Stereospecific synthesis of isomeric 4-benzoyloxycyclohexane-spiro-5'-hydrantoins from 4-benzoyloxycyclohexanone was achieved via the Bucherer hydantoin synthesis and the Strecker cyanate route. Subsequent hydrolysis of both hydantoins resulted in the formation of 1-amino-trans- and cis-4-hydroxycyclohexane-1-carboxylic acids. The stereochemistry of both amino acids was established unequivocally bythe transforma, -tion of phthalimide of the cis-amino acid to the corresponding lactone. Thus, it is concluded that while the Strecker synthesis leads to the exclusive formation of the cis-amino acid, the Bucherer synthesis gives the trans-amino acid predominantly. The present result provides chemical evidence for the stereochemistry of 1-amino-4-alkylcyclohexane-1-carboxylic acids which have been assigned ambiguously. Physicochemical data of pairs of isomeric 4-substituted amino acids and their derivatives are also summarized.

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As the analog of thioinosine, 2-methyl-, 2-ethyl-, 2-methylthio-, and 2-methyiamino-6-mercapto-9-β-D-ribofuranosylpurine were synthesized. From thio-AICA-riboside, 5-formamido-1-(2', 3', 5'-tri-O-formyl-β-D-ribofuranosyl)-4-imidazolethiocarboxamide and 5-acetamido-1-(2', 3', 5'-tri-O-acetyl-β-D-ribofuranosyl)-4-imidazolethiocarboxamide were also prepared.

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Meerwein-Ponndorf reduction of 3-methoxy-8, 14-secoestra-1, 3, 5 (10), 9, 15-pentaene-14, 17-dione (III) yielded a mixture of rac-17α- and 17β-hydroxy-3-methoxy-8, 14-secoestra-1, 3, 5 (10), 9, 15-pentaen-14-one (XI and XII). Cyclization of 17β-benzoate of XII gave 3, 16α-dimethoxy estra-1, 3, 5 (10), 8, 14-pentaen-17β-ol 17-benzoate (XV), which was further transformed to rac-estrone (XXT).

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The more stable compound, 9, 14α-epoxy-3-methoxy-8, 14-secoestra-1, 3, 5 (10)-trien-17-one (IVa), given by cyclization of 14α-hydroxy-3-methoxy-8, 14-secoestra-1, 3, 5 (10), 9-tetraen-17-one (II), has been assigned to a 9α, 14α-epoxy compound (9S configuration).

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A neutral polysaccharide and an acidic polysaccharide have been isolated from the dried fruits of Zizyphus vulgaris LAMARCK var. inermis BUNGE. The former, named Zizy-phus-arabinan, possesses one mole of D-galactose per thirty moles of L-arabinose residues. As the results of methylation and periodate oxidation studies, it is able to concluded that the arabinan has a chain of 1 5 1inked α-L-arabinofuranose units having a highly branched structure with 1 2 branch point. The component sugars of the acidic polysaccharide were D-galacturonic acid, L-rhamnose, L-arabinose, D-xylose and D-galactose.

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N-Acylmethylpyridinium salts (Ia-c) were applied to some pyridine and quinoline N-oxides in the presence of acetic anhydride. 4-Methoxyquinoline 1-oxide (IV) readily reacted with Ia-c to give N-(α-acyl-4-methoxy-2-quinolylmethyl) pyridinium compounds (Va-c) in good yields. Whereas N-oxides of lepidine (VIII), pyridine (XII) and 4-picoline (XV) reacted similarly with N-acetonylpyridinium chloride (Ia). Quinaldine and 2-pi-coline N-oxides did not react even with Ia.
The pyridinium salts thus obtained afforded smoothly the corresponding quinaldyl (XVIIIa, b; XIX) or α-picolyl ketones (XXI, XXII) upon treatment zinc powder and acetic acid.
The tautomeric structures of the quinaldyl ketones (XVIIIa, b; XIX) were discussed.

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Intramolecular hydrolyses of amides and anilides were examined over wide pH ranges at 90° Shape of pH-rate plofiles indicates that the relative reactivity of ionized (k'_RO^-) and un-ionized (k'_ROH) alcohol functions toward amide linkage is governed by difference in pKa between attacking group alcohol and leaving group amine. As predicted from the theoretical consideration, their rate constants, k'_RO^- and k'_ROH, were found to have good linear free-energy correlation.

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Diketene reacted with diazoacetophenone (Ia) to give two isomeric spiro compounds, 2-(trans-2-benzoyl-1-hydroxycyclopropane)-acetic acid β-lactone (IIa) and 2-(cis-2-benzoyl-1-hydroxycyclopropane)-acetic acid β-lacton.e (IIa'). Similarly, p-methoxy-α-diazoacetophenone (Ib) was transformed to 2-[trans-2-(p-methoxybenzoyl)-1-hydroxycyclopropane]-acetic acid β-lactone (IIb) and 2-[cis-2-(p-methoxybenzoy1)-1-hydroxycyclopropane]-ace tic acid β-lactone (IIb'). Reaction of diketene with ethyl diazoacetate (Ic) gave furanone derivatives, 2, 5-dihydro-2-ethoxycarbonyl-3-methylfuran-5-one (VII) and 2, 5-dihydro-4-ethoxycarbonyl-methylfuran-2-one (VIII), together with 2-(trans-2-ethoxycarbony1-1-hydroxycyclo-propane) acetic acid β-lactone (IIc).

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An approach to the evaluation of antihistaminic preparations were studied by quantitative measurement of the inhibitory action of histamine skin response in intact dogs. The size of the papule, which was produced by subsequent intracutaneous injection of histamine in the foreleg of dogs, was quantitatively measured without any intravenous injection of dye. The inhibition of histamine skin response was proportional to the increase of the dose of chlorpheniramine maleate and of clemastine fumarate which were given orally. The linear regression between the logarithmic dose and the tested area was highly significant in both cases. Clemastine was approximately five times more effective than chlorpheniramine when analyzed by the parallel line assay of the dose response relationship. The intensity and the duration of the inhibitory effect of clemastine tablets were compared with those of chlorpheniramine tablets following oral administration and it was found that the effects of the former was stronger and longer than the effects of the later. From these observations, it is concluded that this method seems to be useful for the evaluation of the effects of oral antihistaminic preparations during preclinical test.

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Treatment of 10-halogeno-2, 3, 5, 6, 7, 11b -hexahydro -7-methyl-11b-phenylbenzo [6, 7]-1, 4-diazepino [5, 4-b] oxazol-6-one (IIIa-d) with dimethyl formamide in the presence of sodium hydride gave exo -methylene compounds (Va-d). On the other hand, the compounds (IIIe-g) having halogen at o-position of the 11b-phenyl group gave no exomethylene compounds, but isoindoles (XVIIIe-g) and acridanone derivatives (XIXe-g). A mechanistic assumption for the formation of these compounds from benzo [6, 7]-1, 4-diazepino [5, 4-b] oxazole derivatives was given.

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Reaction of Δ^{1, 10}-hexahydroquinolizine (I) with methyl iodide in various solvents were carried out. The reaction in the presence of methanol or ethanol proceeded at low temperature to give 10-methoxy-5-methyloctahydroquinclizinium iodide (IIIa) or the corresponding 10-ethoxy methiodide (IIIb), respectively, besides the methiodide (II). Using 70% aqueous methanol as a solvent, the reaction gave 1-methyl-6-decahydroazecinone (IV) accompanied with IIIa and II. The reaction in 70% aqueous tetrahydrofuran or aqueous acetone led to the formation of V besides II. Methiodides, IIIa and IIIb, were respectively converted into IV by heating with hydrobromic acid.

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A new colorimetric method for the determination of 4-hydroxylaminobenzenesulfonamide was examined. It is said that this compound is a hapten inducing drug allergy due to sulfanilamide and is formed in vivo and in vitro.
4-Hydroxylaminobenzenesulfonamide produced a red violet complex having λ max at 515mμ in aqueous solution, when it was reacted with sodium pentacyanoammineferroate. Therefore, the estimation of 4-hydroxylaminobenzenesulfonamide using this reagent was attempted in biological materials.
The effects of variation of times, pH and reagent concentration on the color development have been determined. This method was highly selective for the compound among the large amount of sulfanilamide and its metabolites. All the procedure was carried out in phosphate buffer solution at room temperature. The precision of the method which was obtained by performing 20 analyses on urine, was 50.02±1.76μg (mean±SD).

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N-Salicylidene-4-aminobenzothiazole forms fluorescent complexes with zinc, cadmium and magnesium, which are extractable with isoamylalcohol and the optimum pH for the formation and the extraction of zinc, cadmium and magnesium complexes are 8.9, 10.7, and 8.7, respectively. Especially the fluorescence of the zinc complex is very strong and it is possible to utilize N-salicylidene-4-aminobenzothiazole for the fluorometric determination of zinc in the range of 1.6×10^-6M to 0.5×10^-8M. Interfering ions except cadmium are suppressed by simple addition of masking agents.

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Benzyne reaction of 1-(2-bromo-4, 5-methylenedioxybenzyl)-1, 2, 3, 4-tetrahydro-7-hydroxy-6-methoxy-2-methylisoquinoline (III) with sodium amide in liquid ammonia gave domesticine (II), amurine (X), and cryptowoline (XI) in one-step. The same reaction of the phenolic bromoisoquinoline (VI) gave thaliporphine (XV) O-methylflavinantine (XVI), and cryptaustoline (I).

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Reaction of thiamine analogues (8, 14, and 17) with diethyl benzoylphosphonate (20) was carried out and an interesting difference in reactivity in aprotic solvent according to substituents and nuclei was observed.

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Reaction of thiamine free base (I) with ethyl pyrocarbonate afforded the 1: 1 adduct (VIII) which was hydrolyzed to IX via N-C bond cleavage of pyrimidopyrimidine nucleus of I. The reaction of I with ethyl chloroformate also afforded VIII, together with IX. On the other hand, the reaction of I with benzoyl chloride yielded dibenzoate (IV) as the major product and monobenzoate (V) as the minor product, these compound being analogues of IX. The mechanisms of these reactions are discussed as shown in Chart 2.

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The chemical structure of senegin-II (I), C₇₀H₁₀₄O₃₂·4H₂O, mp 247-248°, [α] _D²⁰-6.2°(MeOH), which was isolated from Senegae Radix (root of Polygala senega LINNE var. latifolia TORRY et GRAY) was established to be presenegenin-(3)-[β-D-glucopyranosyl]-(28)-[β-Dgalactopyranosyl (1_gal→4xyl)-β-D-xylopyranosyl (1_xyl→4_rham)-α-L-rhamnopyranosyl (1_rham→2_fuc)-4-(3', 4'-dimethoxycinnamoyl)-β-D-fucopyranoside], on the basis of physical data of senegin-II, its derivatives and degradation products.

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Quinoline N-oxide (I) reacted with cyanogen bromide in ethanol solution to give ethyl N-(8-quinolyl) carbamate (IIa), ethyl N-(2-quinolyl) carbamate (III), N-(α-quinolyl) carbostyril (IV), carbostyril (V) and quinoline (VI). Similar results were obtained from reactions in methanol and n-propanol (Table II). The presence of alcohols is essential for the smooth proceeding of the reaction, no definite product being isolated unless alcohols are present. The effect of the reaction temperatures (Table I) and that of other additives (Table III) were examined, and the reaction mechanism was discussed.

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Treatment of 10-chloro-2, 3, 5, 6, 7, 11b-hexahydro-7-methyl-11b-phenylbenzo [6, 7]-1, 4-diazepino [5, 4-b] oxazol-6-one (IV) with sodium hydride in dimethyl acetamide gave the two compounds, 6-chloro-3-(2-hydroxyethyl)-1-methyl-4-phenyl-2 (1H)-quinolone (V) and 6-chloro-3-hydroxy-1-methyl-4-pherryl-2 (1H)-quinolone (VI). A mechanistic assumption for the formation of V was discussed.

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The reactions of sodium 2-phenylcarbamoylethylthiosulfate, sodium 2-cyclohexylcarbamoylethylthiosulfate and sodium 2-benzoylethylthiosulfate with aqueous alkylamines were attempted and found to give the corresponding N-β-carbonylethyl-N-alkylamines and sometimes bis (β-carbonylethyl) sulfides, though the same reactions in anhydrous state is known to give the corresponding disulfides as the only product isolated. The reaction between bis (2-phenylcarbamoylethyl) disulfide or bis (2-cyclohexylcarbamoylethyl) disulfide and aqueous cyclohexylamine was also attempted under similar conditions and found to give the corresponding sulfides. The mechanisms of these reactions were also discussed.

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The excretion and tissue distribution of radioactivity were comparatively investigated between D- and L-isomers of 3, 4-dihydroxyphenylalanine (DOPA)-2-¹⁴C after intravenous and oral administration to rats. Both D- and L-DOPA was eliminated mainly through the urinary route and the initial rate after intravenous administration was faster in the D- than the L-isomer. After oral administration (60 mg/kg), most of radioactivity (85%) from L-DOPA was recovered in the urine, while approximately 50 and 23% from D-DOPA in the urine and feces, respectively, indicating a low absorbability of D-DOPA from the gastrointestinal tract in contrast to an almost complete absorption of L-DOPA. After intravenous administration, the tissue uptake of L-DOPA was significantly higher in most of tissues such as the brain, skeletal muscle, liver, intestine and adrenal. In the pancreas, both isomer showed a high accumulation. After oral administration, the tissue uptake of L-DOPA was significantly decreased and higher than the D-isomer only in the intestine, liver and adrenal, while in all of other tissues including the brain, skeletal muscle and pancreas the n-isomer showed a higher accumulation and a longer retention. This was considered to be due to a considerable metabolism of L-DOPA to dopamine at the peripheral sites as the gastric and intestinal mucosa and liver, while to a gradual absorption and accumulation in the tissues of D-DOPA without being metabolized.

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The radioactive metabolites of D-and L-isomers of 3, 4-dihydroxyphenylalanine-(DOPA)-2-¹⁴C in the urine and the main tissues were comparatively investigated after intravenous and oral administration to rats. After administration of L-DOPA, eighteen metabolites were detected in the urine and dopamine conjugate, dopamine, homovanillic acid (HVA), 3, 4- dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenyl ethanol (MHPE) conjugate were found to be the main metabolites, while excretion as DOPA was only less than 1%. After administration of D-DOPA, an appreciable amount (20%) was excreted as unchanged DOPA, but dopamine, mostly in the free form, was found to be the main metabolite. After administration of L-DOPA, dopamine and its metabolites were the main component in the tissues including the brain and skeletal muscle, while after that of D-DOPA, 3-O-methyl-DOPA was the only metabolite, except the kidney where dopamine and its metabolites were found to be formed. It was demonstrated that approximately 67 and 53% of the brain radioactivity was dopamine and its metabolites at 10 and 60 min after intravenous and oral administration of L-DOPA-¹⁴C, respectively. The main metabolite in the pancreas and intestine from L-DOPA was DOPAC and dopamine conjugate, respectively, while unchanged DOPA from D-DOPA. In the liver, where D-DOPA dose not accumulate, dopamine conjugate was the main metabolite from L-DOPA, while no dopamine from D-DOPA. From these results, D-DOPA was considered to be metabolized to dopamine only in the kidney, most of which is excreted directly into the urine.

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A new alkaloid, 1-hydroxymethyl-β-carboline (V) has been isolated from the stems of Picrasma ailanthoides PLANCHON (Simaroubaceae) along with methyl β-carboline-1-carboxylate. The structure of V has been established by physical and chemical means.

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Injection of 3-amino-1, 2, 4-triazole into rats resulted in a rapid fall of liver catalase activity which gradually returned to the normal level, but the amount of catalase protein determined by the immunochemical method remained constant without any decrease in parallel with the enzyme activity. Inactivation occurred more rapidly with soluble catalase (or Catalase-II) than with catalase in peroxisomes (Catalase-III). Rate of recovery in enzyme activity from maximum inactivation was also investigated for Catalase-II and -III, and its results indicated that Catalase-II is synthesized more rapidly than Catalase-III.

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Durch Überführung des Asperulosids (5) in Morronisid (1) wurde die Struktur des letzteren Glucosids bewiesen. Dabei wurde auch die Stereochemie von 1 and seiner Abkömmlinge diskutiert.

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Photolysis of 1, 2, 3, 4-tetrahydro-6, 7, 4', 5'-tetramethoxyisoquinoline-1-spiro-2'-indan-1'-one (II) gave 5, 6-dihydro-2, 3, 10, 11-tetramethoxyberbinium salt (IV) which was further converted into 2, 3, 10, 11-tetramethoxyberbine (VI) by treatment with sodium borohydride. In the same reaction sequence, 1, 2, 3, 4-tetrahydro-6, 7, 5', 6'-tetramethoxyisoquinoline-1-spiro-2'-indan-1'-one (IX) was transformed into xylopinine (VII)

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The ring opening-closing reaction of the thiazolium moiety of thiamine was studied by the pH-stat method at 20° and 30°. The reaction could be represented by the following equations.
thiazolium salt_??_pseudo-base_??_thiol form;
k₁=k₁'(OH^-); k₄ =k₄'(H⁺)
Between pH 7 and pH 11, the rate constant k₂ was nearly equal to k₃ but it was considerably larger than k₁, and k₄ in magnitude. The negative dependency of k₁ and k₄ on the ionic strength was observed. The rate constants, k₁' and k₄', were also obtained in the analogous reactions of 3-benzyl-4-methylthiazolium chloride, 4-methyl-3-phenylethylthiazolium bromide and 3, 4-dimethylthiazolium iodide.
Reference was made to the mechanism of the thiol exchange reactions between thiamine derivatives of disulfide type (IV) and thiols, and it was confirmed that the rapid ring closing reaction to the thiazolium salt hindered the formation of IV from thiol form of thiamine below neutral pH.

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Reaction of phenyltetrafluorophosphorane (III) with 1-pentanol (IV) or 2-pentanol (V) resulted in the formation of olefins and fluoroalkanes considered to have been formed via the olefins. This is in contrast with the fact that the reaction of difluorotriphenylphosphorane (I) and diphenyltrifluorophosphorane (II) with IV and/or V preferentially gives fluoroalkanes thought to have been formed by direct fluorination of the alcohols. The experimental results were investigated by the stereochemistry of phosphorus.

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A stationary disk method for dissolution rate measurement in aqueous solution was improved and simplified. Also its application to solubility determination has been attempted for substances such as salicylic acid and benzoic acid, and satisfactory results were obtained in rather short time. Polyvinylchloride (PVC) powder was used as an inert solid “binder, ” and was mixed with sample powder to form into disks, if a substance cannot be prepared into the compressed disk in pure powder form. No effect of PVC on solubility determination was observed. Also, results obtained by application of the method to sulfathiazole polymorphic forms were discussed, and their solubilities were determined to be 479.2 mg/liter and 819.2 mg/liter for the stable form and the metastable form, respectively.

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A new method to determine the polymorphic transition temperature was developed by measuring the initial dissolution rates of polymorphic substances automatically, and was applied to α- and β-forms of sulfathiazole (ST). The transition temperature and the heat of transition between both forms were found to be 102.7° and 1.60 kcal/mole, respectively. It was also confirmed that the dissolution processes for both forms are diffusion controlled. Further, the metastable solubilities of β-crystals were estimated from those of the stable a-form and ratios of dissolution rates of α- and, β-forms at various temperatures. Since practically “stable” β-crystals could successfully obtain after many trials of crystallization, the solubilities of, β-form were also directly measured by solubility equilibrium method. By comparing the solubility data obtained by dissolution rates and solubility equilibrium method, a good agreement was obtained. In addition, thermal methods such as differential thermal analysis and differencial scanning calorimetry will not give accurate transition temperature, because the transition is always suspended by molecular hysteresis. However, the present method will give more correct value, since it utilizes the phenomenon of the delayed transition of the metastable crystals itself. Thus, it will be adopted generally as an universal and less time-consuming one and be applicable even for the determination of the imaginary transition temperature between monotropic polymorphs of organic substances which can not be determined practically by other methods.

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