Twelve kinds of 1-(p-tolylthio)-3-alkylurea (III) were synthesized and their hypoglycemic action was examined. Butyl compound (III-6) was found to have a powerful hypoglycemic action comparable to D-860 but none of the other alkyl derivatives showed a powerful action, the ethyl compound (III-3) showing a weak activity. Acute toxicity, LD₅₀, of (III-6) was 3030mg./kg. by oral administration in mice.

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Separatory determination of isonicotinic acid hydrazide (INAH) (I) and its metabolites, 1-acetyl-1-isonicotinoylhydrazine (II), isonicotinic acid (III), glucose isonicotinoylhydrazone (IV), and pyruvic acid isonicotinoylhydrazone (V) was established by the use of ion exchange resins, Dowex 1-X8 (Cl type) and Amberlite CG-50 (H type) and Amberlite CG-50 (Hform) (100-200 mesh). Separation of (I), (III), and (V) is effected by passing the sample urine through Dowex-1 column and its effluent is continuously passed through the Amberlite CG-50 column, by which (III) and (V) are adsrobed by the Cl-type resin and (I) by H-type resin. The Dowex-1 column is eluted with sodium chloride solution to desorb (III) alone and then eluted with 0.5N hydrochloric acid to desorb (V). Amberlite CG-50 column is eluted with 0.5N hydrochloric acid to desorb (I). For the separation of (II) and (IV), two Dowex-1 columns are prepared. The sample urine is passed through the first Dowex-1 column to remove (III) and (V), the effluent is acidified with acetic acid, and oxidized with potassium dichromate to convert (I) and (IV) into isonicotinic acid. This solution is neutralized and passed through the second Dowex-1 column to desorb isonicotinic acid and (II) alone is flown out. Isonicotinic acid is eluted with 0.5N hydrochloric acid. From the sum of these (I) and (IV), the amount of (I) determined separately is substracted and the difference is the quantity of (IV).
Each of these metabolites was determined colorimetrically using cyanogen bromide. The separated sample solution, neutralized if necessary, was oxidized and decomposed with the bromine reagent to convert all to isonicotinic acid, colored by 7.5% cyanogen bromide in sodium carbonate-sodium hydrogen carbonate buffer, and determined colorimetrically (E₄₂₅). This method makes it possible to determine INAH and its metabolites in the urine when INAH was used with streptomycin, PAS, thioacetazone, or pyrazinamide.

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A temperature scan method was introduced to indicate the behaviors of aqueous solution or solubilized solutions of nonionic surfactants subjected to temperature changes. This method enabled one to measure tempratures at which the clarity of a solution changed by means of scanning the temperature of a solution; the results obtained were classified following Winsor's classification. By examining temperature changes due to changes in xylene/water ratio in the solubilized system, it was possible to examine the reactivity or stability of solubilized pharmaceutical preperations against temperature changes. The cloud point of the nonionic surfactants used, i.e., Triton X-100, OP-7 mol, and OP-15 mol, were discussed.

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The effect of dilution with water on surfactant-oil mixtures was studied with the temperature scan method. The results obtained led to an assumption of the stability of solubilized preperations diluted with water. Triton X-100-xylene mixtures in definite proportions were diluted stepwisely with water and the solubilization temperatures at each dilution were measured (Fig. 1). Variations in solubilization temperature with surfactant concentrations appeared markedly in S°₁ and G°₁, but not so markedly in S°₂ and G°₂ (Table I, II, and III). It was suggested that an increase in the concentration of a surfactant in solubilized solution improved the stability in a low-temperature region, but not in a high-temperature region. Changes in clarity or Winsor's type in solubilized preperations being diluted with water at a constant temperature (25°) were shown in Table IV.

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Jervine, rubijervine, and a new ester alkaloid were isolated from Veratrum stamineum MAXIM. growing in Hokkaido. This ester alkaloid, m.p. 175°, [α]_D¹²-7.8°, C₃₂H₅₁O₈N⋅3H₂O, was determined as 3-(l-2-methylbutyryl)zygadenine.

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The structure of bilobanone, the chief constituent of the essential oil contained in the heartwood of Ginkgo biloba L. was determined as (I). Previous experiments had revealed that bilobanone contained a group -CH₂-CO-CH=CH-, two double bonds, and one ether-oxygen, and formed two moles of acetone and methyl 4-methyl-3-cyclohexenyl ketone by alkaline decomposition, which suggested formula (I).
In order to prove this structure, fission of the ether bond in bilobanone was attempted with metallic lithium in ethylenediamine and a hydroxy-ketone compound (III) was obtained. Oxidation of this ketone compound with chromium trioxide gave a diketone (V) which was treated with dilute alkali and a cyclized hydroxy-ketone (VI) and an unsaturated ketone compound (VII) were obtained. Reduction of (VI) with lithium aluminium hydride afforded a dihydroxyl compound (VIII), m.p. 66-67°, whose dehydrogenation with selenium gave an oil. The picrate, m.p. 115°, of this oil showed no depression of the melting point on admixture with an authentic sample of cadalene picrate.

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As a part of a search for new antipyretic-analgesics, amino acid-type derivatives of salicylic acid were prepared to effect lowering of toxicity and increase of solubility. Application of aqueous alkali or various amine solutions to 3-substituted 2H-1, 3-benzoxazine-2, 4(3H)-diones (IV to XI), obtained by the reaction of sodium salt of 2H-1, 3-benzoxazine-2, 4(3H)-dione and α-halo acid derivatives (ester or amide), effected ring-cleavage or concurrent ring-cleavage and amidation to form N-substituted 2-salicylamidoacetamides (XII to XVIII), and these were O-alkylated to form N-substituted 2-o-alkoxybenzamidoacetamides (XIX to XXVII). Of the compounds synthesized, N, N-dimethyl-2-o-methoxybenzamidoacetamide (XXI) possessed excellent antipyretic, analgesic, and antiphlogistic actions and was highly soluble in water. Several reactions were carried out in an attempt to obtain this compound by another route and to prepare analogous compounds (XXVIII to XXXVIII).

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Difference in the solubility of alkylsulfates of various amino compounds in ethanol, butanol, chloroform, and water was examined. Solubility in a certain solvent is affected by gegenion. In general, these alkylsulfates have greater affinity to these solvents than mineral acid salts and become very sparingly soluble in water below the Krafft point with increasing number of carbon atoms in the straight alkyl chain. The Krafft phenomenon in aqueous solution of alcohol with 1-4 carbon atoms was examined and it was observed that the Krafft point decreased in proportion to concentration of alcohol, as was observed earlier in the case of thiamine alkylsulfates and that a linear relationship existed between the logarithm of the lowering of the Krafft point (b) and number of carbon atoms in the alcohol. Alkylsulfates of quinine and tetracycline, whose Krafft point in aqueous solution was too high to be measured, showed a clear Krafft point in alcoholic solution. It was found that the Krafft point of the alkylsulfates of an amine became higher with increasing number of carbon atoms in the straight alkyl chain. In these alkylsulfates, lowering of the Krafft point and concentration of alcohol were not in linear relation and the Krafft point was found to lower suddenly after a certain concentration.

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3-Chloro-4-methyl-6-sulfanilamidopyridazine(VI-B), 3-chloro-4, 5-dimethyl-6-sulfanil-amidopyridazine(VI-C), and 3-chloro-4, 5-tetramethylene-6-sulfanilamidopyridazine(VI-E) were prepared by hydrolysis of N⁴-acetylated compound of (VI), obtained by condensation of the corresponding 3-chloro-6-amino derivatives (V) with p-acetamidoben-zenesulfonyl chloride in pyridine. 1-Chloro-4-sulfanilamidophthalazine (VI-D) was prepared by fusion of 1, 4-dichlorophthalazine (IV-D) with potassium salt of sulfanilamide. Heating of (VI-B) and (VI-D) with sodium alkoxide afforded the corresponding alkoxyl derivatives (VIII). Catalytic reduction of (VI-B) and (VI-C) respectively gave 4-methyl-6-sulfanilamidopyridazine (VII-B) and 4, 5-dimethyl-6-sulfanilamidopyridazine (VII-C). 3, 6-Dichloro-4, 5-tetramethylenepyridazine (IV-E) failed to undergo amination on heating with aqueous ammonia but afforded 3-chloro-6-amino derivative (V-E) on being heated with alcoholic ammonia. 4, 5-Tetramethylene-6-methyl-3-pyridazinol (XVIII) was obtained by heating 3, 4, 5, 6-tetrahydrophthalic anhydride and malonic acid in pyridine and addition of hydrazine hydrate to ethanolic solution of its product.

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Relationship between absorption spectrum and components of a hot-spring water was examined and following facts were revealed.
1) Absorptions appearing in the ultraviolet to visible region are chiefly due to the iron (III) complex ions (Fe³⁺-aquo, FeSO₄⁺, FeOH²⁺, etc.) or sulfur compounds (H₂S, S₂O₃^2-, etc.).
2) Marked variation in the absorption spectra is observed when acidic vitriol spring containing hydrogen sulfide is left in the air. At first, absorption due to H₂S appears in the shorter wave-length side at around 260 mμ, which diminishes as the spring water is left in the air, and an absorption of iron (III) complex ion appears in a wide range from ultraviolet to visible region as Fe²⁺ is oxidized to Fe³⁺.
3) The absorption with a maximum at 300 mμ appearing in the strongly acidic iron spring is due to FeSO₄⁺, and this absorption is overlapped by the absorption due to FeOH²⁺ in weakly acidic iron spring and by that due to FeCl²⁺ in iron springs containing chlorine ion. Absorption maxima of Fe³⁺-aquo, FeOH²⁺, and FeCl²⁺ appear respectively at around 240, 300, and 330-350 mμ, but they overlap the absorption of FeSO₄⁺, and are not clearly observed.

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Oxidation of 3-chloro-6-methoxypyridazine with hydrogen peroxide in acetic acid afforded 3-chloro-6-methoxypyridazine 1-oxide (II), 3-chloro-6 (1H)-pyridazinone (III), and 3-methoxy-6 (1H)-pyridazinone (IV). 3-Methoxy-6-pyridazinol 1-oxide (V) was obtained by heating (II) with sodium acetate in acetic acid or warming 3, 6-dimethoxy-pyridazine 1-oxide in dilute hydrochloric acid. (V) was found to exist as 1-hydroxy-3-methoxy-6 (1H)-pyridazinone from the result of ultraviolet and infrared spectra, and of alkylation.

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3-Methyl-(IV and V), 3-chloro-6-methyl-(VI), and 3-methoxy-6-methyl-pyridazine N-oxide (VII), and 6-methyl-3-pyridazinol N-oxide (VIII) were synthesized and the N-oxide group in (IV), (VI), (VII), and (VIII) was proved to be in the same position with respect to the methyl group. This N-oxide group was concluded to be in the position adjacent to the methyl group from the formation of 6-methoxy-3-pyridazinemethanol acetate (XIII) by the reaction of (I) or (VII) with acetic anhydride, formation of (VII) from (VIII) by treatment with methyl iodide and silver oxide, from the comparison of ultraviolet and infrared absorption spectra of (VIII), (X), and 1-hydroxy-3-methoxy-6(1H)-pyridazinone (IX), and by comparison of infrared absorption spectra of (IV), (V), and pyridazine 1-oxide. Consequently, the nitrogen further removed from the methyl group is oxidized in (V). Ultraviolet spectra of several pyridazine N-oxides are also given.

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Nitration of pyridazine 1-oxide (I), 3-methylpyridazine 2-oxide (II), 3, 6-dimethyl-pyridazine 1-oxide (III), 3-methoxy-6-methylpyridazine 1-oxide (IV), and 3-chloro-6-methylpyridazine 1-oxide (V) afforded nitrated derivatives, which were all assumed to be 4-nitro compound, and it was confirmed that the same position is nitrated with respect to the N-oxide group in (II), (III), (IV), and (V). The nitro group in these compounds substituted with methoxyl by treatment with sodium methoxide. The nitro group alone is reduced by catalytic reduction over palladium-carbon but both the nitro and N-oxide group are reduced by catalytic reduction over Raney nickel, forming aminopyridazines. Effect of a substituent present is marked in nitration and nitration progreses smoothly when an electron-releasing group is present in the ring.

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2, 2′-Diphenyl-, 2, 2′-dianilino-, and 2, 2′-bis (p-methylanilino)-4, 4′-bithiazole, and (4, 4′-bithiazole)-2, 2′-dithiol (I) were prepared by the reaction of 1, 4-dibromo-2, 3-butanedione respectively with thiobenzamide, 1-phenylthiourea, 1-p-tolylthiourea and ammonium dithiocarbamate. Oxidation of (I) in carbonate alkaline solution afforded dipotassium (4, 4′-bithiazole)-2, 2′-disulfonate.
(4, 4′-Bithiazole)-2, 2′-dicarboxaldehyde (II) was obtained by hydrolysis of (4, 4′-bithia-zole)-2, 2′-dimethanol benzoate, obtained by the reaction of 2-benzoyloxythioacetamide and 1, 4-dibromo-2, 3-butanedione, with ethanolic potassium hydroxide to the alcohol compound and its oxidation with chromic acid. By a similar process, 2, 2′-diacetyl-4, 4′-bithiazole (III) was prepared from 2-benzoyloxythiopropionamide and 2, 2′-dibenzoyl-4, 4′-bithiazole from 2-benzoyloxy-2-phenylthioacetamide.
The compound (II) was derived to 2-benzothiazolylhydrazone, oxime, and thiosemicarbazone, and also to the azomethine compounds of aniline, p-toluidine, p-anisidine, and N, N-dimethyl-p-phenylenediamine.

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Absorption of orally administered drugs through the digestive tract must be made after dissolution of that drug and the difference in the blood level of powders of different granules must be due to the difference in rate of solubility from difference in granular diameter. Experiments were carried out with sulfaethylthiadiazole powders and this relationship was clarified. A formula for blood level was derived by considering the granular diameter as affecting the solubility of drugs and its theoretical value was found to correspond well with measured value.

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Addition reaction of alkyl 2-halovinyl ether and acetals was carried out with boron trifluoride-ethyl ether or iron trichloride as a catalyst. This reaction was also found to be possible in inactive acetals such as formaldehyde acetal and 2-haloacetaldehyde acetal, which didn't yet succeeded in the reaction with alkyl vinyl ether. Reaction of alkyl 2-halovinyl ether with orthoformic acid ester was found to give 1, 1, 3, 3-tetraalkoxy-2-halopropane in a good yield.

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Numerous works have been reported on the chemical reaction of alkyl vinyl ethers and similar work was carried out for utilization of alkyl vinyl ether and its derivatives. Attempt was also made for improvement of synthetic process for a few new derivatives of this system, such as chloroalkane-1-carboxaldehyde methyl acetate. Reaction of alkyl vinyl ether with orthoformic acid ester, in the presence of a Friedel-Crafts type catalyst and other acid catalysts afforded 1, 1, 3, 3-tetraälkoxypropane.

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Consistency curves of procaine penicillin G inaqueous suspension were measured with varying concentrations. When measured at a small rate of shear, a non-Newtonian flow was observed but a Newtonian flow was observed at a greater rate of shear. In the region of this Newtonian flow, a relationship represented by the Robinson equation, with relative sedimentation volume measured in centrifugal field as the parameter, was found to exist between relative viscosity, ηr, and volume fraction of dispersed particles, φv

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The theory of destruction of viscous material was introduced into the linear theory of visco-elasticity and correlation between visco-elasticity and non-Newtonian flow was represented by equations (9) and (10), where _Tc-Γ_Mυ, η(υ) is the viscosity at the rate of distortion, υ, G(_T) and ψ (ln _T) are the distribution function of relation time, and Γ_M is the limit of elastic strain. It was thereby found that a mathematical relationship indicated in Fig. 4 exists between visco-elasticity and non-Newtonian flow.

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Mathematical relationship between visco-elasticity and non-Newtonian flow, derived theoretically and described in the preceding paper, was examined experimentally. Dynamic visco-elasticity, non-Newtonian flow, and limit of elastic strain were measured in five kinds of dispersion system and distribution function of relaxation time calculated from dynamic visco-elasticity and that calculated from non-Newtonian flow were found to agree well, as indicated in Fig. 5. These facts have experimentally proved the theory postulated in the preceding paper.

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Using the theory described in Part II of this series, method of reduced variables for visco-elasticity by Ferry and Tobolsky was extended to non-Newtonian flow and equation (7) was obtained theoretically, where S_T (υ) is shearing stress at temperature T₀ and shearing rate υ, S₀ (a_Tυ) is shearing stress at temperature T₀ and shearing rate a_Tυ, and a_T is a shift factor. Experiments with six kinds of dispersion system showed that experimental and theoretical results agreed well, except for methylcellulose at above 39°, which was considered to be due to gelation. In two kinds of suspension, barium sulfate in water and zinc oxide in oil, activation energy calculated from a_T agreed well with that of the dispersion medium.

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Reaction of mercury (II) with thioglycollic acid results in formation of mercury bis-thioacetate. Based on this reaction, a new volumetric analysis of mercury (II) was examined. The end point in potentiometric titration can be observed by the jamp in potentials between platinum and calomel electrodes but not by naked eye. A sharp color change was observed, however, by the addition of over 4 moles of sodium acetate and a small quantity of copper (II) to 1 mole of mercury (II) and the end point was easily observed. Addition of sodium chloride is necessary in the case of mercury (II) salts other than mercury (II) chloride. Determination of mercury (II) can be made easily, rapidly, and accurately by the present method.

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Colorimetric determination of tetracycline was carried out with p-nitrobenzenediazonium chloride as the reagent. To 5cc. of the test solution (0-20γ/cc.), 1cc. of the reagent, prepared by dissolving 200mg. of p-nitroaniline in a mixture of 3cc. of conc. hydrochloric acid and 5cc. of glacial acetic acid, and adding 2cc. of 15% aqueous solution of sodium nitrite and 40cc. of glacial acetic acid, was added and the mixture was warmed at 65° for 45minutes. The colored solution thereby produced has a maximum absorption at 435mμ and follows the Beer's rule in a concentration range of 0 to 20γ/cc.
Tetracycline solutions of various pH were allowed to stand to effect its decomposition and resulting solutions were submitted to determination by the present method. The potency of the solution was compared with the value obtained by biological method and there was a slight difference in acid side but the two values agreed well on neutral and alkaline side.

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By the modification of the past process of paper chromatography for veratrum alkaloids, it became possible to separate and estimate each derivative of free and ester alkaloids, and alkamines by the use of a new solvent system. A better result was obtained by this method for the veratrum alkaloids themselves.

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Condensation of methyl 2-cyano-2-ethyllevulinate (VI), obtained from methyl 2-cyano-butyrate (V) and bromoacetone, with phenylhydrazine affords a hydrazone (VII) which, on being boiled with alcoholic hydrochloric acid containing a small amount of water or with sulfuric acid, undergoes cyclization to form 2-phenyl-3-oxo-4-ethyl-6-methyl-2, 3, 4, 5-tetrahydro-4-pyridazinecarboxamide (VIII). Similar condensation of dimethyl ethylmalonate (IX), obtained by boiling (V) with alcoholic hydrochloric acid with bromoacetone, afforded methyl ethylacetonylmalonate (X) which was also obtained by boiling (VI) with alcoholic sulfuric acid.

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Boiling of 3, 6-dichloro-4-methylpyridazine (II) with methanolic solution of sodium methoxide results in formation of two kinds of monomethoxyl derivatives (IVa and b). Heating of these two with 28% ammonia water in a sealed tube results in demethylation of the methoxyl group to form chlorohydroxy derivatives (Va and b). Amination of (Va) in the presence of bronze powder gives 4-methyl-6-amino-3-pyridazinol (VII), which can also be obtained by demethylation of 3-methoxy-4-methyl-6-aminopyridazine (VIII), obtained by methoxylation of 3-chloro-4-methyl-6-aminopyridazine (IIIa) formed by amination of (II), with ammonia water. Catalytic reduction of (III) and (V) afforded the corresponding (IX) and (VI) compounds. Monodimethylamino derivative (XI) was prepared by heating (II) with 40% dimethylamine in a sealed tube but this compound was not separated into two kinds of isomers. Methyl group in (Va) and (Vb) was oxidized to obtained the corresponding carboxylic acids (XIIa and b).

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A quaternary base, berberine (II), was isolated and identified from the whole herb of Thalictrum actaefolium SIEB. et ZUCC. (Japanese name “Shigin-karamatsu”). A quaternary base was also isolated from the root of the same plant growing in Gifu Prefecture but the base did not crystallize. It was identified by derivation to tetrahydroberberine (III) by reduction with zinc dust and acetic acid. Other quaternary bases are under investigation yet due to the minute amount available.

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