In order to establish a common methodology for the highly stereoselective and efficient synthesis of macrolide and polyether antibiotics, two macrolide aglycons, 12-membered ring methynolide and 16-membered ring tylonolide, were first synthesized mainly from D-glucose, with the aid of 4-methoxybenzyl (MPM) type protecting groups and construction of three consecutive chiral centers, via the syntheses of respective fragments followed by their coupling (Yamaguchi's esterification) and cyclization (Wittig-Horner reaction). This method was extended to the synthesis of 14-membered ring pikronolide and, together with conformational analysis and control of macrolide rings, some typical 16-membered ring aglycons such as carbonolides, leuconolides, maridonolides, etc. Erythronolide A was also synthesized via an extremely efficient macrolactonization by virtue of conformational control and super activation of a seco-acid. For the synthesis of polyether antibiotics a new synthetic method of substituted tetrahydrofuran and-pyran rings was first established via a cyclization of styryl derivatives by acid catalyzed and/or chelation controlled reactions under kinetic and/or thermodynamic conditions. Highly complex polyether salinomycin was synthesized via coupling of three fragments prepared from D-glucose, D-mannitol, and ethyl L-lactate essentially by the same method developed in the synthesis of macrolides. In this synthesis the MPM type protecting groups acted a crucial role. The synthesis of isolasalocid A was completed via isolasalocid ketone, in which two tetrahydrofuran rings were constructed by the above acid catalyzed and chelation controlled cyclizations. Similarly lasalocid A was synthesized from D-glucose via lasalocid ketone.

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Cetraxate hydrochloride (1) (antiulcer agent) can be produced by the enzymatic debenzylation of cetraxate benzyl ester hydrochloride (2). In order to use the enzymatic method as an industrial procedure, it is essential to obtain the crystal of cetraxate (3, free compound of 1) as an intermediate from the enzymatic reaction solution. Cetraxate (3) was found to have four polymorphic forms, two anhydrides (A, B) and two hydrates (dihydrate I, II). It is very important for the practical procedure that cetraxate (3) crystal forms transform from the light crystal form (dihydrate I) to the heavy one (dihydrate II) in the enzymatic reaction solution. The transformation was strongly prevented by the cetraxate related substance, tranexamic acid-cetraxate hydrochloride condonsate (TS-1). The heavy crystal forms (dihydrate II, anhydride B) are thermodynamically more stable than the light one (dihydrate I). Crystal forms of 3 are stabilized as dihydrate II in water below 29°C and as anhydride B over 29°C.

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(-)-Frontalin was synthesized from D-lactose in two ways.

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A series of 2-substituted-4, 4a, 5, 6-tetrahydrobenzo [h] cinnolin-3 (2H)-ones and related compounds were synthesized and tested for their ability to displace [³H] diazepam from rat brain membranes. Among them, compounds bearing 4-methoxyphenyl, 4-chloro-phenyl, or 4-methylphenyl group at the position-2 were found to have high affinity to the benzodiazepine receptor. 2-(4-Methoxyphenyl)-9-methyl- and 2-(4-methoxyphenyl)-9-methoxy-4, 4a, 5, 6-tetrahydrobenzo [h] cinnolin-3 (2H)-ones (8b-14 and 8b-15, respectively) showed a potent affinity comparable to that of diazepam. These results suggest that a topographical planarity or pseudoplanarity of these molecules is essential for high affinity to the benzodiazepine receptor. The structure-activity relationships are discussed.

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A series of 2-aryl-4, 4a, 5, 6-tetrahydropyridazino [4, 3-c] quinolin-3 (2H)-ones, 2-aryl-4a, 5-dihydro-2H-(1) benzothiopyrano [4, 3-c] pyridazin-3 (4H)-ones, and related compounds were synthesized and tested for their ability to displace [³H] diazepam from rat brain membranes in vitro, and to prevent bicuculline-induced convulsions in mice in vivo. Among them, 2-(4-chlorophenyl)-4a, 5-dihydro-2H-(1) benzothiopyrano [4, 3-c] pyridazin-3 (4H)-one (16b) showed remarkable activities both in vitro (K_i 48 nM) and in vivo (ED₅₀ 12.4 mg/kg, p.o.). The trans sulfoxide (19a) of 16b exhibited anxioselective pharmacological activities. Compound 19a was equipotent with diazepam in the anticonflict assay (Vogel type, rat, MED 10 mg/kg, p. o.) while exhibiting reduced muscle relaxation (rotarod test) and narcotic potentiation. The structure-activity relationships are discussed.

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A new tracer technique, in which a ¹³C-labeled compound as a biological tracer and ¹³C nuclear magnetic resonance (NMR) as an analytical tool are used, is proposed. In order to verify the applicability of the method to clinical chemistry, [1-¹³C] benzoic acid was administered and [1'-¹³C] hippuric acid excreted in the urine was quantitated by NMR, by using [1-¹³C] hippuric acid as an internal standard.

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Effects of the amount of bridging liquid on the growth and compaction processes of wet spherical agglomeration were studied by using glass beads as model powder. Compaction of agglomerate was enhanced by increasing the amount of bridging liquid used, producing the mechanically strong agglomerate with low porosity, i. e. large coordination number. Compaction process of agglomerate was represented by the modified Kawakita's equation. When the degree of saturation of voids in agglomerate with bridging liquid (R_f)<0.6, the growth process of agglomerate was described by use of a non-random coalescence mechanism and a coalescence mechanism at the later stage with R_f≒1.0.

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The effects of bile and meal on the gastrointestinal absorption of 2-[3-(3, 5-di-tert-butyl-4-hydroxyphenyl)-1H-pyrazolo [3, 4-b] pyridin-1-yl] ethyl acetate (1), were investigated in rats and dogs. Compound 1 was lipophilic and soluble in bile, but extremely insoluble in water. The important role of bile in the dissolution step in the absorption process of 1 was confirmed on the in situ absorption study with rats. Oral absorption of 1 was insufficient and showed a marked individual difference in fasting dogs. When the same compound was administered after ingestion of a meal, the absorption increased with decreasing scatter. Three kinds of meals had different potencies to enhance the bioavailability of 1 in the order of lard > mashed potatoes > skimmed milk. The absorption behavior of 1 reflected small intestinal transit time and the stimulated bile output after ingestion of meal.

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The present study was designed to examine the effects of methanolic extract (PE-ME), isoflavonoid fraction (PF-IF), triterpenoid saponin fraction (PF-SP) and N-acyl-N₁-glucosyl-tryptophan (PF-P) isolated from puerariae flos on alcohol-induced unusual metabolism (as for glucose (BG), triglyceride (TG), and urea nitrogen (BUN) level in blood) and experimental liver injury (model : CCl₄-and high fatty food induced) in mice. These alcohol-induced increasing responses were inhibited by the extracted and refined substances from puerariae flos. In short, PF-ME (4500 mg/kg) and PF-P (400 mg/kg) inhibited an increase in BG level induced by alcohol, whereas PF-IF (1000 mg/kg) and PF-SP (1000 mg/kg) did not. Similary, PF-ME and PF-SP inhibited an increase in TG induced by alcohol, whereas PF-IF did not. In addition, PF-IF and PF-SP inhibited increasing BUN level. Still more, PF-IF and PF-SP significantly inhibited an increase in gulutamate oxalacetate transaminase or gulutamate pyruvate transaminase level induced by high-fatty food and CCl₄ in control animals. Especially PF-IF (250 mg/kg) administration showed a remarkable effect (inhibition : 76.3%) in control animals. These results suggested that puerariae flos or its combination drugs may be a useful drug as a traditional medicinal system for counteraction to drinking.

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The changes in lipid peroxides (LP) content and antioxidant enzyme activities were investigated on airway surface during the aggravating process of bronchitis induced by SO₂ exposure in rats. LP content in broncho-alveolar lavage fluid (BALF) has gradually increased from 3 weeks after starting of SO₂ exposure. Whereas, the activities of antioxidant enzymes, superoxide dismutase and glutathione peroxidase, increased at 1 week and then gradually reduced from 3 weeks. The ratio of LP to each antioxidant enzyme activity in BALF of the exposed rats was higher than that of normal rats. Morphological changes of the lung, a decrease of PaO₂ and an increase of PaCO₂ of blood depended on the increase of LP on airway surface. These findings indicate that LP may be involved in the development of bronchitis.

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