The oxidation of tetrahydrofuran, tetrahydropyran or n-butyl ether with N, N-dibromobenzenesulfonamide (DBBS) in the presence of water gave γ-butyrolactone, δ-valerolactone or n-butylbutyrate, respectively (Table I). The mechanism of reaction was discussed in connection with the reaction of tetrahydrofuran with DBBS in nonaqueous solvent.

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Treatment of benzo [6, 7]-1, 4-diazepino [5, 4-b] oxazole derivatives (IIIa and IIId) with acetic anhydride and pyridine gave isoindole compounds (IV, V, VI, IX, X and XI) with ring contraction. A plausible mechanism of the reaction and the physical properties of these products are presented.

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Two new alkaloids, corydamine hydrochloride, C₂₀H₁₉O₄N₂Cl, mp235-239° (decomp.) and N-formyl corydamine, C₂₁H₁₈O₄N₂, mp159.5-160.5°, were isolated from Corydalis incisa PERS. (Papaveraceae) and their structures were established to be II and IX, respectively, by spectroscopic analyses and their chemical conversion to coptisine iodide and anhydrodihydroprotopine-B. Corydamine hydrochloride and N-formyl corydamine are noted as the first naturally occurring alkaloids having the 3-phenyl isoquinoline skeleton.

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Active methylene compounds were allowed to react with 9-phenylxanthylium perchlorate (I) and with 9-phenylthioxanthylium perchlorate (II). The products were only those that were formed by the attack of 9-position of I or II by the active methylene compound. When t-BuOK was used as a base, deacetylation occurred in the reaction between I and acetylacetone. When triethylamine was used as a base, expected results were obtained. By the reaction of I or II with KCN, V or VI, in which a cyano group was introduced to 9-position, was obtained with a high yield. The reactivities of I and II in electrophilic and nucleophilic reactions were discussed from the viewpoints of qualitative electronic theory and the theoretically calculated reaction indices. The results indicated that the contribution of the carbonium ion structure is more in I than in II and that I is more reactive than II in the nucleophilic reaction. The contribution of the onium ion structure is more in II than in I. Therefore, II is theoretically reactive than I in the electrophilic reaction. This conclusion well agrees with experimental results.

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The oxidation of cysteine with hydrogen peroxide was performed in a nitrogen atmosphere and in the presence and absence of Cu (II) ion. The reaction was followed spectrophotometrically by measuring the decreases of cysteine and hydrogen peroxide. One molar hydrogen peroxide could oxidize exactly two molar cysteine and this stoichiometric relation was satisfied under any condition examined. As pH was raised, the oxidation was advanced monotonously. Though addition of Cu (II) to oxygen-free cysteine solution containing hydrogen peroxide enhanced the oxidation significantly, cysteine was oxidized at a fairly rapid speed even in the absence of Cu (II) ion. From the observation on the anaerobic oxidation with hydrogen peroxide, as well as on the autoxidation, a probable mechanism for the copper ion-catalyzed autoxidation of cysteine was deduced.

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2-Substituted thiazokines (IIa-d) were prepared from 2-thiothiazokidone. IIa-d were converted to 2-(ethoxycarbonylcyanomethylene) thiazolidine (III) and its N-acetate and N-methyl derivative. Thiolester analogs of III were obtained by the reaction of IIa-d and cyanoacetic acid in acetic anhydride.

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2-Alkylthiothiazokines were reacted with heterocycles such as rhodanines and thiazolidine-2, 4-dione in acetic anhydride to give the condensed products, (Va) and (X). The intermediates, (IIIa), (IVa) and (IX) were also obtained. The structures of these compounds were established by spectral data.

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Two new flavanones, I and VII, and daidzein were isolated from Guang-Dou-Gen (the root of Sophora subprostrata CHUN et T.CHEN). Fom the spectral data and comparison with sophoranochromene and its derivative, the structure of I was established as 2-[{3'-hydroxy-2', 2'-dimethyl-8'-(3-methyl-2-butenyl)} chroman-6'-yl]-7-hydroxy-8-(3-methyl-2-butenyl) chroman-4-one. The structure of VII was formulated from the spectral data and biogenetic speculation as 2-[{2'-(1-hydroxy-1-methylethyl)-7'-(3-methyl-2-butenyl)-2'3'-dihydrobenzofuran}-5'-yl]-7-hydroxy-8-(3-mehtyl-2-butenyl) chroman-4-one.

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Solubility and dissolution rate of four kinds of sulfonamides (sulfanilamide, sulfisoxazole, sulfadiazine, and sulfisomidine) were determined in various pH solutions. The in vivo absorption patterns of four sulfonamides after administration to rabbits as a suppository with or without buffer reagents were compared by estimating the blood concentration of sulfonamide as a function of time. Higher alkalinity of the buffer solution increases the solubility and dissolution rate. The results of blood concentration studies demonstrated that both the rate and extent of absorption of sulfonamides were considerably enhanced by the rectal administration of the buffered suppository. The in vitro dissolution charactristics of the four sulfonamides at 37°±1 correlated well with the in vivo absorption data ; the logarithm of the absorption rate constant is proprotional to the dissolution rate. From the results obtained, it would be expected that a buffered suppository of sparingly soluble sulfonamides was more effective than that of unbuffered suppository with respect to their absorption from the rectum.

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Mechanism of action of cyclocytidine was examined in cultured cells (L5178Y). Cyclocytidine was active against the leukemia in vitro as well as in vivo and its IC₅₀ was 0.041μg/ml, whereas that for aracytidine was 0.023μg/ml. This compound was also inhibited the thymidine incorporation into DNA and its IC₅₀ was 110μg/ml, while that was 1.1μg/ml for aracytidine. Cyclocytidine itself was therefore considered to have no direct inhibitory effect. Since cyclocytidine seems to act in vitro as aracytidine after transformation, the factor influencing the transformation was examined and revealed to be only pH of the aqueous solution. Ratio of the transformantion under physiological conditions (pH7.3, 37°) was about 30 and 70% after 4 and 24 hr incubations, respectively.

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Methylation of 2, 4-dialkoxypyrimidines with methyl iodide gave the reactive 1-methyl-pyrimidinium salts, the intermediates to 1-methyl-4-alkoxy-2-pyrimidinones. The isolation of the 1-methylpyrimidinium salt verifies the postulated mechanism of the Hilbert-Johnson reaction for pyrimidine nucleoside synthesis. The results of the substitution reaction of various 2, 4-disubstituted 1-methylpyrimidinium salts are described and the device of the extension of the Hilbert-Johnson procedure for the general method of the synthesis of 2-substituted pyrimidine nucleosides is discussed.

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Although a two-compartment model represents an adequate model for a reasonably sophisticated description of the time course of many drugs in the body, the still simpler one-compartment model provides certain pharmacokinetic parameters which are useful, particularly in clinical application. A single-compartment approximation may be made under certain conditions by omitting blood level data in the period shortly after rapid intravenous administration. Pharmacokinetic calculations utilizing the parameters from this approximation were compared with those based on the true two-compartment model. Simple equations were developed to test the validity of the single-compartment approximation. Errors in the calculated values based on the single-compartment approximation were expressed in terms of the smaller exponent β and ratios (m=A/B and n-α/β) of the coefficients and the exponents from biexponential fitting to blood level data after rapid intravenous administration. It was shown that the single-compartment approximation may or may not be satisfactorily used for clinical purposes depending upon size of m and n or relative size of m and n. Using the formulas derived in this report and data from intravenous administration on a few patients, it is possible to determine for a particular drug whether the one-compartment model is an adequately approximate model for clinical purposes, or whether the two-compartment model is really necessary.

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The Bene-Jaffe MCNDO method, combined with extensive CI treatment, has been applied to the calculation of the valence-shell-electronic structures of the purine tautomers. Consequently, promising results have been obtained for the electronic transitions as well as the ground-state properties.

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Variable β-SCF-CI calculation on the π-electronic transitions and π-electronic energies were performed over a number of possible tautomers of the purines and pyrimidines substituted with potential amino- or hydroxy-groups. The theoretical results, in particular on the monohydroxy-derivatives, were in good accord with the experimental informations about the preferable tautomers. On the whole, the theoretical data on the electronic transitions were fornd to be rather useful for classification of various tautomers into predominant and rare forms.

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Fischer indolization of ethyl pyruvate 2-methoxyphenylhydrazine (1) and its N-methyl derivative with protic acids give a variety of unpresumable indole products. Main products have been found to be 6-substituted indole derivatives formed by substitution of the methoxy group of the starting phenylhydrazone (1) with nucleophiles in the reaction medium. The tentative mechanism including an important key intermediate cation (15) is presented for the formation of the unexpected indole products.

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Treatment of ethyl pyruvate 2-methoxyphenylhydrazone (1) with Lewis acid gave 5-substituted and/or 5-methoxy-indole products with ethyl 7-methoxyindole-2-carboxylate (2) as a main product. It contrasts strikingly with the results reported in the previous paper¹⁾ on a reaction center of the abnormal Fischer indolization. It was also found that differences of the acid strength of the reagent and of the electron density on a benzene ring due to introduction of some other additional substituents could be the determinant for the direction of the adnormal transformation.

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Aus den Wurzeln von Polygonum cuspidatum SIEB. et ZUCC. (=Reynoutria japonica HOUT.) wurde ein Polysaccharid mit einem Mol-Gewicht von ca.6000 isoliert, uber dessen Struktur diskutiert wurde.

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Several 3- and 4-alkylaminomethylpyridazines were prepared from 3-hydroxypyridazine 1-oxide and 3-hydroxy-6-chloropyridazine 1-oxide, respectively, using the Mannich reaction. 3, 5-Bis (morpholinomethyl) pyridazine was analogously prepared from 3-hydroxy-pyridazine 1-oxide.

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Irradiation of a mixture of pyridazine N-oxide (I) and primary amine dissolved in dichloromethane resulted in the formation of the corresponding N-substituted pyrrole. Thus, from pyridazine 1-oxide (IA), N-substituted pyrroles (VIIAa-d) were obtained. From 6-methylpyridazine 1-oxide (IB), N-substituted 2-methylpyrroles (VIIBa-d) were obtained. From 3-methylpyridazine 1-oxide (IC), 2-methylpyrroles (VIIB) and their isomers, 3-methylpyrroles (VIIIC) were obtained.

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7-Chloro-2-hydrazino-5-phenyl-3H-1, 4-benzodiazepine was synthesized by the reaction of 2-amino-7-chloro-5-phenyl-3H-1, 4-benzodiazepine with hydrazine.³⁾ The compound was, however, obviously different from the one to which the same structure was assigned by Derieg, et al.⁴⁾ In order to distinguish between them, an X-ray analysis was carried out on some crystalline derivatives of these compounds and the structure of Derieg's compound was revised to 2-amino-8-chloro-3, 4-dihydro-6-phenyl-1, 4, 5-benzotriazocine. The conformation of the 1, 4-benzodiazepine clarified in the present analysis resembled to the 1, 4-benzodiazepine derivatives previously reported.^5-7) But the conformations of the 1, 4, 5-benzotriazocines, especially the arrangement of the two aromatic rings and the positioning of electron-donating groups in each molecule, were not identical to those of 1, 4-benzodiazepines. Such conformational difference may account for the differences in pharmacological activities of these compounds.

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Treatment of 4-amino-2-methylthiopyimidine with 2, 3, 5-tri-O-benzoyl-D-ribosyl chloride afforded the ribosylpyrimidinium chloride (VI), which, on treatment with hydrogen sulfide, gave 2', 3', 5'-tri-O-benzoyl-2-thiocytidine (VII) and 2-thiocytidine (VIII) by further de-benzoylation. Methylation of VIII afforded 2-methylthiopyrimidinium derivative (IX). Treatment of IX (or VI) with methanolic ammonia gave 2, 4-diamino-1-(β-D-ribofuranosyl)-pyrimidinium salt. With alkali IX (or VI) gave cytidine. This condensation can be regarded as an extended Hilbert-Johnson procedure for pyrimidine nucleoside synthesis. Relationships between stability of ribosylpyrimidinium salts and structure of their pyrimidines are discussed. The mechanism of the Hilbert-Johnson reaction was established therefrom.

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Deamination of cytidine derivatives especially of cyclocytidine by mouse kidney cytidine deaminase was examined. Cyclocytidine was not deaminated at either pH6.5 or pH7.3 by the enzyme. Furthermore, cyclocytidine did not inhibit the deamination of aracytidine and ([I]/[S])_0.5 value for cyclocytidine was over 100. As a result, cyclocytidine is found to be markedly active compound with resistance against cytidine deaminase.

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Degradation of polyvinylpyrrolidone (PVP) by ball-milling in air in the presence of each of the seven kinds of organic powders and seven kinds of inorganic powders with Mohrse's hardness between 1 and 9 was investigated. The organic powders added to PVP were chloranil and Vitamin K₃ (good electron accepters), phenothiazine (a good electron donor), acridine and methylene blue (good electron accepters and good electron donors at the same time), and p-hydroquinone and barbituric acid (poor electron donors and poor electron accepters as well). The rate of a decrease of molecular weight of PVP by ball-milling was represented by equation (1). [numerical formula] In case of the addition of organic powders, β was larger than 1.0 in the presence of poor electron donors, and approximately equal to 1.0 in the presence of good electron donors. In case of the addition of inorganic powders, β was between 0.4 and 1.9. In the presence of hard powders, t_i was zero and β was large. In the presence of soft powders, β was small and t_i was larger than zero. In case of the addition of p-hydroquinone, barbituric acid or hard inorganic powders other than silica sands and zinc oxide, the peak in the molecular weight distribution curve of PVP shifted from the molecular weight of approximately 10⁶ to lower molecular weight with the lapse of ball-milling time. In case of the addition of the other powders, the original peak decreased and a new peak at molecular weight lower than that of the original peak increased by ball-milling.

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From a crustose lichen belonging to the genus Caloplaca, a new trichloro-depsidone named caloploicin (Ia) has been isolated in addition to a dichloro-depsidone : vicanicin (IIa) and four known anthraquinone derivatives : parietin (III), fallacinol (IV), fallacinal (V), and emodin (VI), and the structures Ia and IIa have been elucidated on the bases of chemical and physicochemical evidences. It has been suggested that caloploicin would be a common constituent of some species of the genus Caloplaca. As for vicanicin, it has been demonstrated that the accumulated evidences are in good accord with the revised structure (IIa) rather than the previously proposed one [E].

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Dependence of biliary excretion behavior of a quaternary ammonium compound on administration route was reported. When valethamate bromide or scopolamine-N-butyl bromide was infused through portal vein at a constant rate, it produced a higher biliary excretion rate and total excreted amount than when they were infused through femoral vein at the same rate. This phenomenon was discussed to estimate the availability of an absorbed drug from a small intestine with biliary excretion data when the excretion data of the intravenously administered drug was taken as the standard which corresponded to the complete absorption. That is, if the dependence is overlooked, the estimated availability from biliary excretion data would be overestimated, because a drug through portal vein was more excretable than that through femoral vein.

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Nine new methanesulfonic acid ester of aminoglycols were prepared. Their anticancer activities were evaluated against Yoshida sarcoma, mouse leukemia L-1210 and rat leukemia DBLA-6. From these compounds 3, 3'-(morpholinopropylimino)di-1-propanol, dimethanesulfonate (ester), dihydrochloride (No.888) and 3, 3'-(dibutylaminopropylimino)di-1-propanol, dimethanesulfonate (ester), dihydrochloride (No, 893) were found to be very active. No. 893 was unique in its effect against rat leukemia DBLA-6 (GV) by the intravenous inoculation system.

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The chemical structures of senegin-III (Ia), C₇₅, H₁₁₃O₃₅, [α]²⁰_D-6.6°(MeOH) and senegin-IV (Ib), C₈₁H₁₂₂O₃₉, [α]²⁰_D-20.2°(MeOH), which were isolated from Senegae Radix (root of Polygata senega LINN var. latifolia TORRY et GRAY), were established to be presenegenin-(3)-[β-D-glucopyranosyl]-(28)-{2-[β-D-galactopyranosyl (1_gal→4_xyl)-β-D-xylopyranosyl (1_xyl→4_rham)α-L-rhamnopyranosyl]-3-(α-L-rhamnopyranosyl)-4-(4'-methoxycinnamoyl)-β-D-fucopyranoside} and presenegenin-(3)-[β-D-glucopyranosy-1]-(28)-{2-[4-[β-D-galactopyranosyl-(1_gal→4_xyl)-β-D-xylopyranosyl]-3-[α-L-rhamnopyranosyl]-α-L-rhamnopyranosyl]-3-(α-L-rhamnopyranosyl)-4-(4'-methoxycinnamoyl)-β-D-fucopyranoside}, on the basis of physical data of both compounds and several of their derivatives and degradation products.

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Conjugated heterocyclic compound of low aromaticity, s-triazines (I) with CF₃ and/or CF₂Cl group, were irradiated and dihydro compounds (II), adducts (III), and substituted compounds (IV) were obtained. Ratio of II, III, and IV depended on the kind of the substituent present and the solvents working as reagent. Mechanism of these reactions was proposed from considering their effects.

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Behavior of the chemical shifts in ¹⁹F-nuclear magnetic resonance spectra of [polyfluoro-(chloro) methyl]-dihydro-s-triazine derivatives in deuterochloroform and in methanol was examined and it was concluded that these compounds exist in the form of 1, 4-dihydro type (A) and 1, 2-dihydro type (B and B') and that they are in equilibrium in methanol solution.

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Es wird die Struktur des Corydamins (1), C₂₀H₁₈O₄N₂, ein neues Alkaloid aus Corydalis incisa, beschrieben. Die Struktur des Corydamins (1) wurde durch die spektroskopischen Daten von 1 selbst sowie seinen Derivten (1)-Acetat (2), Tetrahydrocorydamin (3), Tetrahydrocorydamin-Monoacetat (4) und Tetrahydrocorydamin-Diacetat (5) diskutiert und angegeben. Durch die Uberfuhrung des bekannten dl-Tetrahydrocoptisins (6) in Corydamin (1) ist diese Struktur synthetisch festgestellt.

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The transition temperature and the heat of transition between the hydrate and the anhdrous forms of phenobarbital were determined to be 36.4° and 1.87kcal/mole, respectively by the initial dissolution rate measurements. These values were in good agreement with values obtained by the conventional solubility equilibrium method and by the differential scanning calorimetry (DSC), as well as with transition temperature estimated by the electrical conductivity and vapour pressure measurements. Furthermore, metastable solubility values calculated from experimentally determined stable solubility values and ratios of dissolution rates for both forms agree closely with values obtained by the conventional solubility method. The assumption that the dissolution processes for both forms of phenobarbital are diffusion controlled was further supported in this study by the equality of dissolution activation energy for both forms, as well as by the magnitude of this activation energy, and by the diffusion layer thickness.

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