The yellow substance found in rat bile after oral administration of 2-amino-3-ethoxycarbonyl-6-benzyl-4, 5, 6, 7-tetrahydrothieno[2, 3-c]pyridine (Y-3642) was confirmed to be identical with one of chemica1 degradation products (Ia) produced from Y-3642 under light-irradiation. Ia was reduced to Y-3642 with sodium borohydride. From the results of nuclear magnetic resonance and infrared absorption spectra, the structure of Ia was established as the carbonic acid salt of dihydropyridinium compound derived by dehydrogenation of Y-3642 at 7-position.

View full abstract

Metal chelate formation of 1-phenazinemethanol (PMO), which has an aliphatic hydroxyl group, with various metal ions was examined. Synthesis of metal chelate compounds of PMO with Cu²⁺, Zn²⁺, and Ni²⁺ was carried out by refluxing in ethanol solution and the complexes were identified by elementary and infrared spectral analyses. The chelate of PMO is considered to be not so stable as that of 1-phenazinol having a phenolic group and the interaction between PMO and metal ions (Co²⁺, Fe²⁺, Mn²⁺) in 99.5% ethanol was investigated by spectrophotometry. Binding ratio of the chelates was found to be 1 : 1 and their structures are discussed.

View full abstract

For the synthesis of streptonigrin skeleton by the Ullmann reaction, 2-chloroquinoline derivative was obtained from p-anisidine as the starting material. p-Anisidine was converted to 6-methoxy-5-nitroquinoline 1-oxide (V) by a three-step procedure. Treatment of V with phosphoryl chloride gave 2-chloroquinoline derivative (VI). Reduction of the nitro group with stannous chloride in ethanol solution saturated with hydrogen chloride gas afforded an amino compound (VIIa), which was submited to the oxidation using Fremy's salt. Further, p-quinolinedione (VIII) was reduced to IXa, which was methylated with diazomethane to afford 2-chloro-5, 6, 8-trimethoxyquinoline (IXc).

View full abstract

Reaction with 1-phthalazinecarboniteile (I) was attempted with active methy1ene compounds and ketones as the compounds forming a carbanion, in benzene, in the presence of sodium amide. Active methylene compounds used were pheny1acetonitri1e (IIa), ethyl cyanoacetate (IIb), ethyl malonate (IIc), and ethyl acetoacetate (IId), and ketones used were diethyl ketone (IIIa), acetophenone (IIIb), and cyclopentanone (IIIc). From the types of reaction products formed, two types of the reaction was assumed ; one (A-type reaction) in which the carbanion attacks the ring-carbon at 1-position in I to form 1-substituted phthalazine and the other (B-type reaction) in which the carbanion attacks the ring-carbon at 4-position to form 3, 4-dihydro-1-phthalazinecarbonitrile derivatives (Chart 1). In addition, products correspondnig to secondary reactions (B₁, B₂, and B₃ types) were obtained indicating that the reaction progressed after attack of the ring-carbon at 4-position. Product from A-type reaction was a-phenyl-1-phthalazineacetonitrile (IV) from IIa and that from B-type reaction was 3, 4-dihydro-4-(1-methyl-2-oxobutyl)-1-1-phthalazinecarbonitrile (V) from IIIa. In the case of B₁-type reaction, ethyl α, 4-dicyano-1-phthalazineacetate (VI) was obtained from IIb and 4-phenacyl-1-phthalazinecarbonitrile (VII) from IIIb (Chart 3). In the case of B₂-type reaction, 4, 4'-methylene-bis-(1-phthalazinecarbonitrile) (VIII) was obtained from both IIc and IId (Chart 4), and as B₃-type reaction product, 2, 3-dihydro-1H-benz[f]indene-4-carbonitrile (IX) was obtained from IIIc (Chart 5).

View full abstract

The essential oil isolated from the bark samples of Magnolia obovata THUNB. (Magnoliaceae) was examined. The oil contained α- and β-pinenes, camphene, limonene, bornyl acetate, caryophyllene, caryophyllene epoxide, α-, β-, and γ-eudesmols, and three unknown sesquiterpene hydrocarbons. Three eudesmols were main components of the oil. Eudesmols content in the oil increased as branches grew older and reached 87% of the oil in the branch 10 -15 years old. Chemo-type differing in the components of the oil was not observed in the samples collected in various districts in Japan. The commercial crude drugs, Wakoboku (bark of M. obovata) and Houpo (bark of M. officinalis or its variety) contained about 0.3% of essential oil and 94-98% of the oil consisted of α-, β- (main), and γ-eudesmols.

View full abstract

From the methanol extract of the bark of Magnolia obovata THUNB. (Magnoliaceae), a new phenolic compound, honokiol (VI), mp 87.5°, was isolated along with cryptomeridiol (XI). VI was a position isomer of magnolol (I) which was isolated previously from the bark of this species. Structure of VI was established as 3, 5'-diallyl-4, 2'-dihydroxy-biphenyl. Phenylpropanoids which possess oxygen at position ortho to the allyl or propenyl side chain, as in VI, are scarcely found in nature. Biogenetically, XI is related closely to eudesmols which are main components of the essential oil of this bark.

View full abstract

Distribution of magnolol (I) and honokiol (II) in plants was examined by thin-layer chromatography and gas-liquid chromatography. 1) I and II were contained in the bark but not in sapwood, heartwood, or leaf of Magnolia obovata. 2) In M. obovata, I and II were already contained in the bark of branches when they first appeared and increased as branches grew older, reached 4.38% of I and 0.92% of II in the dried bark of 20-year-old tree. 3) The bark of small branches of Magnolia spp. (9 sections, 12 species, 4 varieties) and Michelia spp. (2 species, 1 variety) were examined. I and II were found in Magnolia obovata var. yanagidana, M. officinalis, and M. tripetala, besides M. obovata. They belong to Rytidospermum section. The dried bark of M. tripetala contained 4.03% of II. From Magnolia virginiana, which belongs to Magnoliastrum section, a small amount of I was isolated. Other species of Magnolia and Michelia did not contain I or II.

View full abstract

Some experiments were carried out on the effect of various additives powders for the improvement of mixing on some medicinal powders and granular preparations in pharmaceutical dispensing. ^113mIn was adsorbed on some medicinal powders (A) such as lactose (<74 μ), crystalline lactose (74-149 μ), corn starch, and synthetic aluminium silicate. For granular preparations (B), lactose granules with particle size of 420-590 μ and five kinds of general dispensing granules were used. Mixing ratio was 1 : 2 for A to B in principle. Effect of additive powders was determined from the coefficient of variation in radioactivity of A components using fine crystalline cellulose, dry yeast, fine lactose, and corn starch. Experimental results indicated that crystalline lactose showed a good mixing with lactose granules (420-590 μ) and other medicinal granules by the addition of 5% dried corn starch.

View full abstract

Gas chromatographic method has been devised for the determination of oxprenolol, an adrenergic β-receptor blocking agent, in blood after oral administration of an officinal dose. This compound showed a single peak with satisfactory sensitivity, when treated with trifluoroacetic anhydride and then applied to gas chromatograph equipped with a 1.5% OV-1 column and an electron capture detector. The calibration curve for quantitation was constructed with the use of p, p'-DDE(1, 1-dichloro-2, 2-bis(p-chlorophenyl) ethylene) as an internal standard. Separation of the drug from blood was attained by extraction with ether-dichloromethane followed by partition with dilute hydrochloric acid. The derived product from oxprenolol thus separated was identified as the N, O-bis(trifluoroacetate) by means of gas chromatography-mass spectrometry. A known amount of oxprenolol added to blood plasma was recovered at the rate of ca. 96% by this procedure. The amount of the unchanged drug in blood after oral administration to man was determined by the established method.

View full abstract

The flavonoid and xanthone constituents were examined in four kinds of Swertia spp., and the results are shown in Tab1e I. Two of these were new glycosides which were proved to be isovitexin-x" arabinoside (x"=3", 4", or 6") and norswertianin-1-glucoside, respectively.

View full abstract

In the reinvestigation of the constituents of Uncaria rhynchophylla MIQ. (Japanese name "kagikazura"), the presence of two oxindole alkaloids, corynoxeine and isocorynoxeine, was demonstrated, besides the reported rhynchophylline and isorhynchophylline.³⁾ Furthermore, four indole alkaloids were newly isolated ; hirsutine, hirsuteine, dihydrocorynantheine, and corynantheine. A chemical structural evidence of hirsutine was obtained from its epimerization to dihydrocorynantheine with acetic acid catalysis.

View full abstract

Low mass volatile components in the hydrolysate of Wasabia japonica, Brassica juncea, and Cocholearia armoracia were determined by gas chromatography-mass spectrometry. In the hydrolysate of Wasabia japonica, the following 10 volatile components were detected : Methyl, isopropyl, allyl, sec-butyl, 3-butenyl, 4-pentenyl, 5-hexenyl, hexyl, 6-heptenyl, and β-phenylethyl isothiocyanates. Volatile components of Brassica juncea comprised 11 kinds as follows : Methyl, isopropyl, allyl, sec-butyl, butyl, 3-butenyl, 4-pentenyl, phenyl, 3-methylthiopropyl, benzyl, and β-phenylethyl isothiocyanates. Volatile components of Cocholearia armoracia had 8 kinds as follows : Isopropyl, allyl, 3-butenyl, 4-pentenyl, phenyl, 3-methylthiopropyl, benzyl, and β-phenylethyl isothiocyanates. From these results, it was decided that the volatile components of above three materials had different isothiocyanates.

View full abstract

Adsorption of ions and molecules on glass particles were studied in primary and quaternary alkylammonium chloride solutions. It was found by the streaming potential method that the amount of adsorption of primary alkylammonium ion increased with increase of alkyl chain length, but the amount of adsorption of quaternary alkylammonium ion was less than that of primary compounds and showed minimum in tetraethylammonium chloride solution. The difference was explained by static electric and hydrophobic characters of alkylammonium ions. The ammount of adsorption of primary alkylammonium ions plotted against reduced concentration c/c₀ showed a single curve for C₆-C₁₄ alkylammonium chloride. From these treatments, the energy of adsorption at glass-solution interface and that of formation of micelles per methylene group of primary alkylammonium ions were determined. The amounts of adsorption of alkylammonium ions, chloride ions, and hydrated alkylamine at Stern layer and diffuse layer were calculated from the values of Γ_σ, Γ_AA, Γ_Cl, and Γ_pH obtained by the experiments.

View full abstract

An examination was made for individual separation of prostaglandins (PGs) from living tissues or body fluid. Total PGs, extracted by the previously reported procedure¹⁾ were separated into PG E₁, E₂, F_1a, and F_2a by a stepwise development method applied to thin-layer chromatography on 5% (w/v) silver nitrate-sprayed silica gel HR plate after first development for separating to PGs E and PGs F. Rabbit PG E₂ antiserum, which has a high specificity to PG E₂, was also obtained. With the use of this antiserum, radioimmunoassay capable of measuring low levels of PG E₂ was developed. It was concluded from the results of PG levels measured by the individual separation method and the group separation method reported previously that each prostaglandin should be measured by the individual separation method.

View full abstract

Five methods (A to E) were examined for the preparation of 5-aryl- or 5-alkyl-dibenzothiophenium salts and 10-aryl- or 10-alkyl-9, 9-dimethylthioxanthenium salts, and the scope and limitation of these methods were determined. Behavior of dibenzothipohene 5-oxide (I) and of 9, 9-dimethylthioxanthene 10-oxide (XXI) was compared and it was found that I was quantitatively reduced with conc. hydrochloric acid at room temperature to give dibenzothiophene (XIII). Reaction of I and 70% perchloric acid-phosphoryl chloride afforded 5-(2-dibenzothienyl)dibenzothiophenium perchlorate (XXVIII). The mechanism for the formation of XXVIII was found to be the Friedel-Grafts type condensation of I', formed by protonation of I, and XIII formed by the reduction of I.

View full abstract

From the roots of Amsonia elliptica ROEM et SCHULT (Apocynaceae) collected at Saitama and Mie Prefectures, several indole alkaloids were isolated, including tetrahydrosecamine (Ib), pleiocarpamine (III), yohimbine (IV), β-yohimbine (V), and antirhine (VI). From the same plant, new indole alkaloids, antirhine methochloride (VII), 3, 4, 5, 6-tetradehydro-β-yohimbinium chloride (VIII), and 10-hydroxygeissoschizol (IX) were isolated and characterized by chemical means.

View full abstract

An equation was derived from the Donnan theory on the equilibrium state in which two phases of electrolyte solution are in contact through a membrane or a boundary surface, with the presence of a fixed charge in one (M phase) and not in the other (B phase), and this equation was solved for electrolyte solutions under various conditions. Systematic calculations were made on the effect of charge density of the fixed charge in the M phase, and valency of ions in the electrolytes, volume fraction of the M phase, and binding nature of the fixed charge and ions on the distribution of ionic concentration in the M phase and B phase, and on the Donnan potential between the two phases. Examinations were also made on the relationship between the Donnan equilibrium and apparent binding rate of the ions and the fixed charge obtained by the dialysis equilibrium method. Guntelberg's approximation formula, based on Debye-Huckel's theoretical formula, was used for the activity coefficient of the ions and it was concluded that, according to the result of this calculation, the effect of activity coefficient is considerable for bivalent and trivalent ions, and that the effect was greater when the electrolyte concentration is lower, rather than when it was higher.

View full abstract

Irradiation of Escherichia coli transfer RNA (tRNA) with visible light in the presence of oxygen and riboflavin led to the loss of its amino acid-accepting activity. In an attempt to elucidate the basic mechanism involved in the riboflavin-sensitized photoinactivation of tRNA, changes in base compositions of tRNA as a result of photodynamic treatment were examined. The photodynamic inactivation of tRNA was found to be ascribable to the selective destruction of guanine residues in tRNA and to the changes in its tertiary structure, which involved decrease in the degree of base stacking and disruption of base pairs. The modification of 4-thiouracil residues in tRNA may also be involved in the riboflavin-sensitized photoinactivation, since its characteristic absorption maximum near 335 mμ disappeared by the photodynamic treatment. Though guanine and adenine derivatives are susceptible to the riboflavin-sensitized photodegradation, the adenine residues in tRNA were unaffected even when amino acid-accepting activity of tRNA was almost completely lost.

View full abstract

Several kinds of 3-(N, N-disubstituted amino)-1-phenylpropyl phenyl ethers were prepared according to the reaction scheme shown in Chart 1 (Substituted amino groups were dimethylamino, diethylamino, diisopropylamino, piperidino, morpholino, methylpiperidino, etc.). A related compound having a sulfonium group instead of amino group was also synthesized. In the case of 3-(2-methylpiperidino)-1-phenylpropyl phenyl ether and 3-(2-ethylpiperidino)-1-phenylpropyl phenyl ether, two kinds of diastereoisomers were respectively separated. The anticholinergic and mydriatic activities of 28 new compounds were examined. Piperidino, 2-ethylpiperidino, and 2-methylpiperidinopropyl phenyl ether derivatives showed a stronger activity than other compounds.

View full abstract

Alkyl or aryl 1-phenyl-3-piperidinopropyl ethers (2) and alkyl or aryl 3-(2-methylpiperidino)-1-phenylpropyl ethers (3) were systematically synthesized. These newly synthesized 68 compounds were subjected to anticholinergic and mydriatic examination. 2-Chlorophenyl 3-(2-methylpiperidino)-1-phenylpropyl ether methoiodide (64a) and 3-(2-methylpiperidino)-1-phenylpropyl 2-tolyl ether methobromide (61) showed one-half the anticholinergic activity of atropine sulfate and also 30-50 times the antibarium activity of papaverine hydrochloride.

View full abstract

Mannich reaction of 1-(3-hydroxy-4-methoxybenzyl)-6, 7-methylenedioxy-1, 2, 3, 4-tetrahydroisoquinoline (IX) at room temperature at pH 1.2, 6.0, 7.2, and 7.8 was examined and nandinine (II), 11-hydroxy-10-methoxy-2, 3-methylenedioxytetrahydroprotoberberine (X), and 9-hydroxy-12-hydroxymethyl-10-methoxy-2, 3-methy1enedioxytetrahydroprotoberberine (XI) were obtained in every case. Mannich reaction of 1-(3-hydroxy-4-methoxybenzyl)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline (XII) under heating in alkaline media also gave 9-hydroxy-12-hydroxymethyl-2, 3, 10-trimethoxy-7, 8, 13, 13a-tetrahydroprotoberberine (XIII).

View full abstract

The apparatus used for measuring carbon-14 in a biological sample by wet combustion method was improved. In order to treat a few samples at the same time and to expel the evolved ¹⁴CO₂ promptly, the decomposition flask was made as small as possible. A biological material, usually an organ itself or its homogenate equivalent to about 100 mg of wet sample, was placed in the decomposition vessel, and 15 ml of oxidizing agent, prepared from chromic trioxide (25 g), potassium iodate (5 g), phosphoric acid (d 1.7, 167 ml), and 60% fuming sulfuric acid (333 ml), was added by turning the reservoir 180°. The vessel was heated at 180-200° for 1 hr. ¹⁴CO₂ was expelled with nitrogen and bubbled through a scintillator containing ethanolamine. This method was applicable not only to biological materials but also to such an insoluble sample as a resin. Recovery of carbon-14 was 98-100%. Scatter of measured values was examined with the same liver homogenate of a rat administered l-ephedrine[α-¹⁴C] and its standard deviation was 2.1%.

View full abstract

The reaction of typical compounds related to drugs of alkylbenzene having an amino group on side-chain with Marquis reagent was investigated to clarify the mechanism of the coloration. Considering the results obtained by using spectroscopic methods and from elementary analysis, the coloration may be ascribed to the formation of condensation products of the amines with formaldehyde.

View full abstract

Cyclitol in the stems and leaves of Trachelospermum species was investigated. Dambonitol was isolated from all the Trachelospermum species investigated (Table I).

View full abstract

D-Glucose linkage in tracheloside (Ia) was chemically proved to be the 4'-position by converting acetylethyltrachelogenin (II) to ethylarctigenic acid (V) of the established structure. The "methyltrachelogenin" reported by Takano and others was not the titled compound but identical with methylarctigenin (VIII). Therefore, the trachelogenin derivatives reported by Takano and others were re-examined. As a result, the compounds reported by them as "isotrachelogenic acid, " "methyltrachelogenin, " "isomethyltrachelogenic acid, " "methyl methyltrachelogenate diacetate, " and "isomethyltrachelogenin" are assumed to be identical with trachelogenic acid (X), methylarctigenin (IX), methylarctigenic acid (XVI), methyl methyltrachelogenate monoacetate (XIII), and 3-(hydroxymethyl)-6, 7-dimethoxy-4-(3', 4'-dimethoxyphenyl)-2-naphthoic acid lactone (XIX), respectively, judging from the properties. Therefore, the "trachelogenin derivatives" should be correctly revised to the compounds as follows ; trachelogenin (VI), methyltrachelogenin (VII), trachelogenic acid (X), methyltrachelogenic Acid (XI), methyl methyltrachelogenate (XII), methyl methyltrachelogenate monoacetate (XIII), and methyl methyltrachelogenate diacetate (XIV), respectively. Also it is concluded that the isotrachelogenin derivatives do not exist.

View full abstract