Some thiamine derivatives were compared pharmacokinetically about their elimination from blood after intravenous injection in rat. TPD (thiamine propyl disulfide), CCT (cyclocarbothiamine) and BTMP (S-benzoylthiamine monophosphate) were used as the typical thiamine derivatives. 1) It was found that the rates of conversion of TPD and CCT to thiamine in blood were rapid, but that of BTMP was slow. 2) TPD formed thiamine mainly through erythrocytes, but CCT formed thiamine mainly through plasma. 3) Volume of distribution (Vd or V₁) of TPD, BTMP, CCT and thiamine were 37.6, 93.5, 187.5 and 256.1 ml, respectively. After intravenous injection of TPD, BTMP, CCT and thiamine rate constants of elimination of thiamine (k_eI or k'_el) were 0.145, 0.151, 1.61 and 1.98 hr_-1 respectively. Elimination constant of TPD was nearly equal to that of BTMP, and that of CCT to that of thiamine. 4) TPD and CCT behaved almost same in blood in vitro, except elimination of them from blood. 5) Since both TPD and BTMP were considerably taken up into erythrocytes, and also their elimination constants were equal to each other, the elimination constant must mean the constant of transfer rate from erythrocytes to plasma. 6) Pharmacokinetic model was proposed for each derivative.

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A rapid polarographic microdetermination of D-glucose with β-D-glucose oxidase in direct oxygen consumption mode is described. The apparatus composed of polarographic oxygen electrode, recorder (2 mV full scale), voltage prebox for increasing the sensitivity by cancelling unnecessary voltage of the output voltage of oxygen analyzer, and specially designed vial fixed on the magnetic stirrer. A trace amount of sodium azide was used to inhibit catalase contained in the biological sample and crude glucose oxidase. In this method, the relation between the amount of D-glucose and the amount of consumed oxygen gave a straight line at the range of 0.5 to 600 μg of D-glucose. The results obtained by this method on serum glucose with internal standard were enough consistent with those obtained by o-toluidine-borate method. The result on blood is obtainable within 5 min after a blood sample (5 μl) was collected from a patient.

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A new alkaloid designated as erythroculine was isolated from the leaves of Cocculus laurifolius DC. (Menispermaceae). From degradative and spectroscopic studies, the structure (I) was assigned to this alkaloid and this assignment was then definitely confirmed by chemical correlation of erythroculine with tetrahydroerysotrine (XXII) of established stereochemistry. From the view point of biosynthesis of erythrina alkaloid, a carbomethoxyl group on a benzene ring is unusual and the isolation of this alkaloid makes the third example of erythrina alkaloid in Cocculus species.

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Syntheses of 20-nor tricyclic diterpene derivatives and determination of their structures are described. In the A/B-cis ring system, it is revealed by the analysis of proton magnetic resonance, infrared spectrum and reaction that the steroid type conformation of 10-methyl series is preferred to nonsteroid type conformation, conversely, nonsteroid type conformation is preferred in 20-nor derivatives.

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The syntheses of (±) -dihydroactinidiolide and (±) -actinidiolide, and partial synthesis of dihydrosecurinine were described. Lithium ethoxyacetylide procedure was shown to be a useful method for the preparation of fused ring α, β-unsaturated lactones.

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Irradiation of 5, 6β-dihydroxy-17β-acetoxy-5β-androstan-19-oic acid 5, 19-lactone (I) at room temperature using a mercury arc (450W) was found to yield in 30% yield 5, 6β-dihydroxy-17β-acetoxy-5α-androstan-19-oic acid 6, 19-lactone (II : R=Ac), structure of which was synthetically established. This photoreaction was proved to proceed through the keto-ketene intermediate (XV) generated upon irradiation of β-lactone moiety in I. On the other hand irradiation of 5-hydroxy-6-oxo-17β-acetoxy-5β-androstan-19-oic acid 5, 19-lactone (XIX) afforded 17β-acetoxyestra-5 (10) -en-6-one (XX) in about 60% yield.

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Condensation reaction of 2-aminobenzothiazole and bromoacetone under the condition of boiling alcohol afforded a molecular compound of equimolecular of 2-amino-benzothiazole and 2-methylimidazo [2, 1-b] benzothiazole. When the reaction condition under standing at room temperature was adopted, 2-imino-3-acetonyl-2, 3-dihydrobenzothiazole was obtained. 3-Phenylimidazo [2, 1-b] benzothiazole was prepared from 1- (m-chlorophenyl) -2-mercapto-4-phenylimidazole and potassium amide in liquid ammonia. Imidazo [2, 1-b] benzothiazole was also prepared from 1- (m-chlorophenyl) -2-mercaptoimidazole.

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Reaction of 1-tosylaminomethylphenothiazine (VI) and methylene iodide gave 2-tosyl-1, 3-dihydro-2H-pyrimido [5, 6, 1-kl] phenothiazine (VII). 3-Tosyl-1, 2-dihydro-3H-pyrazino- [3, 2, 1-kl] phenothiazine (XIV) or 2-tosyl-1, 2-dihydroimidazo [4, 5, 1-kl] phenothiazine (XVIII) was synthesized from 1-tosylaminophenothiazine (XIII) and ethylene bromide or methylene iodide. Detosylation of VII, XIV, and XVIII gave 1, 3-dihydro-2H-pyrimido [5, 6, 1-kl] -phenothiazine (VIII), 1, 2-dihydro-3H-pyrazino [3, 2, 1-kl] phenothiazine (XII), and 1, 2-dihydroimidazo [4, 5, 1-kl] phenothiazine (XVII), respectively. In addition, syntheses of these new four-ringed nitrogen heterocycles were studied by other routes.

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As a part of continuing studies on the synthesis of pyrazolone derivatives, synthesis of 1-methyl-2-phenyl-1, 2, 3, 10-tetrahydro-4H-pyrazolo [3, 4-c] [1] benzothiepin-3, 4-dione (VI) and its derivatives was described.

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The reactions of 4-methyloxazole N-oxides substituted in the 2-position (Ia-d) with phenylisocyanate were studied. The oxazole N-oxides were easily attacked on the 2-position by the nitrogen of phenylisocyanate, followed by ring-cleavage and re-cyclization to give 5-hydroxy-4-methylene-1, 2, 5-trisubstituted 4, 5-dihydroimidazoles (IIa-d). The structures of IIa-d were determined by their chemical behavior and spectral data.

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The structures of securinol B and C were determined as Ib and III by conversion of them into viroallosecurinine (II) and allosecurinine (IV), respectively, and from spectral evidences.

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The π-bond orders calculated by HMO method and infrared frequencies of aliphatic carbonyl compound were successfully correlated. Each parameter of hetero-atoms in this calculation was selected as applicable to the treatments of a variety of infrared spectra. Auxiliary inductive parameter was found to be necessary.

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In order to achieve the desired separation of cholesterol-lowering and estrogenic effect, some A-ring aromatic 16-keto steroids were synthesised. All of these compounds lacked estrogenic effect and their lipid-shifting activities were also weak.

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The alcoholysis reaction of sulfamic acids catalyzed by pyridine was investigated with piperidine-N-sulfonic acid-cyclohexanol system and a possible formation and participation of the intermediate "pyridine-SO₃ adduct" in the reaction was suggested. To apply this reaction to the preparation of sulfate esters, the experimental conditions such as the kind of sulfamic acids, molar ratio of reactants, and temperature and time of reaction were examined. Biochemically related sulfate esters, adenosine 5'-sulfate, riboflavin 5'-sulfate, and D-galactose 6-sulfate, were synthesized by this reaction.

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Reaction of 2-aminothiophenols and phenylglicidic esters gave 2-hydroxy-3- (2-aminophenylthio) -3-phenyl-propionic esters (VI) and 2-phenyl-3-hydroxy-2, 3-dihydro-1, 5-benzothiazepin-4 (5H) -ones (VII). Hydrolysis of the amino esters (VI) to the amino carboxylic acids (VIII) and cyclization of the amino acids gave satisfactory yield of the cyclic amides (VII). Reaction of 2-nitrothiophenols (XII) and phenylglicidic esters (V) was also studied. Rearrangement of VIIa to 2-benzilidene-3-keto-benzothiazine (XV) was presented.

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A new method is described for the synthesis of 1-benzyl-6, 7-dihydroxy-1, 2, 3, 4-tetra-hydroisoquinolines starting from 3, 4-dihydroxyphenylethylamine and α-formyl (or equivalent) -phenylacetic acid derivatives under Pictet-Spengler's working conditions.

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DL-Mevalonolactone-2-¹⁴C was administrated to Gentiana triflora and Swertia japonica. Degradation of labelled gentiopicroside (I) from Gentiana triflora and swertiamarin (II) and sweroside (III) from Swertia japonica established that these compounds are monoterpenoid glucosides synthesized biologically via mevalonic acid.

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3-Azabicyclo [3. 3. 1] nonane derivatives were prepared and tested biologically. Some of these, 3-methyl-9β-alkoxy-9α-phenyl-3-azabicyclo [3. 3. 1] nonane (6-8) and their 3- (β-phenylethyl-) analogs (18-20) exhibited promising analgesic activities. Furthermore, 3-methyl-9-benzoyloxy-3-azabicyclo [3. 3. 1] nonane (24 and 25) displayed a marked local anaesthetic action.

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The Ullmann reaction of 1-phenyl-2-methyl-3- (2-aminophenyl) thiomethyl-4-bromo-3-pyrazolin-5-one (VII) in the solvent of xylene gave 1-methyl-2-phenyl-1, 2, 3, 10-tetra-hydro-4H-pyrazolo [3, 4-c] [1, 5] benzothiazepin-3-one (XI). However, the same reaction in the solvent of dimethylformamide afforded 1-phenyl-2-methyl-3- (2-benzothiazolyl) -3-pyrazolin-5-one (X). Similarly, 1-phenyl-2-methyl-3- (5-substituted-2-benzothiazolyl) -4-substituted-3-pyrazolin-5-one (XXIV, XXV, XXVI) were synthesized.

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The reaction of ethyl 2- (3-chloro-2-quinoxalinyl) -2-cyanoacetate (I) with various amines : ammonia, methylamine, ethanolamine, γ-dimethylaminopropylamine, benzylamine, and p-phenetidine, gave the corresponding 1-substituted ethyl 2-aminopyrrolo [2, 3-b] quinoxaline-3-carboxylates (IIIa-f) at about 80-90% yield. The similar reaction of α- (3-chloro-2-quinoxalinyl) -malondinitrile (II) with various primary amines was carried out to give the corresponding 1-substituted 2-aminopyrrolo [2, 3-b] quinoxaline-3-carbonitriles (VIIa-d) at 86-94% yield (Table I).

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In the microbial transformation by Trametes sanguinea, 14β-bromocodeinone (IV) was first converted enzymatically into 14β-bromocodeine (VI), which was gradually affected chemically to form VII, II, and VIII as the final products.

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C-Alkylations of some N-acetonyl- and N-phenacylamides were effected with alkyl halides by means of sodium ethoxide in ethanol or potassium amide in liquid ammonia. The present paper deals with its scope and structural limitation for these alkylation reactions.

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C-Alkylations of α-N, N-dialkylaminoketones were effected with alkyl halides by means of potassium amide in liquid ammonia. The reaction scope and an application for preparation of (±) -ephedrine are described.

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Ring closure reactions of γ-cycloheptatrienyl-substituted α, β-unsaturated carbonyl compounds by acid were examined. Treatment of 2-methyl-4- (2, 4, 6-cycloheptatrien-4-yl) -2-pentenal (II) with hydrobromic acid at room temperature in acetic acid afforded 1, 3-dimethyl- (III) and 2, 4-dimethyl-5H-benzocycloheptene (IV) accompanied by the production of 1, 3, 8-trimethylnaphthalene (V). On the ring closure of 5- (2, 4, 6-cycloheptatrien-4-yl) -3-hexen-2-one (VIII) by a similar procedure, 1, 4-dimethyl-5H-benzocycloheptene (IX), 1, 4, 5-trimethylnaphthalene (X), and 1, 4, 6-trimethylnaphthalene (XI) were isolated.

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Nitration of 2-anilino-4-methylquinoline (I) with mixed acids gives different products according to the concentration of sulfuric acid used. In 50% sulfuric acid solution, 2- (o-nitroanilino) -4-methylquinoline (II) and 2- (p-nitroanilino) -4-methylquinoline (IV) are formed in approximately equal quantity, while in 85% sulfuric acid solution, IV and 2- (p-nitroanilino) -4-methyl-6-nitroquinoline (V) are mainly formed. In 95% sulfuric acid, V and a small amount of 2- (2', 4'-dinitroanilino) -4-methyl-6-nitroquinoline (VI) are formed. On the other hand, nitration of I with acetyl nitrate results in the characteristic formation of II and 2- (2', 4'-dinitroanilino) -4-methylquinoline (III). It is certain, therefore, that nitration of I with nitric acid in 95% sulfuric acid and that with acetyl nitrate have a different reaction mechanism ; the former reaction proceeding in [chemical formula] type and the latter in [chemical formula] type.

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With a view to establishing a method to investigate the effect of various barrier on the transport of drugs, a transport cell was devised which consisted of three compartments A, B and C partitioned with two semipermeable cellulose membranes, the central compartment B being thin and keeping a solution of non-permeable 3rd compornent as the model barrier to drug transport, and discussions were made on the relationship among the whole permeability constant, P, the permeability constant through the partitioning membrane, P_m, and the transport constant through compartment B, P^*. Then, the experimental examination was performed on the transports of barbital and benzoic acid through the central compartment solution of polyvinylpyrrolidone (PVP). The transport cell devised was useful enough to obtain satisfactorily reproducible results. NaCl which was added in compartment C to make isotonic in the whole system gave no notable effect on the flow of drug. The reasonable results were obtained regarding P, P_m and P^*. Analyzing the obtained values of P^* on the assumption that the interaction between drug and PVP might be expressed by a Langmuir type isotherm, a quantitative indicator was given to the extent of the above interaction in kinetical process. As a result, the interaction of PVP-benzoic acid was greater than that of PVP-barbital in the present system.

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New neutral proteinases, designated retikinonase I and II, have been isolated from the cultured broth of a Streptomyces strain. Both enzymes are purified by gradient column chromatography on DEAE-cellulose and gel filtration on a column of Sephadex G-75. Retikinonase I and II are of basic protein nature and contain the same constituent amino acids. Both enzymes have enzymatic characteristics similar to neutral proteinases of microbial origin and hydrolyze bradykinin by the same manner with kinonase AI, AIII or BI. Retikinonase I showed very high anti-inflammatory activity for carrageenininduced edema in the hind paw of rats, but retikinonase II did not show the significant activity. The retikinonase-producing strain is considered to be similar to Str. uerticillatus. Taxonomic studies of the producing organism, production, isolation, purification, pysicochemical properties, effect of pH on proteolytic activity, pH stability, effect of temperature on proteolytic activity, thermal stability, effect of inhibitors on proteolytic activity, andsubstrate specificities of retikinonase I and II are reported in this paper.

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Gas chromatographic method has been devised for determination of the metabolites of 3-deoxyestrone. Satisfactory separation of the standard steroids was achieved, when the mixture was trimethylsilylated as pretreatment and then was subjected to gas chromatography using a connected column of 3% SE-30 and 2% OV-17 as the stationary phase. The established procedure was applied to quantitation of the urinary metabolites of 3-deoxyestrone administered to a rabbit. The typical gas chromatogram and cumulative excretion curve of the principal metabolites are shown in Fig. 2 and 3, respectively.

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Faculty of Pharmaceutical Sciences, Osaka University / Faculty of Pharmaceutical Sciences, Osaka University

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