The preparation and synthetic applications of the heteroaromatic N-imines, ammonium N-imines, sulfilimines, and sulfoximines are summarized.

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The reactivity of D-3-acetoacetyl-4-phenyl-2, 5-oxazolidinedione (III) was investigated. Reaction of D-4-phenyl-2, 5-oxazolidinedione (II) with diketene in the presence of a catalytic amount of hydrogen chloride afforded III, which was converted to D-6-methyl-2, 4-dioxo-α-phenyl-2H-1, 3-oxazine-3 (4H)-acetic acid (VI) with sodium bicarbonate. D (-)-α-Aminobenzylpenicillin was prepared by reacting 6-aminopenicillanic acid with III, followed by removal of the protecting group.

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The synthesis of D (-)-α-aminobenzylpenicillin using β-amino-α, β-unsaturated sulfones (II) as an amino-protecting group is described. Treatment of D (-)-2-phenylglycine (I) with 1-methylsulfonyl-2-propanone or 1-(p-tolylsulfonyl)-2-propanone in methanolic potassium hydroxide or sodium hydroxide gave equilibrium mixtures of cis- and trans- II whose compositions were determined by nuclear magnetic resonance spectroscopy. D (-)-α-Aminobenzylpenicillin was prepared by reacting 6-aminopenicillanic acid with the mixed anhydrides of II, followed by hydrolysis of the protecting group.

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6-[D (-)-α-(Acylamino) phenylacetamido] penicillanic acids (1-34) were prepared by reacting ampicillin with the appropriated acylating derivatives of nitrogen-containing heterocyclic compounds (II). These penicillins were tested for in vitro activity against S. aureus, E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa. The 7-chloro-4-hydroxyquinoline derivative (23) and the 4-hydroxy-1, 5-naphthyridine derivatives (29-31, 33) were found to have potent antibacterial activity against E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa.

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Apalcillin sodium is a novel semisynthetic penicillin derivative that possesses a broad spectrum of in vitro and in vivo antibacterial activities. Apalcillin sodium (I) and its L-isomer were prepared by reacting D (-)-α-aminobenzylpenicillin or its analogs with the appropriate acylating derivatives of 4-hydroxy-1, 5-naphthyridine-3-carboxylic acid (II). Treatment of the crude I with dimethyl sulfoxide gave the highly-purified dimethyl sulfoxide adduct (I·DMSO), which was converted to the highly-purified I. L-Isomer was active against S. aureus, but not against E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa.

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A spin-labeled derivative of testosterone was prepared by coupling testosterone-3-(O-carboxymethyl) oxime with 3-aminomethyl-2, 2, 5, 5-tetramethyl-1-oxylpyrrolidine and used to develop a method for measuring testosterone glucuronide in human male urine. The samples were brought to pH 6.8 and incubated for 24 hr with β-glucuronidase. The released steroid was extracted by hexane-ethyl ether (4 : 1) and measured by spin immunoassay (SIA). With a 1 ml urine sample, the ultimate sensitivity of the assay was 18 ng of testosterone. Testosterone levels were determined in 8 normal male urine samples simultaneously by SIA and radioimmunoassay. The coefficient of correlation was 0.986. The method was found to be speedy and simple, but not sensitive enough to measure testosterone glucuronide in human female urine.

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A survey of the toxigenic fungi contaminating crude drugs was carried out. Among 125 samples (93 kinds) of crude drugs commercially available in the Tokyo area and some prepared in our laboratory, 14 were found not to be contaminated. In 38 samples, 1-10 isolates of fungi were found to be growing, whereas in only 17 samples, over 50 isolates of fungi were found. On the productivity of mycotoxins, aflatoxin B₁ from Aspergillus flavus group (4/15), sterigmatocystin from A. versicolor and Emericella nidulans (4/7) and fumitremorgin from Aspergillus fumigatus (7/8) were detected. An aflatoxin-producing fungus was isolated from the bark of Akamegashiwa (Mallotus japonicus) collected in Gunma prefecture, Kanto area. Sterigmatocystin productivity in Emericella nidulans var. dentata and E. nidulans var. lata was first demonstrated. It was concluded that the crude drugs examined in this experiment were not seriously contaminated with fungus. It was especially interesting that some drugs originated in the Zingiberaceae plants, i.e. Fructus Alpiniae, Amomi, Byakuzuku, Cardamomi or Soka, were found to be only slightly contaminated.

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Two new eremophilenolides, 8β-hydroxyeremophilenolide (I) and 3β-angeloyloxy-8β, 10β-dihydroxyeremophilenolide (II), were isolated and characterized, together with previously known 3β-angeloyloxy-8-epi-eremophilenolide and 3β-angeloyloxy-6β-hydroxy-8-epi-eremophilenolide, from Farfugium japonicum (L.) KITAM. (Ishigakijima Type). Furthermore, (I) was also isolated from a plant of same genus, F. japonicum (L.) KITAM. var. luchuense (MASAM.) KITAM.

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In order to investigate the stability of betamethasone (I) in the pharmaceutical preparation, degradation in acid or alkaline medium, photolysis, and oxidation reaction of I were performed under various conditions. On degradation in acid medium, I gave a mixture of two isomers of 9α-fluoro-11β, 20-dihydroxy-16β-methylpregna-1, 4, 17 (20)-trien-21-al-3-one, (IIa) and (IIb), and 9α-fluoro-11β, 21-dihydroxy-16-methylpregna-1, 4, 16-triene-3, 20-dione (III). On the other hand, in alkaline conditions, I afforded two products, 9α-fluoro-11β, 17α-dihydroxy-16β-methylandrosta-1, 4-dien-3-one-17-carboxylic acid (IV) and 9α-fluoro-11β-hydroxy-16β-methylandrosta-1, 4-diene-3, 17-dione (V). Compound V was also obtained by oxidation with KMnO₄. The photolysis product, 9α-fluoro-11β, 17α, 21-trihydroxy-16β-methyl-1, 5β-cyclopregn-3-ene-2, 20-dione (VI) was obtained by photo rearrangement of the 1, 4-diene-3-keto steroid in considerable yield.

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Sodium bisulfite, which is frequently added as an antioxidant to ascorbic acid injections, was found to react with ascorbic acid and to effect the reduction of the vitamin concentration under anaerobic conditions. The rate of disappearance of ascorbic acid by sodium bisulfite in solution was pseudo first-order. In the pH range of 4 to 8 the dominating degradation process may be a reaction between monohydrogen ascorbate ion and bisulfite ion. The accompanying degradation of sodium bisulfite also followed the pseudo first-order. From the observed reaction rate constants of sodium bisulfite, the following Arrhenius equation was obtained. [numerical formula] k'_obs at 25° was calculated as 2.30×10^-4 hr^-1. Assuming the average ambient temperature to be 25°, sodium bisulfite added to ascorbic acid injection will remain for as long a period as 300 to 400 days during its shelf-life. It was also found that cyanocobalamin was degraded by sodium bisulfite at considerably high velocity ; i.e., the half life of cyanocobalamin in aqueous solution of pH 5.3 at 25° was shortened to 180 and 38 minutes by the addition of 10 and 100 times moles of sodium bisulfite respectively. Therefore, cyanocobalamin injection is incompatible with commercially available ascorbic acid injections which generally contain sodium bisulfite. In conclusion, utilizing such an intra- and inter-formula reactive substance as sodium bisulfite seems not to be reasonable in the formulation of parenteral preparations.

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A new convenient synthesis of 2-substituted quinolizidines was developed. Basecatalyzed cyclization of 4-(2-chloromethylpiperidin-1-yl) butyronitrile (14) afforded 2-cyanoquinolizidines (17a and 17b), which were converted to 2-ethoxycarbonyl- (18a and 18b), 2-benzoyl- (19a and 19b) and 2-thenoylquinolizidines (20a and 20b). Quinolizidine (18a) was transformed via diarylmethanol derivatives (21a and 22a) into 5-alkyl-2-diarylmethylenequinolizidinium bromides (2), which exhibit potent anticholinergic activities. 2-Ethoxycarbonyl- (18a and 18b) and 2-benzoyl-quinolizidines (19a and 19b) were also obtained by cyclization of the chloroester (15) and the chlorobenzoyl derivative (16), respectively. The stereochemistry of all 2-substituted quinolizidines synthesized here was established.

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N-L-Lysyl-D-glucosamine and its derivatives were synthesized as model compounds of N-aminoacylaminosugars which are commonly found in the structure of streptothricin and related antibiotics. L-Lysine was condensed with the amino group of D-glucosamine and the aminoacyl chain was elongated stepwise with the same amino acids.

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1-, 2-, and 3-Diarylhydroxymethylquinolizidine methohalides (4-8) were synthesized by quaternization of the corresponding tertiary amines (9-13) in order to develop new antispasmodics. Complete stereoselectivity was observed in the quaternization of the amines (9-13). The stereochemistry of these methohalides was confirmed by the chemical shift of N⁺-methyl signals in the ¹H- and ¹³C-nuclear magnetic resonance spectra. Some of these methohalides exhibited potent anticholinergic activities. Some structure-activity relationships are also discussed.

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Drug disposition of 4-Ethoxy-2-methyl-5-morpholino-3 (2H)-pyridazinone (M73101) was studied in mice, rats, rabbits, and dogs. Following intravenous administration of 20 mg/kg, the plasma concentration of unchanged M73101 was decreased according to first-order elimination with the rate characteristic for each animal. The biological half-lives were 25.3, 40.7, 55.0, 67.2 and 80.1 min in mice, rabbits, dogs, male and female rats, respectively. The distribution volumes in the animals were approximately 600 ml/kg. On the other hand, after oral administration, the plasma concentration of unchanged M73101 or radioactivity reached a peak at 30 min in mice and dogs, and at 60-120 min in rats and rabbits. The levels of unchanged M73101 within the early period in mice and rats were 43.2, 41.5 and 49.1μg/ml in rats and 96.9, 93.3 and 74.3μg/ml in mice at 5, 15 and 30 min after administration, respectively. These differences were confirmed from the fact that the residual contents in the gastrointestinal tract were 64.1, 59.5 and 52.1% of the dose administered in rats and 40.5, 28.0 and 22.8% in mice at the same period. In case of direct administration into the stomach or intestine, 21.6% of the dose administered was absorbed in rats and 40.6% in mice from stomach within 30 min, and from intestine the drug was absorbed almost completely within 15 min in both species. It was concluded that M73101 administered orally was rapidly absorbed through the gastrointestinal tract and then excreted after the biotransformation, in the metabolic rate characteristic for each species.

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A series of S-alkyl cysteine- (R=Me, Bzl, All) and dipeptide derivatives with the sequences Cys (R)-Ser and Ser-Cys (R), fully or partially protected or free at the terminals, were prepared for use in a study of antioxidative action against the autoxidation of linoleic acid. N-Acyl-S-alkyl cysteins (1-5) and S-alkyl cysteine methyl esters (6-8) were prepared from the corresponding S-alkylcysteine in the usual manner. Further, the former were condensed with serine methyl ester and the latter with N-acyl serine by the mixed anhydride or DCC method to give BOC- or Z-Cys (Bzl)-Ser-OMe (9, 10) and BOC- or Z-Ser-Cys (Bzl)-OR (15, 16), respectively. Saponification and/or acidification of these peptides led to the partially protected peptides (11, 17-19) or free peptides (12, 20). With the same procedure, cysteinylcysteine derivatives (13, 14) were also prepared.

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Constituents of the essential oil from Trapa natans L. var. rubeola MAKINO were described in this paper. The oil was separated into three fractions, i.e. aqueous sodium bicarbonate soluble, aqueous sodium hydroxide soluble and neutral fractions. Neutral fraction was fractionated by column chromatography. Each fraction was separated into its individual components by preparative gas chromatography. The following compounds were identified by IR, NMR, MS spectral and chromatographical data : hexyl acetate, cis-3-hexen-1-ol, benzyl acetate, dodecyl acetate, dodecanol, tetradecyl acetate, eugenol, isoeugenol, C₁₈-C₂₇ alkanes and C₁₀-C₁₈ fatty acids.

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