The formations of two kinds of red-violet complex were observed in the reaction of cysteamine (2-mercaptoethylamine) with copper. They were considered to be mixed valence complex and that containing molecular oxygen respectively. Their structures and processes of the formations were presumed from the results of pH, potentiometric and photometric titrations, visible and infrared spectra, and the estimation of copper (I) in the complexes. Analogous results were obtained in some of the related compounds of cysteamine.

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Effect of 5-n-butyl-1-cyclohexyl-2, 4, 6-trioxoperhydropyrimidine (BCP), an antiinflammatory agent, on the sulfonamide transfer in the rat has been investigated with special attention to the protein binding. Four sulfonamides used in the experiment were sulfamethoxazole, sulfaphenazole, sulfisoxazole, and sulfamethizole. Protein binding and the extent of displacement of a sulfonamide by BCP were studied both in vivo and in vitro techniques using fresh rat plasma. Effect of BCP on the sulfonamides transfer in the rat was investigated in terms of the change of the apparent biological half-life period by the analyses of urinary excretion rate and blood level data. Apparent biological half-life periods of sulfonamides, displaced by BCP to a lesser extent in the in vitro studies, were hardly changed at all, whereas those of sulfonamides, displaced highly by BCP in the same condition, were significantly decreased except sulfamethizole. For the latter compound, it is conceivable that rapid elimination by itself obscures the effect of displacement by BCP. Direct action of BCP on the active renal tubular transport as well as the acetylation of sulfonamides could be ruled out by the apparent lack of the effect of BCP on the accumulation of sulfonamides to the rat kidney cortical slices and the rate of sulfonamide acetylation by acetone powders of the pigeon liver.

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Permanganate oxidation of O-methyllythranidine gave the evidence for the presence of 2, 2'-disubstituted diphenyl group in the molecule. O, N-Dimethyllythranidine was subjected to repeated Hofmann degradations followed by hydrogenations to give des-N base V, which was oxidized to diketone VI. Subsequently, the presence of a piperidine ring in the alkaloid was proved by a series of reactions. Some reactions and nuclear magnetic resonance spectra investigations of the products led to a conclusion that O-methyllythranidine has structure A.

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2'-O-Triisopropylbenzenesulfonyl-8-bromoadenosine was converted to 8-oxy derivative either by treatment with sodium acetate in acetic acid or by sodium acetate in acetic anhydride-acetic acid mixture. 2'-Triisopropylbenzenesulfonyl-8-oxy-adenosine or its N⁶, 3', 5'-triacetyl derivative was cyclized to 8, 2'-anhydro-8-oxy-9-β-D-arabinofuranosyladenine with sodium acetate in dimethyl formamide (DMF). Cyclization of 2'- and 3'-triisopropylbenzenesulfonyl-8-oxy derivative was kinetically followed and it was found that the former cyclized easier than the latter compound and decomposition of both cyclonucleosides differed greatly in its rate. Using short cyclization time 8, 3'-anhydro-8-oxy-9-β-D-xylofuranosyladenine was first synthesized from 3'-O-triisopropylbenzenesulfonyl-8-oxyadenosine. Optical rotatory dispersion (ORD) and circular dichroism (CD) curves of these cyclonucleosides were described.

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3, 3', 4'-Trihydroxyflavone combines with magnesium ion in N, N-dimethylformamide to form a strongly fluorescent chelate which is useful for the determination of micro amounts of magnesium. A linear relationship between the fluorescence intensity and concentration of magnesium was found in the range from 0 to 5.0 μg of magnesium. The chelate which shows excitation maximum at 450 mμ and a fluorescence maximum at 503 mμ has a metal to ligand ratio of 1 : 1.

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In the previous study of this series, morphine was shown to be metabolized not only to morphine-3-glucuronide, but also to morphine-6-glucuronide in rabbits. The present study have demonstrated that this is common in rabbits, guinea pigs, rats, mice and human. As a minor metabolite of morphine, normorphine was also detected in the urine samples of these species by thin-layer chromatography. However, the excretion of this metabolite into the urine of guinea pigs given morphine was not conclusive, since the similar spot was also observed on the thin-layer chromatogram of the urine extract from untreated animals. Quantitative estimation of major metabolites of morphine in the urine of rabbits and guinea pigs indicated that most of the dose was accounted for as conjugated morphine, but in rats morphine was excreted mostly as free morphine and in lesser amount as the conjugates in 24 hr urine.

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3-Chloro-4-mercapto-5-ethoxypyridazine (1) was heated under reflux in abs. ethanol for three hours to form concurrently four products with novel rings in the dipyridazo-1, 4-dithiin system, 4, 9-diethoxydipyridazo [3, 4-b : 3', 4'-e]-1, 4-dithiin (pale yellow needles, mp 211°, 13% in yield) (Ia), 4, 6-diethoxydipyridazo [3, 4-b : 4', 3'-e]-1, 4-dithiin (colorless needles, mp 260°, 12% in yield) (IIa), dipyridazo [3, 4-b : 3', 4'-e]-1, 4-dithiin-4, 9 (1H, 6H)-dione (colorless solid, mp>300°, 24% in yield) (Ib), and dipyridazo [3, 4-b : 4', 3'-e]-1, 4-dithiin-4, 6 (1H, 9H)-dione (colorless solid, mp>300°, 16% in yield) (IIb). Structural assignment of the compounds, Ia, IIa, Ib and IIb, was confirmed by their physico-chemical constants and chemical experimental evidences. Similar concurrent formations of an isomeric pair of 4, 9-disubstituted dipyridazo-[3, 4-b : 3', 4'-e]-1, 4-dithiins (I series isomers) and 4, 6-disubstituted dipyridazo [3, 4-b : 4', 3'-e]-1, 4-dithiins (II series ones) were also observed in those cases in which heating 3, 5-dichloro-4-mercaptopyridazine (3), 3-chloro-4-mercapto-5-benzylthiopyridazine (4) and 3-chloro-4-mercapto-5-morpholinopyridazine (5) in similar reaction conditions (heating in proper polar solvents for proportionatd periods) formed a pair of the 4, 9-dichloro- (colorless needles, mp 275°, only trace in yield) (Ic) and 4, 6-dichloro derivative (pale yellow needles, mp 307°(decomp.), only trace in yield) (IIc), 4, 9-dibenzylthio- (yellow crystals, mp 230°, 29% in yield) (Id) and 4, 6-dibenzyl derivative (red crystals, mp 252°, 23% in yield) (IId), and 4, 9-dimorpholino- (colorless crystals, mp 268°, 38% in yield) (Ie) and 4, 6-dimorpholino derivative (colorless needles, mp 291°, 25% in yield) (IIe), respectively. A rather complex cyclization furnishing the concurrent formation of two pairs of the dipyridazo-1, 4-dithiin derivatives was found in the reaction of heating 3-chloro-4, 5-dimercaptopyridazine (6) in a similar reaction condition, followed by benzylation, in which a pair of the derivatives with another novel ring, dipyridazo [3, 4-b : 4', 5'-e]-1, 4-dithiin, the 4, 9-dibenzylthio- (colorless plates, mp 168°, 5% in yield) (VI) and 4, 6-di-benzylthio derivative (yellow needles, mp 210°, 11% in yield) (VII) and another pair of derivatives with a known ring, dipyridazo [4, 5-b : 4', 5'-e]-1, 4-dithiin, the 1, 6-dibenzylthio-(yellow needles, mp 178°, 19% in yield) (IV) and the 1, 9-dibenzylthio derivative (colorless needles, mp 170°, 9% in yield) (V) and none of Id and IId or 1, 6-dichlorodipyridazo-[4, 5-b : 4', 5'-e]-1, 4-dithiin (If) and 1, 9-dichloro derivative (IIf) was detected. NMR spectra of some dibenzylthiodipyridazo-1, 4-dithiin derivatives were compared. A discussion of the cyclization mechanism involved in these reactions is also proposed.

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The kinetic investigation about the factors affecting the biliary excretion was tried with azo and indigoid dye in rat. Five azo dyes, i.e., Azorubin S, Amaranth, New Coccine, Ponceau R, Ponceau SX, and Indigo Carmine as indigoid dye were used. (1) All dyes except New Coccine used here began to be excreted within 2-5 min and the peak of the excretion rate appeared between 10 and 20 min after administration. But as for New Coccine which had the very low excretion ratio, the delay of the excretion was observed and the peak of the excretion rate was hardly observed. (2) The dose dependency of biliary excretion which had been found in riboflavin was also found in dyes, and accordingly, the dependency was considered not to be specific to a biological substance such as riboflavin. (3) In the excretion rate constant, all dyes which showed high dose type excretion pattern had two rate constants k₁ and k₂ as shown in riboflavin, and the ratios of them were between 1.4 and 3. (4) It was also found that not only the number of sulfonate groups, but also the position of them had an effect on the biliary excretion ratio. (5) The biliary excretion pattern of Indigo Carmine which is likely to be excreted in urine was not different essentially from those of azo dyes of which the ratio was high.

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Starting from 2'-deoxyadenosine, 5'-O-trityl-3'-O-tosyl-2'-deoxy-8-bromoadenosine (IV) was synthesized. From the compound IV 8, 3'-anhydro 8-oxy-9-(2-deoxy-β-D-threo-pentofuranosyl) adenine (VII) was obtained by treatment with sodium acetate in acetic anhydride and sodium acetate in DMF, followed by the removal of the protecting group. The structure of the compound VII was confirmed by elemental analysis, ultraviolet and infrared spectra, as well as an optical rotatory dispersion measurement. 8, 3'-Anhydro-8-mercapto-9-(2-deoxy-β-D-threo-pentofuranosyl) adenine (X) was obtained by treatment of IV with thiourea. Desulfurization of X with Raney nickel gave 2', 3'-dideoxyadenosine.

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Mechanism of the albumin-induced metachromasy of 2-(4'-hydroxyphenylazo) benzoic acid (HABA) has been investigated with regard to its interactions with monomeric amino acids and some dipeptides, spectral effect of polarity of the dye environment, and azohydrazone tautomerism of HABA. The metachromasy is concerned not with the monomeric amino acids or the primary structure of serum albumin, but with its intramolecular environment of lower polarity corresponding to that of isopropanol. HABA, once bound to serum albumin by electrostatic forces etc., is buried in such an environment of lower polarity in the interior of the protein molecule, and is converted into the hydrazone form which has an absorption maximum at about 480 mμ. Thus, the metachromasy may occur. The azo-hydrazone tautomerism is supported by the infrared spectra, and is compatible with the results of quantum chemical calculations on 4-hydroxyazobenzene.

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Byakangelicol (I) was treated with dimethylamine or piperidine in benzene below 60°(condition A), in methanol near room temperature (condition B), and in benzene in a sealed tube at 125°(condition C). Amine amides (VIII and IX), neutral amides (X and XII), and neutral amides (XI and XIII) were obtained under conditions A, B, and C, respectively. Results of ultraviolet and nuclear magnetic resonance measurements and chemical treatment showed that X-XI and XII-XIII were in geometrical relationship, X and XII being cis isomers and XI and XIII trans isomers. An equilibrium between XII and XIII in a 87 : 13 ratio was established within 25 hr when either XII or XIII in 0.1N NaOH-EtOH was exposed to diffused light.

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Application of N³→N⁹(N⁷) migration reaction of purine derivatives led to a novel synthetic procedure of purine nucleosides and nucleotides. Direct transfer of ribosyl moieties of acylated pyrimidine nucleosides, nucleotides and trimethylsilylated nucleotides to purine bases was successfully carried out in the pressence of catalyst. Adenosine, N⁶, N⁶-dimethyladenosine, inosine, guanosine, 7-D-ribofuranosylguanine, 7-D-ribofuranosyl theophylline, adenosine 5'-phosphate, 7-D-ribofuranosyl theophylline 5'-phosphate and other glycosyl derivatives were obtained by transglycosylation reaction. Preparation of purine nucleosides and nucleotides by this transglycosylation reaction must be a valuable method for utilization of useless pyrimidine nucleotides which are produced during degradation of RNA together with useful purine nucleotides as seasoning.

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Based upon our finding of a novel active site in enamino carbonyl compounds, the details were investigated using some active electrophiles. 1-Phenyl-3-N-pyrrolidinyl-2-buten-1-one (Va) reacted with p-nitrobenzaldehyde in acidic or basic media to afford 1-phenyl-3-N-pyrrolidinyl-5-hydroxy-5-p-nitrophenyl-2-penten-1-one (VI) as the result of IVd-type reaction. The reaction of enamino ketones Va, 4-N-pyrrolidinyl-3-penten-2-one (Vd) and an enamino ester, 1-methoxycarbonyl-2-N-pyrrolidinyl-propene (Vc) with 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (VIII) gave the corresponding enamino azlactone derivatives (IXa, IXb, IXc), respectively. The reaction of Va and Vb with dichloroketene also afforded IV-d type reaction products, 1, 1-dichloro-4-N-pyrrolidinyl-6-phenyl-3-hexene-2, 6-dione (XIIa) and 1, 1-dichloro-4-N-pyrrolidinyl-3-heptene-2, 6-dione (XIIb), respectively. But Vc reacted with dichloroketene to give the ordinary IVb type reaction product. Methanesulfonyl chloride reacted with Vb to yield the cyclic sulfone XIV, which would be produced via sulfonylated intermediate XVII as the result of IVd-type reaction.

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The NOE's of the pyrrolidine ring protons, H_A and H_B, on the phenyl ring protons of the N-substituent, H_D, were determined in 1-(p-methoxyphenyl)-3, 4-epiminopyrrolidine (2), its N-benzyl derivative (1), and its N-acetate (12). Notable differences of NOE's observed in the latter two compounds suggested that the p-methoxyphenyl group is preferentially situated on the same side as the cis-fused aziridine ring in these compounds. Synthesis of some 3, 4-epiminopyrrolidines was also reported in connection with this NOE study.

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The reaction of di-substituted methyl bromides such as dimethyl bromomalonate (IIa), bromomalonamide (IIb), bromocyanoacetamide (IIc), and methyl bromocyanoacetate (IId) with aromatic amines (pyridine, isoquinoline, and 1, 6-naphthyridine) gave stable N-ylides, IVa-IVd, VIa, VIb, and VIIa. From the reaction of bromomalononitrile (IIe) and quinoline or isoquinoline afforded diquinolinium-(VIII) and diisoquinolinium pentacyanopropenide (IX). From the reaction of IId with quinolines in MeOH, azirino [1, 2-a]-cyclopropa [c] quinoline derivatives (Xa and Xc) with new ring system were given. When treated with hydrogen chloride in MeOH, Xa was converted to dimethyl 3-quinolinemalonate (XII). When IVd was treated with sodium methoxide in DMF, methyl α-cyano-[1, (4H), 4'-bipyridine]-△^{α, 4}-acetate (XVI) was produced. VIc, VIb, and VIIb, when treated with sodium methoxide in MeOH, gave fused imidazole derivatives (XVIII, XIX, and XX).

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Catalytic hydrogenation of six kinds of N-methylpyridinium iodides gave pairs of geometrical isomers in a certain ratio for each methiodide. ortho-Dimethyl derivatives afforded almost exclusively cis isomers, meta derivatives gave cis isomers predominantly, and para derivative produced almost same amounts of both isomers. N-Methylpiperidines thus produced were quaternized with methyl iodide to N, N-dimethylpiperidinium iodides. The chemical shifts of equatorial and axial N-methyl protons were compared with each other, from which the substituent effects of α methyl groups was deduced. The results from nuclear magnetic resonance study enabled us completely to analyze the configurations and conformations of the hydrogenation products and their quaternary salts.

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A series of new stable acetylenic sulfonium ylids, dimethylsulfonium 1-benzoyl-3-phenyl-2-propynylide derivatives, were prepared by the reaction of dimethyl 3-phenyl-2-propynylsulfonium bromide derivatives with benzoic anhydride. While, treatment of dimethyl 3-phenyl-2-propynylsulfonium bromide or dimethyl 2-butynylsulfonium bromide with benzoyl chloride gave methyl 3-phenyl-3, 3-dibenzoyl-1-propynyl sulfide and methyl 3, 3-dibenzoyl-1-butynyl sulfide, respectively. Treatment of dimethyl 2-propynylsulfonium bromide, however, afforded two different type compounds, methyl 1, 1-dibenzoyl-2-propynyl sulfide and methyl 1, 1-dibenzoyl-4-phenyl-4-oxo-2-butynyl sulfide.

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Treatment of 2-butynyl phenyl sulfone (V) and five benzaldehyde derivatives with sodium hydride afforded six kinds of products. Two 1 : 2 adducts of V and benzaldehyde derivatives were assigned to cis- and trans-1, 3-dioxin (VI and VII, respectively), and the third group of compounds produced by condensation of VI and/or VII with benzaldehydes and subsequent dehydration were assigned to VIII. The fourth type of products were 1 : 1 addition compounds of V and benzaldehyde derivatives, and ascribed to 3-methyl-4-aryl-1-phenylsulfonyl-3-buten-2-one, IX. The condensation products of IX and the corresponding benzaldehydes were assigned to X. Moreover the direct condensation product of V and m-methoxybenzaldehyde was ascribed to the structure of XI. The plausible mechanisms of the reactions and the physical properties of these products are presented in detail.

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Phenyl 2-propynyl sulfone (IV) and five kinds of benzaldehyde derivatives were treated with sodium hydride to give the corresponding 1 : 1 addition products, respectively. The structures were assigned to 1-phenylsulfonyl-4-substitutedphenyl-trans-3-buten-2-ones (V) based on the spectroscopic data. The confirmation of the elucidated structure was made by an alternative unambiguous synthesis which consisted of treating methyl phenyl sulfone and ethyl cinnamate with sodium hydride, affording V and 1-phenylsulfonyl-4-phenyl-3-penten-2-one (VI). When phenyl 3-phenyl-2-propynyl sulfone (VII) was treated with the five substituted benzaldehydes, were obtained similar products to V, 1 : 1 addition compounds of VII and benzaldehydes. These were assigned to be 1-phenylsulfonyl-3-phenyl-4-substitutedphenyl-3-buten-2-ones (VIII) by the spectroscopic data and the comparison with V. The plausible mechanism of the reaction and the physical properties of these products are presented in some detail.

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A simultaneous determination by gas chromatography of urinary uronic acids and saccharic acids is described. Uronic acids are converted into corresponding stable aldonic acids with sodium borohydride, and contaminative basic, aromatic and neutral substances are removed with columns of Amberlite CG-120, XAD-2 and CG-400. After trimethylsilylation of carboxyl and hydroxyl groups, these acids are separately determined by gas chromatography. By this method, D-glucuronic acid and D-glucaric acid were determined and moreover, free D-gluconic acid and alkali-labile glucuronides were analyzed from normal human urine.

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A novel spectrophotometric method for microdetermination of 2-deoxy-2-sulfamido-hexose and 2-acetamido-2-deoxyhexose residues in heparin is described. Application of MBTH method to heparin and acid hydrolysate of heparin gives sulfamidohexose content and total hexosamine content, respectively. The difference of the two values corresponds to acetamidohexose content of the mucopolysaccharide.

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Nalorphine-3- and -6-glucuronide were synthesized according to the method used in the synthesis of morphine glucuronides. These glucuronides were then utilized as reference standards for identification of the urinary metabolites of nalorphine in rabbits, and nalorphine-3-glucuronide was established as a major metabolite. No other metabolite could be detected in the 24 hr urine samples, except a small amount of unchanged nalorphine was detected. Isolation procedure of the urinary glucuronides adopted in the present and previous studies was confirmed to be very effective especially for the morphine alkaloids.

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The antitumor activity of several constituents of Sophora subprostrata and related compounds were tested against Sarcoma-180 in mice, and also against Ehrlich ascites tumor of mice as well in vivo as in vitro. Matrine, one of its alkaloids demonstrated antitumor activity against Ehrlich ascites tumor of mice, in vitro as well as in vivo. No anti-Ehrlich ascites tumor activity was observed with oxymatrine. Both alkaloids showed remarkable antitumor activity against solid Sarcoma-180 in mice. Anti-Sarcoma-180 activity of one new base was also demonstrated. The chemotherapeutic index of oxymatrine for Sarcoma-180 was about 7.8 times larger than that of Mitomycin C. Pterocarpoids also had definitive antitumor activity. Parent compound, chromanocoumarane, itself showed slight antitumor activity against solid Sarcoma-180 in mice. In general, the glucoside had greater antitumor activity than its aglycone, and the d-isomer showed relative greater antitumor activity than the l-isomer.

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One of the alkaloidal components of Nelumbo nucifera embryo was isolated in crystalline form and identified with 1-(p-hydroxybenzyl)-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline. This is the first tetrahydroisoquinoline alkaloid with a secondary base isolated from Nelumbo nucifera.

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