by condensation of 2-0-benzyl-3, 4, 6-tri-O-p-nitrobenzoyl-α-D-glucopyranosyl bromide (I) with 1, 2, 3, 4-tetra-Oacetyl-, β-D-glucopyranose (II) and with O-(2, 3, 4-tri-O-acetyl-α-D-glucopyranosyl)-(1→6)-1, 2, 3, 4-tetra-O-acetyl-β-n-glucopyrancse (V), respectively, in the presence of mercuric cyanide, followed by the conventional removal of the blocking groups. Concurrent formation of theβ-isomers was less than 30% of the corresponding a-linked oligosaccharides, and these concomitants were readily eliminated by column chromatography. The chromatographic behavior of these oligosaccharides are also described.

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The Diels-Alder reaction of 2-methoxy-5-methoxycarbonylbenzoquinone (6) with various 1-substituted isoprenes (5a-d) was studied and the 8β-substituted cis-tetrahydronapthoquinone-8αα-carboxylates (19a-d) were obtained and characterized. Some of the latter compounds are important intermediates for synthesis of the A and B rings of siccanin (3), an antifungal antibiotic.

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An alkaline protease (peptidylpeptide hydrolase, EC class 3.4.4.) of Bacillus natty KMD 1126 was purified by ammonium sulfate fractionation, DEAE cellulose chromatography, CM cellulose chromatography, and Sephadex G 100 gel filtration. It had a pH optimum over the range of 8.5-9.5 toward casein substrate. It was not inactivated by chelating agents or sulfhydryl reagents, but completely inactivated by incubation with DFP. From these results and the substrate specificity, this enzyme resembles to alkaline protease of Bacillus natto Ns. However, the two enzyme differ in specific activity and kinetic properties. This enzyme had not cytolytic activity on Ehrlich ascites carcinoma cells. However, when a mixture of surfactin, the protease, and EDTA was incubated with carcinoma cells, synergetic effect on the cytolysis was observed.

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A facile synthesis of lactosan hexaacetate (2) was described. 6-Acetamido-6-deoxylactose (9) was synthesized starting from 2 via hepta-O-acetyl-6-O-methylsulfonyl-β-lactose (3), benzyl hexa-O-acetyl-6-O-methylsulfonyl-fl-lactoside (4), and benzyl hexa-O-acetyl-6-azido-6-deoxy-il-lactoside (6), followed by catalytic reduction of compound (6), successive acetylation and deacetylation. Compound (9) did not show antibacterial activity against twenty microorganisms.
Methyl 6-acetamido-6-deoxy-β-lactoside (14) was also synthesized using the analogous synthetic route. Syntheses and properties of seven new lactose or lactoside derivatives were also described.

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R-S Conversion of R (+)-α-methylphenylalanine (R (+)-V), one of the typical α-alkyloc-amino acids, was accomplished with 75.6% retention of its optical integrity, since the R (+)-isocyanide (R (+)-X) easily derived from R (+)-V afforded the S (+)-cyanide (S (+)-XI) with 75.6% retention of configuration when a diphenyl ether solution of R (+)-X was heated at 280°.
Preliminary experiments using racemic compounds were also reported in experimental part.

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In vitro metabolism of ³H-testosterone 17-sulfate (³H-TS) and ¹⁴C-testosterone 17-tetrahydropyranyl ether (¹⁴C-TP) was studied by incubation with 20000×g or 105000×g supernatant and microsomal fractions of male rat liver homogenate under carbon monoxide atmosphere or in air. The results demonstrated that the steroidal ring A of ³H-TS was readily metabolized by microsomal Δ⁴-5α-hydrogenase, while ¹⁴C-TP was a good substrate for 4-5α-hydrogenase present in the 105000×g supernatant fraction as well as microsomal Δ⁴-5α-hydrogenase. On the other hand, ³H-TS and ¹⁴C-TP were not good substrates for microsomal hydroxylases. The influence of the substituent at C-17 of testosterone upon the biotransformation of ring A was discussed.

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In order to examine the structure-activity relationship the syntheses of some progestagens with the abnormal 13α-configuration have been undertaken. Epimeric 17-ethynyl-17-hydroxy derivatives (II and VII) having Δ⁴-3-ketone system were prepared from the corresponding Δ⁵-3β-ols (I and VI) by Oppenauer oxidation, respectively. 17-Acetoxy-13oc-pregn-4-ene-3, 20-diones (V and Xb) were prepared by Jones oxidation from 3β, 17-dihydroxy-13α-pregn-5-en-20-one 17-acetates (IIIc and VIIIc) which were readily available from the 3, 17-diacetates (IIIb and VIIIb) by partial hydrolysis. The occurrence of Dhomo-annulation of 17-hydroxy-13α-pregnen-20-ones (IIIa and Villa) with aluminum isopropoxide has also been described.

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Spectrophotometric and colorimetric methods for the assay of thiamphenicol (TP) and their application to that of chloramphenicol (CP) are described.
The spectrophotometric method is based upon the reaction of TP with alkali to produce hydrolyzed TP, D-threo-2-amino-3-p-methylsulfonylphenyl-1, 3-propanediol, which then converted to p-methylsulfonylbenzaldehyde by periodate oxidation.
The other is a colorimetric determination of the aldehyde with APHS reagent (diethanolamine salt of azobenzenephenylhydrazinesulfonic acid). The new reagent, in comparison to the free acid, has the advantages in the stability on storage both in crystalline and solution state and in the solubility in some solvents.

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It was demonstrated that the precipitate at 105000×g of cell-free extracts of Cephalosporium caerulens exhibited the activities for cyclizing 2, 3-oxidosqualene into lanosterol and 3β-hydroxyprotosta-17 (20)[16, 21-cis], 24-diene. However, the cell-free preparations possessed no activity for cyclizing into 3β-hydroxyprotosta-13 (17), 24-diene. Major part of these activities were located in the microsomal fraction which precipitates at 105000×g and deoxycholate treatment solubilized these cyclases.

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Two alkaline proteinases, designated as alkaline proteinases a and b, are isolated from the cultured broth of Streptomyces H 61B-SY1, calssified as Streptomyces griseoviridis. The optimum pHs of alkaline proteinases a and b for casein are 10.5-11 and 11-11.5 respectively. Production, isolation, purification, effect of pH on the proteolytic activity, pH stability, effect of temperature on the proteolytic activity, effect of enzyme inhibitors on the proteolytic activity, substrate specificities and anti-inflammatory activity for the carrageenin-induced edema of alkaline proteinases a and b are described.

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To analyze the process of dynamic compression, especially in tabletting, a new methodof drawing curves that corresponds to the normal creep curve in the static compressionprocess was devised.The creep curve obtained by this method can be expressed usingviscoelastic three elements model like E=(P/γ₁)^m+(P/γ₂)ⁿ·[1-exp(-t/τ)], where E is cornpressionstrain, P, compressed force, t, time, τ, retardation time and γ₁, γ₂, m, n are constants. This equation can also be treated as in the case of normal creep equation.

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The kinetics of decomposition of four N-monosubstituted dithiocarbamic acids (I) toparent amines and carbon disulfide were investigated over a wide range of acid concentrationsfrom pH to acidity function regions. The experimental first-order rate constantsin acidity function region are proportional to the mole fraction of I as with the case of pH region, and decrease with increasing acid concentrations. The reaction pathway is establishd based on the rate-acidity profile. The linear relationship between log k and pKa of parent amine (pK_N), (eq.6), is interpreted in terms of the rate-determining N-C bond cleavage along with the synchronous proton transfer.

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Irisflorentin, a new isoflavone has been isolated from the rhizoma of Iris florentina L.(Iridaceae) besides irigenin, iristectorigenin B and irisolone. The structure of irisflorentinhas been determined as 5, 3', 4', 5'-tetramethoxy-6, 7-methylenedioxyisoflavone by chemical degradation and spectral means.

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During a research of the Friedel-Crafts'reaction using xanthate, it was found thatxanthates rearrange to dithiolcarbonates by the catalysis of aluminum chloride in carbondisulfide. This rearrangement needs at least a molar equivalent of aluminum chlorideto xanthates and proceeds even at room temperature. With respect to solvent, carbon disulfide can be replaced by chloroform without essential effect on the product distribution. It was presumed from a study of crossover reaction that this rearrangement might have the nature of intermolecular reaction.

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Three penta-N-phenylalkylideneaminosidins, two penta-N-phenylalkylaminosidins, and two N-methylaminosidins were prepared, and their antimicrobial activities in vitro were determined. Penta-N-phenylalkylideneaminosidins had antimicrobial activity approximatelyequal to or slightly less than that of aminosidin. However, penta-N-phenylalkylaminosidinsand N-methylaminosidins were devoid of antimicrobial activity.
Penta-N-benzylideneaminosidin protected mice from death by Staphylococcus aureus and Escherichia coli infections, and acute toxicity of the penta-N-benzylideneaminosidin was less than that of aminosidin by a subcutaneous route.

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Synthesis is described of bradykinyl-Val-Ala-Pro-Ala-Ser-OH.All the fragment condensations were carried out by Rudinger's azide method in order to minimize the racemization during the coupling steps involving peptide fragments. The ensuing tetradecapeptide with a high degree of homogeneity was found to be identical with bradykinyl-Val-Ala-Pro-Ala-Ser-OH of natural origin with respect to chemical and biological properties.

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The enzymes responsible for the degradation of nitrofuran derivatives in rat small intestinal mucosa were examined in vitro. As a result, it was suggested that the initial reactions in the degradation of 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide (AF-2) and 5-nitro-2-furfural semicarbazone (nitrofurazone) are mainly catalyzed by xanthine oxidase, while that of 2-amino-5-[2-(5-nitro-2-fury1)-1-(2-furyl) viny1]-1, 3, 4-oxadiazole (NF-161) is catalyzed by alternative enzyme beside xanthine oxidase, too.
Furthermore, the present results suggest that a part of metabolites formed from AF-2 by hypoxanthine-dependent or NADH-dependent reaction in rat small intestinal mucosa might be tightly bound to or physically adsorbed to the macromolecules of cellular constituents.

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The flash photolysis of N-chloroacetyl-m-tyramine (V) in non-degassed aqueous solution afforded a transient absorption spectrum which consists of two groups with different intensities and life-times. The weak bands at 380, 386, and 412nm (τ=200-400μsec), which were also observed in the photolysis of N-acetyl-m-tyramine (VIII), correspond with the spectrum of the phenoxy radical.
The strong bands at 322 and 330nm decay according to a first-order kinetics (τ=530μsec in neutral solution, τ=48μsec in alkaline solution) and are attributed to the cyclohexa-2, 4-dienone (1, 2, 4, 5, 9, 9a-hexahydro-3H-3-benzazepin-2, 9-dione (X)), which is an intermediate of the photocyclization of V to 9-hydroxy-1, 2, 4, 5-tetrahydro-3H-3-benzazepin-2-one (VI). In conclusion, the photocyclization of V may be initiated by an electron transfer from the aromatic system to the chlorinated amide group, followed by ortho-cyclization of X, which aromatizes to yield VI.

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Pyridiayl diradicals, Py(Ac)·(CH₂)_nPy(Ac), (in which Py (Ac)·is 4-CH₃OCC₅H₄N·, and n=3 and 4) were obtained. Intramolecular electronic interaction between two 4-acetylpyridinyl moieties in the diradical n=3 was observed. Temperature dependence of absorption spectra suggests the conformational equilibrium between the open and closed forms in the, diradical n=3 (-ΔH=7.6 kcal and ΔS=-14 e.u.). Electronic absorption spectroscopy and SCF-CI molecular orbital calculation reveal that a strong visible absorption band in the closed form diradical (n=3) is ascribed to a charge-transfer band between two pyridinyl moieties.

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A new lignan glycoside was isolated from the stems of Trachelospermum asiaticum NAKAI var. intermedium NAKAI (Apocynaceae) and its structure has been determined as 4'-hydroxy-3, 3', 4-trimethoxy-lignan-olid (9, 9')-4'-(6-O-β-D-glucopyranosyl)-β-D-glucopyranoside (=arctigenin-4/-β-gentiobioside)(V), which is a sole example of naturally occuring of lignan having glucosyl glucose moiety.

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7-Oxo esters (IV) and (V) derived from l-abietic acid (III) were converted to half esters (XI) and (XV), respectively. Intramolecular cyclization of XV gave the expected 11-methoxy oxo ester (XVI), but that of XI yielded the undesirable bicyclo [3, 3, 1] n onane ester (XVII) via a methoxy migration of the methoxy carbonyl group. 11-Hydroxy diterpenoid is not only a potential intermediate for the syntheses of taxodione (I) and callicarpone (II), but also is regarded as an important substance for an oxidative substitution of A-ring or 10-methyl group from its 11-hydroxyl group.

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7-Oxo-dehydroabietamide (XI) derived from l-abietic acid (III) was converted to methoxycyano acid (XVI) via cyano lactone (XIII) and the intramolecular cyclization of XVI gave the expected 11-methoxy-7-oxo-dehydroabietonitrile (XVII). The cyclized compound (XVII) was converted to some 11-methoxy-dehydroabietic acid derivatives, which could be regarded as potential intermediates for synthesis of natural products having 11-hydroxyabietane skeleton.

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Non-steroidal anti-inflammatory drugs such as phenylbutazone and sulfinpyrazone have been known to bind strongly with plasma proteins and inhibit the binding of a sulfonamide by competing with the drug for the same binding sites on plasma proteins.^{3, 4)}Furthermore, it has been shown that the liberation of a sulfonamide from its binding sites on plasma proteins by the non-steroidal anti-inflammatory drugs affects on the distribution and excretion of the sulfonamide in animals.For example, Anton⁵⁾ observed that sulfinpyrazone altered the concentration of sulfaethylthiadiazole between plasma and tissues in rats.Also, Arita, et al.⁶⁾reported that sulfinpyrazone and oxphenbutazone inhibited the renal tubular secretion of sulfonamides in dogs.However, there is not yet enough evidence to demonstrate the effects of combinations of non-steroidal anti-inflammatory drugs and sulfonamides in view of protein binding.
In the previous paper, ¹⁾the authors demonstrated that the binding of sodium cyclamate and rabbit serum albumin was competitively inhibited by phenylbutazone, consequently the urinary excretion of sodium cyclamate in rabbits was accelerated by simultaneous administration of phenylbutazone.
The purpose of this investigation is to demonstrate the effects of non-steroidal antiinflammatory drugs on the absorption and excretion of sulfadimethoxine in rabbits.

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In the previous paper, thirty two kinds of organic and inorganic powders were ball-milled and the rate of an increase of surface area by ball-milling was considered to depend on coherency of powder particles expressed as a function of surface energy, melting point, solubility in water, true density and so on. In this paper, influence of operational variables on the rate of an increase of surface area of sulfadimethoxine and white alundum by ball-milling was investigated.

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