Three kinds of bitter crude drugs of the Gentianaceae family (Swertia japonica MAKINO, Swertia pseudochinensis HARA, and Gentiana scabra BUNGE var. Buergeri MAXIM.) were examined for promotion of gastric functions and increase in appetite, which are said to be the effect of these crude drugs. Changes in gastric juice secretion was examined by collecting a definite amount of gastric juice from a Shay rat at definite intervals by lavage. Other rats were bred on a low-protein diet and difference in body weight between treated and control rats was examined. Throughout these tests, there was no difference in the treated and control groups, and no evidence was found to endorse the foregoing effects. On the other hand, a parasympathetic nerve stimulant, prostigmine, markedly accelerated gastric juice secretion in Shay rats.

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Rate of moisture absorption of calcium pyruvate isonicotinoylhydrazone anhydrate was measured in 40-90% relative humidity. The velocity of moisture absorption is expressed as x=a₁(1-e^-k₁t) and the velocity constant was calculated from it. Rate of moisture absorption of three anhydrous crystals was compared. At relative moisture above 70%, the amount of moisture absorbed becomes equilibrated after reaching a miximum value and the line velocity during the desorption step was found to be expressed by ξ=1-(l-α₂)^1/3.

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Snake venom protein was separated into lecithinase A-I and A-II by column chromatography using ion-exchange cellulose and examinations were made on the action of inhibitors on the activity of these enzymes, demand for metal ions, effect of pH on the activity, and the product of substrate decomposition. The decomposition was examined with dipalmitoleyl-L-α-lecithin obtained from yeast and its hydrogenated dipalmitoyl-L-α-lecithin. Lecithinase A-II hydrolyzed both these lecithins to about the same degree but lecithinase A-I hydrolysed only dipalmitoleyl-L-α-lecithin and had only a weak action on dipalmitoyl-L-α-lecithin.

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During the purification of lecithin from the ethanolic extract of egg yolk phospholipid as cadmium chloride double salt, the cadmium chloride solution was added while examining Ninhydrin-coloration of the precipitate and the product was separated into lecithin and cephalin. The egg-yolk lecithin so obtained was purified by column chromatography through alumina and a product of high purity was obtained in a good yield.
Application of egg-yolk solution to snake venom in Veronal buffer afforded lysolecithin in a better yield than by the use of a phosphate buffer.

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Egg-yolk and yeast lecithin were purified by alumina column chromatography, the unsaturated lecithin so obtained was hydrogenated, and saturated lecithin was obtained. Lysolecithin contaminated in the foregoing four kinds of lecithin was separatory determined by the use of an enzyme from Serratia plymuthicum or by silica chromatography. The use of Serratia enzyme enables the measurement of lysolecithin contained in saturated lecithin which cannot be detected by the hemolytic method. Based on these results, saturated and unsaturated lecithins free from lysolecithin were separated and purified by fractionation with 60% ethanol. These lecithin samples would be of value in the activity measurement of lecithinase-A and studies on substrate specificity.

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Kinetic considerations were made earlier on the decarboxylation reaction of p-amino-salicylic acid and its sodium salt in solution. In order to examine the decarboxylation in their crystals, experiments were carried out on the solubility, thermal balance properties, and vapor pressure of sodium p-aminosalicylate crystals. Solubility of the crystals is shown in Fig. 1 and it indicated a breaking point at 2°. It was found by the thermal balance method that the liquid at below 2° is a pentahydrate while that above that temperature is a dehydrate. The dehydrate crystal is completely hydrated at a temperature of at least above 70°. Vapor pressure of the dehydrate in solution and saturated solution was measured and, as indicated in Table III, the dehydrate was found to be stable in a fairly wide range of relative humidity (i.e. relative humidity of ca. 19-91% at 30°).

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Determination of p-benzoquinone and 2-methyl-1, 4-naphthoquinone (vitamin K₃) was examined. p-Benzoquinone or the naphthoquinone was weighed accurately in glacial acetic acid to form a ca. 10^-3M solution. A portion of this solution, 2-5cc., was placed in a Photometric titration cell, equivalent amount of titanous salt solution was added, and the whole volume brought to 40cc. with water. This was titrated with 0.004N ceric sulfate, setting the spectrophotometer at 290mμ for p-benzoquinone and 320mμ for the naphthoquinone. The distance from the first to second breaking point is the amount corresponding to each compound. This method was found to effect rapid titration of a minute amount of quinone derivatives without the long procedure of reduction steps.

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In the photometric titration of ascorbic acid with potassium ferricyanide, titration conditions for potentiometric titration with 0.01N potassium ferricyanide was examined. It was found that the determination can be made without the effect of hydrogen sulfite, hydrogen metasulfite, Rongalit, or thiamine if the sample solution and phosphate buffer are prepared with 0.01M to 0.02M ethylenediamine tetraacetate, and the titration carried out at pH 7-8. This result was applied in the case of photometric titration. It was found that the determination is also possible in this case by the use of 0.001M potassium ferricyanide and the wave length of 275mμ, but it seemed more advantageous, when the amount of the sample is minute, to use the photometric titration which can determine the equivalence point as the crossing of two straight lines.

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Dyes having 4-substituted 2, 5-dimethylthiazole ring as the parent skeleton were synthesized and their antibacterial activity was compared with those of dyes having oxazole ring as the parent skeleton. The compounds prepared were 14 kinds of styryl-type dyes with a thiazole ring and 17 kinds of aminovinyl-type dyes possessing isobutyl or methyl group in 4-position. In general, when compared in the same type of dyes, those possessing a thiazole ring generally had stronger antibacterial action than those with oxazole ring. This is in agreement the general tendency found in the past.
Synthesis of thiazoles was carried out with the quaternary salts of 2, 5-dimethyl-4-isobutylthiazole from 3-acetamido-5-methyl-2-hexanone, derived from dl-leucine, and of 2, 4, 5-trimethylthiazole from 3-acetamido-2-butanone, derived from dl-alanine. These quaternary salts were condensed with aromatic aldehydes or formamidine to obtain the dyes.

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In order to make comparative examinations of the effect of substituting the alkyl in 4-position with other groups on the antibacterial action, dyes having 2, 5-dimethyl-thiazole ring possessing a benzyl or phenyl group in 4-position were synthesized. dl-Phenylalanine and 2-phenylglycine were derived to N-(α-acetylphenethyl)acetamide and N-(α-acetylbenzyl)acetamide by the Dakin-West reaction and submitted to substitution-cyclization with phosphorus pentasulfide to form 2, 5-dimethyl-4-benzyl- and 2, 5-dimethyl-4-phenylthiazoles. Using their quaternary salts as the starting material, 12 kinds of styryl-type dyes were synthesized by condensation with aromatic aldehydes and 19 kinds of aminovinyl-type dyes by fusion and condensation with formamidines. The dyes thereby synthesized were submitted to antibacterial tests with four kinds of typhoid bacilli and staphylococci.

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In order to clarify the mode of deacetylation of N¹-acetylsulfisoxazole by enteric bacteria, examinations were made on the washed cell suspension of Escherichia coli communior, Lactobacillus acidophilus, and Streptococcus faecalis R. All these three kinds, of bacteria effected deacetylation, the rate of deacetylation increasing with increasing pH in the range of pH 4-9, and E. coli was found to have the highest deacetylation effect. It follows, therefore, that deacetylation of N¹-acetylsulfisoxazole in the intestine is due partly to the enteric bacteria, such as the foregoing three kinds, present in the intestines, as well as by enteric juice, enteric membrane, and digestive enzyme. It was also found that deacetylation by these bacteria decreased on addition of glucose.

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Enmein (I), C₂₀H₂₆₍₂₈₎O₆, the bitter principle of Isodon trichocarpus KUDO, was submitted to baryta distillation and an optically inactive hydrocarbon (IV), C₁₆H₂₄, was obtained as a colorless oil of b. p₂₁ 145-160°. This hydrocarbon (IV) was brominated with N-bromosuccinimide, dehydrobrominated to (V), and submitted to ozonolysis, from which formaldehyde and a kind of aldehyde semicarbazone (VI), m. p. 217-220° (decomp.), C₁₆H₂₃ON₃, were obtained. The aldehyde (VII) obtained by the hydrolysis of (VI) was submitted to mild oxidation with potassium permanganate and carboxylic acid (VIII) of m. p. 162-165° was obtained. The products (IV), (VII), (VI), and (VIII) were respectively identified with 1-ethyl-4-(3, 3-dimethylcyclohexyl) benzene (C), 4-(3, 3-dimethylcyclohexyl) benzaldehyde (F), its semicarbazone (G), and 4-(3, 3-dimethylcyclohexyl) benzoic acid (H) by comparison with authentic samples prepared by the route shown in Chart 2.

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In the synthesis of 2-aminothiazole derivatives by the reaction of ketone, iodine, and thiourea, examination was made to see which of the methylenes reacted to form the thiazole ring when using asymmetric, straight-chain ketone like R-CH₂COCH₂-R′. Reaction of 1 mole each of the ketone and iodine with 2 moles of thiourea was in the same tendency as the halogenation of ketones. with acid catalyst and the methylene with larger number of carbon atoms reacted to form the ring. If this methylene possessed a substituent, the methylene on the side without a substituent underwent the reaction. Ketones with larger number of carbon atoms, such as 2-octanone, underwent resinification and this reation did not take place.

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During examination of the reactivity of methylene in R-CH₂COCH₂-R′ in the King reaction, thiazole was synthesized from bromoketone for the sake of comparison. The starting compound was obtained by the bromination of ketones but it was found that there were differences in the bromination of ethyl alkyl ketones and methyl alkyl ketones. In the case of methyl alkyl ketones, two isomeric monobromoketones are obtained while only one kind of monobromoketone, accompanied by a by-product dibromoketone, is formed in the case of ethyl alkyl ketones. These monobromo-ketones are oxidized by nitric acid to form α-brominated fatty acids and the position of bromine substituted in the ketone was determined from these acids. It was thereby found that the bromination of ethyl alkyl ketone resulted in the introduction of bromine in the alkyl group and not in the ethyl group.

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Examination was made on the reactivity of active methylene in asymmetric, straight-chain ketone of the formula R-CH₂COCH₂-R′, in the synthesis of 2-aminothiazole by reaction with thiourea and iodine, using a basic catalyst. Contrary to the use of an acid catalyst, the use of a basic catalyst was found to result in different reactivity of the methylene according to the nature of R and R′. When R is hydrogen and R′ is a straight-chain bond, the methylene on the side of R′-CH₂- is more reactive when the catalyst is a weak base, as in the case of an acid base, and both methyl and methylene react when the catalyst is a strong base, affording a mixture of the two kinds of product. However, CH₃CO(CH₂)₅CH₃ is an exception and its methyl group undergoes the reaction to form 2-amino-4-hexylthiazole. When the R′-CH₂- has a branched bond, chiefly the methylene undergoes the reactiton with a weak base and the methyl preferentially reacts when the catalyst is a strong acid. When R is a methyl and R′ is a straight-chain alkyl, the methylene of R′-CH₂-undergoes the reaction, but when R′ is a branched alkyl, the compound undergoes resinification and objective substance is not obtained.

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As a means of elucidating the mechanism of the King reaction, reaction of 1, 1′-dithiodiformamidine salts with ketone was examined. King reported that 1, 1′-dithiodiformamidine dihydrobromide, obtained by the Claus method, reacted with ketones to form a thiazole, that the addition of a base increased the yield, and that the reaction occured even in the presence of water. However, present experimental results showed that none of the compounds reacted, with the exception of hydriodides and a few others. Presence of water, even in the case of a hydriodide, resulted in liberation of sulfur and the reaction did not take place but addition of potassium iodide caused the reaction. From these facts, 1, 1′-dithiodiformamidine is not necessary as an intermediate in the King reaction and, even if it were to be formed during the course of this reaction, it would undergo decomposition in the following manner to take part in the reaction.
[NH₂-C-S]₂⋅2HX⇔2(NH₂)₂CS+X₂

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Ovomucoid was decomposed with barium hydroxide by the method of Stacey, the carbohydrate fragment thereby obtained was treated with acetic anhydride and strongly basic resin (carbonate form) to form an N-acetylated derivative, and purified by fractional precipitation with ethanol and chromatography through carbon-Celite mixture. These treatments separated the carbohydrate residue of ovomucoid into several fractions with different hexosamine/hexose ratio. These saccharide fragments possess amino acids, such as aspartic acid, alanine, and glycine. Removal of free amino acids by treatment with ion exchange resin and separation by paper electrophoresis afforded saccharide fractions which still retained amino acids, probably bonded with the saccharide.

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Mucopeptides were isolated from the pancrease hydrolysate of ovomucoid, submitted to dinitrophenylation, and purified by paper chromatography. Several kinds of dinitro-phenylated mucopeptides so obtained were analyzed for components and for C-terminal amino acids by hydrazine decomposition. It was assumed that the peptide portion is bonded to the saccharide portion through the carboxyl of aspartic or glutamic acid.

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Ovomucoid was decomposed by trypsin and from its dialyzate, dinitrophenylated mucopeptides, TI, TII, and TIII, were isolated by dinitrophenylation, chromatography, and paper electrophoresis. There was a quantitative difference in the componental sugars of these peptides and the ratio of hexose/dinitrophenyl residue was 6, 5, and 4, respectively. There was also a difference in the amino acid components of the peptide portion.

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The saccharide fragment of ovomucoid, obtained by destruction and removal of the peptide portion by decomposition with barium hydroxide, and the mucopeptide fraction (AI), isolated by pancrease decomposition of ovomucoid, were submitted to partial hydrolysis, and DNP-Asp·Gm and DNP-Ala·Asp (Gm). Thr were respectively isolated. DNP-Asp·Gm was submitted to hydrazine decomposition to examine the bonding of aspartic acid and it was revealed that its β-carboxyl group took part in the bonding.

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Pyrazinamide (I) was derived to its 1- or 4-oxide by treatment with hydrogen peroxide and treated with phosphoryl chloride to form chloropyrazinecarbonitrile. Its hydrolysis with hydrochloric acid afforded 5- and 6-chloropyrazinamide (VII and VIII). Thioethers were prepared by application of thiophenol, p-thiocresol, o-mercaptobenzoic acid, p-aminothiophenol, p-nitrothiophenol, and p-acetamidobenzenesulfonyl chloride to (III) and (VII), and various 5-substituted Pyrazinamide derivatives were prepared by oxidation of these obtained thioethers with hydrogen peroxide. Antituberculosis action of these compounds was tested and (IX) and (XI) were found to have excellent action against tubercle bacilli.

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dl-Ephedrine [hydroxymethylene-¹⁴C] (I) was prepared from propiophenone [carbonyl-¹⁴C], obtained by the Friedel-Crafts reaction of benzene and sodium propionate [carbonyl-¹⁴C] (II). The labeled propiophenone was submitted to bromination, aminomethylated, and reduced over palladium-carbon catalyst to the objective (I), whose total yield against (II) was 46%.

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Novobiocin, its decomposition products, and related compounds were classified into 3-acylamino-4-hydroxycoumarin derivatives, with the central skeleton of novo biocin, substituted benzoic acids, and compounds related to binding of sugars. Relationship between chemical structure and antimicrobial activity was examined and it was found that the presence of 3-(o-carbamoyl) novobioside bonded at 7-position of 3-(3-alkenyl-4-hydroxybenzamido)-4-hydroxycoumarin played an important rôle in the antimicrobial activity of novobiocin. It was also found that the esters of 3-alkenyl-4-hydroxybenzoic acid, the structural component of novobiocin, possessed a fair degree of antibacterial and antifungal activity.

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Qualitative examination of the reaction between 1, 2-cyclohexanedione and aniline by the use of infrared spectrum was made and it was found that this reaction proceeded in the following three steps. In the first step, during the four hours after the start of the reaction, there is a marked decrease in the intensity of enol ν_OH and ν_NH2 of aniline, and δ_NH2, with appearance of δ_NH band, which suggest the formation of a keto-enamine. The second step is the formation of enol-imine from the end of this fourth hour, indicated by the intensity decrease of C=O stretching vibration at 1680cm^-1 in 1, 2-cyclohexanedione, disappearance of δ_NH2, and appearance of ν_C=N. At this stage a yellowish brown liquid formed by intramolecular bonding of the enol-imine and keto-enamine is obtained. In the third stage, this yellowish brown liquid begins to precipitate out yellow crystals after about 10 days and the changes observed in the infrared spectrum during this stage are the disappearance of ν_C=O at 1680cm^-1, ν_OH, and ν_C=N, and appearance of ν_C=O at 1648cm^-1, which suggest the conversion of the enol-imine into keto-enamine to form 2-anilino-2-cyclohexen-1-one.

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In spite of the proposal of structural formula for nocardamin by Stoll and others, its synthesis has not been reported to date. In order to confirm this structural formula by synthesis, synthesis of its four-membered ring portion was attempted. Starting with γ-pyrone, it was derived to 1, 1-bis(2-bromoethyl)methylamine, which was tosylated to N-bis-(2-bromoethyl)methyl-p-toluenesulfoamide, and its treatment with alkali resulted in formation of a four-membered ring, yielding N-(p-tosyl)-2-(2-bromoethyl)azetidine. This was treated with silver hydroxide or acetate to form N-(p-tosyl)-2-azetidineëthanol. Attempted liberation of the tosyl group in order to obtain a substance corresponding to the structural formula for nocardamine proposed by Stoll and others did not materialize without opening of the four-membered ring.

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Stoll and others proposed a structural formula for nocardamin but there are no reports on its synthesis. In order to confirm this structure by synthesis, 1-p-tosyl-2-azetidineëthanol was prepared earlier but attempted cleavage of its tosyl group did not materialize. Therefore, this synthetic route was changed to the Gabriel reaction of 1-p-tosyl-2-(2-bromoethyl) azetidine to form 1-p-tosyl-2-(2-p-toluenesulfonamidoethyl)-azetidine whose tosyl group was successfully cleaved by treatment with metallic sodium in liquid ammonia. This method was utilized for synthesis of 2-(2-aminoethyl) azetidine.

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By application of the furoquinoline ring synthesis described in the preceding paper^*1, various substituted derivatives of dihydrofurancarboxyanilide were synthesized and the corresponding dihydrofuroquinoline derivatives were obtained, with the exception of 3′-nitroanilide. Polyphosphoric acid treatment of 3′-nitro (2, 3-dihydro-4-furoyl) anilide resulted in recovery of the starting compound and nitro-furoquinoline was not obtained. Ultraviolet spectra of synthesized furoquinolines were taken and their absorption curves were classified according to the nomenclature of Klevens and others. With consideration of the effect of the substituents on the spectra, the position of the substituents in the furoquinolines obtained by cyclization of 3′-substituted anilides was presumed.

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Codeine phosphate forms crystals with 1.5, 1.0, and 0.5 mole of water of crystallization and the formation of these three kinds of crystals depends on the kind of solvent used, concentration of the solution, and temperature at the time of crystallization at the time of preparation of codeine phosphate. Codeine phosphate with less moisture is more easily soluble in water and is stable to periodic change when heated. The crystal with 1.5 moles of water easily liberates water at a low temperature of 40°, but those with 0.5 and 1.0 mole of water do not. These three kinds of hydrated crystals, dried to a lower hydrate or anhydrate state, were found to return to the corresponding hydrated molecules in the air.
X-Ray diffraction of these codeine phosphate crystals showed that the crystals formed by hydration of the anhydrate crystals regain the same crystal form as the original hydrated crystals. It follows, therefore, that codeine phosphate crystals with 1.5, 1.0, and 0.5 mole of water of crystallization are all in stable form.

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Sulfisoxazole undergoes decomposition in vivo to form various kinds of product and a method for measuring blood level by isolation of unchanged Sulfisoxazole alone from such decomposition products was devised. For isolation of sulfisoxazole, liquid chromatography is employed, using powdered cellulose as the carrier and a mixture of butanol, propanol, and water in 2:1:1 ratio as the developing solvent. Determination of sulfisoxazole is made by colorimetry using p-dimethylaminobenzaldehyde and absorbancy is measured at 453mμ.
Since a fairly satisfactory result was obtained by this method, blood level was measured by this method after oral administration of sulfisoxazole and N¹-acetylsulfisoxazole, and the result was compared with that from the widely used Bratton-Marshall's method.

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5-Nitro-2-furanacrylic acid derivatives with p-substituted phenyl in α-position were synthesized and antibacterial tests of these compounds were carried out, as well as measurement of their ultraviolet absorption spectra. It was found that the compounds with phenyl group substituted with vitro, chlorine, bromine, or iodine, in para position had comparatively strong activity while those with phenyl group substituted with methoxyl, acetoxyl, or acetamido group had weaker but distinct antibacterial activity.

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DL-trans- and DL-cis-2-Iodo-N, N-dimethylaminocyclohexylamines (I and II) were solvolyzed in water, ethanol, cyclohexanol, dimethylaniline, nitrobenzene, xylene, and liquid paraffin. Solvolysis of the trans isomer (I) was affected by the solvent used, giving one or two of cyclohexanone, cyclopentanecarboxaldehyde, and 2-dimethyl-aminocyclohexanol derivatives in different ratio. On the other hand solvolyses of the cis isomer (II) gave only cyclohexanone in all of solvents used. Solvent effects on the reactions were deduced only from analyses of products.

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1, 1′-Dithiodiformamidine has been known for a long time as the oxidation product of thiourea but the method of its synthesis and data of its properties have been variedly reported in the literature. In the necessity to prepared 2-aminothiazole derivatives, these points were examined. The most convenient method of its synthesis is the oxidation with hydrogen peroxide in hydrohalogen acid. Oxidation with halogen in organic solvent gives different products according to reaction conditions. The hydrochloride is the most stable and hydriodide, the most labile, liberating iodine. Salts are soluble in water but not in organic solvents. Addition of organic solvent to the solution of hydriodide immediately starts liberation of iodine.

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Ketones with a double bond in α, β-positions show characteristic ultraviolet absorption spectrum by substitution of these positions. Attempts were made to determine the position substituted with bromine in the monobromoketone obtained by bromination of ethyl alkyl ketone. Dehydrobromination of the bromoketone was carried out and the α, β-unsaturated ketone thereby obtained was submitted to ultraviolet spectral measurement, which gave values satisfying the so-called Woodward rule. It was found from this result that the bromoketone examined had the structure of CH₃CH₂COCH-R.

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Infrared spectra of 4-benzyloxy-1, 3-cyclohexanedione (I) and its p- (II) and o-methoxy (III) derivatives were measured in solid state and in a solution of chloroform, ethanol·chloroform (2% ethanol), and dioxane. The p-methoxyl derivative (II) showed absorption bands of the same series as those of (I) and the previously reported 1, 3-cyclohexanedione derivative. On the other hand, the o-methoxyl derivative (III) showed characteristic bands. Its solution in chloroform, immediately after dissolution, showed absorptions of a keto form but the bands changed with passage of time and enolization of the carbonyl of benzoyl group was observed. The absorption bands of. (III) in ethanol·chloroform and in dioxane were the same. These characteristics were interpreted as the M-effect of the o-methoxyl group in (III).

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Chlorothiazide is decomposed into 4-amino-6-chloro-m-benzenedisulfonamide in acid solution and this decomposition is a first-order reaction. The degradation velocity constants of this reaction at 100°, 80°, and 60° in 0.1N hydrochloric acid solution were 2.80×10^-3, 7.6×10^-4, and 1.28×10^-4, respectively. The activation energy was 17.4 kcal.

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