YAKUGAKU ZASSHI

Studies on the Analysis of Drugs by Use of Radioactive Isotopes. II

Quantitative Determination of Caffeine

Yûzô Nagase, Shigeo Baba

1961 Volume 81 Issue 5 Pages 619-621
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_619

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Isotopic dilution analysis of caffeine was carried out by the use of caffeine[1 N-methyl-¹⁴C], prepared by methylation of theobromine with methyl[¹⁴C] iodide. Satisfactory results were obtained by determination of 30-80mg. of caffeine, either alone or in the presence of acetylsalicylic acid, theobromine, aminopyrine, or acetophenetidine.

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Studies on Application of Naphthoquinone Derivatives as Organic Reagents. I

Precipitation and Color Reactions of Isonaphthazarin with Metal Ions

Yûzô Nagase, Ushiho Matsumoto

1961 Volume 81 Issue 5 Pages 622-626
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_622

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Examinations were made on the precipitation and color reactions of 2, 3-dihydroxy-1, 4-naphthoquinone (isonaphthazarin) and metal ions, and limit of identification was determined. Of the 26 kinds of common metal ions, isonaphthazarine reacted with Bi^III and Cu^II at pH 3.2, and with Bi^III, Cu^II, Hg^II, Cd^II, Sn^IV, Ni^II, Co^II, Zn^II, Mn^II, Fe^III, Al^III, Mg^II, Ca^II, Sr^II, and Ba^II at pH 6.8, forming a bathochromic violet to blue precipitate or colored solution. The reaction with Cu^II, Bi^III, Mn^II, Co^II, Ni^II, and Zn^II was comparatively sensitive and pH at which these metal ions begin to color or form precipitate with isonaphthazarin and the pH at which these reactions are completed were measured. The pH at which the reaction begins was 0.9-1.9 with Bi^III, 2.7-2.9 with Cu^II, and above 4.2-6.0 with other metals. Consequently, specific or selective detection of Bi^III and Cu^II can be made by adjusting pH of the reaction mixture.

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Studies on Application of Naphthoquinone Derivatives as Organic Reagents. II

Precipitation and Color Reactions of 3-Aminolawsone with Metal Ions

Yuzo Nagase, Ushiho Matsumoto

1961 Volume 81 Issue 5 Pages 627-630
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_627

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Examinations were made on the precipitation and color reactions of 2-hydroxy-3-amino-1, 4-naphthoquinone (3-aminolawsone) and metal ions, and their limit of identification was determined. Of the 26 Kinds of common metal ions, the naphthoquinone reacted with Bi^III and Hg^II at pH 3.2 and with Bi^III, Hg^II, Cu^II, Zn^II, Fe^III, and Al^III at pH 6.8 to produce bathochromic violet to blue precipitate or color. The reaction with Bi^III, Cu^II, and Fe^III in neutral solution was comparatively sensitive. The pH at which these metal ions begin to form precipitate or coloration with the naphthoquinone and pH at which the reaction completes were measured. The pH at which the reaction begins was 0.2 with Bi^III, 2.7-2.9 with Hg^II, 3.2-3.3 with Cu^II, 4.7 with Fe^III, 4.8-4.9 with Al^III, and 6.1-6.2 with Zn^II. These facts reveal that selective detection of Hg^II and Cu^II, or specific detection of Bi^III would be possible by adjustment of pH of the reaction mixture.

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Studies on Application of Naphthoquinone Derivatives as Organic Reagents. III

Precipitation and Color Reactions of Lawsone, Jnglone, and 3-Hydroxy jnglone with Metal Ions

Yûzô Nagase, Ushiho Matsumoto

1961 Volume 81 Issue 5 Pages 631-635
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_631

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Reactivity of 26 kinds of common metal ions in producing coloration and precipitation was examined and their limit of detection was determined. Lawsone shows fairly insensitive coloration with Ni^II, Co^II, Hg^II, and Cu^II at pH 6.8, forms a lake with Bi^III, Al^III, and Fe^III, and a precipitate with Hg^II at pH 3.2, but reaction with other metal ions was insensitive. Juglone undergoes sensitive color action withre Ni^II, Cu^II, and Co^II, and fairly sensitive coloration with Zn^II, Mn^II, and Mg^II both at pH 6.8, and forms a lake with Al^III, Fe^III, Bi^III, and Cu^II, the reaction being generally mores ensitive than with lawsone. 3-Hydroxy juglone undergoes fairly sensitive coloration with Cu^II, Ni^II, Co^II, Mg^II, and Mn^II, at pH 6.8, forms a lake with Al^III, Fe^III, Bi^III, and Cu^II, and precipitate with Hg^II at pH 3.2. Binding ratio of the compound to metal ion was determined by the method of continuous variation for juglone with Ni^II and Cu^II, and for lawsone with Ni^II and Hg^II in neutral solution and all showed the ratio 1:2 for metal to quinone.

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Studies on the Syntheses of Oxytocics. I

Syntheses of 2-(Diethylamino) acetamide Derivatives

Zen-ichi Horii, Toshio Watanabe

1961 Volume 81 Issue 5 Pages 636-639
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_636

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A series of 2-(diethylamino) acetamides were prepared and their oxytocic activity was examined but there were none more active than N-(1, 2, 3, 4-tetrahydro-2-naphthyl)-2-(diethylamino) acetamide (621 I. S.).

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Syntheses of dl-4, 4′-Bis(2-methyl-6, 7-dimethoxy-1, 2, 3, 4-tetrahydro-1-isoquinolylmethyl)-biphenyl and dl-5, 5′-Bis(2-methyl-6, 7-dimethoxy-1, 2, 3, 4-tetrahydro-1-isoquinolylmethyl)-2, 2′-dimethoxybiphenyl

Jinsaku Niimi, Kenji Sempuku, Nobuko Sakurane

1961 Volume 81 Issue 5 Pages 640-647
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_640

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Some model compounds of bis(benzyltetrahydroisoquinoline)-type bases with biphenyl structure in the molecule were synthesized. dl-4, 4′-Bis(2-methyl-6, 7-dimethoxy-1, 2, 3, 4-tetrahydro-1-isoquinolylmethyl)biphenyl (XII) was synthesized by the route shown in Chart 1 from 3, 4-dimethoxyphenethylamine (VI) and 4, 4′-biphenyldiacetyl chloride (VII), through bis-acetamide (VIII) and bis-3, 4-dihydroisoquinoline (IX). Through the second route shown in Chart 2, 2, 2′-dimethoxybiphenyl (XIV) was derived to 2, 2′-dimethoxy-5, 5′-diacetylbiphenyl (XV) and then to 2, 2′-dimethoxybiphenyl-5, 5′-diacetic acid (XVII) by the Willgerodt-Kindler method, and further to bis-acetamide (XIX) and bis-3, 4-dihydroisoquinoline (XX) from (XVII) and 3, 4-dimethoxyphenethylamine (VI). (XX) was finally derived to the objective dl-5, 5′-bis(2-methyl-6, 7-dimethoxy-1, 2, 3, 4-tetrahydrol-isoquinolylmethyl)-2, 2′-dimethoxybiphenyl (XXIII) via amino-1, 2, 3, 4-tetrahydroisoquinoline (XXI) or 3, 4-dihydroisoquinoline dimethiodide (XXII).
The ultraviolet spectra of (XII) and (XXIII) so obtained were examined comparatively with tiliacorine (III) assumed to possess biphenyl structure in its molecule and dauri-cine (XXIV) possessing diphenyl ether structure in its molecule.

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Studies on Riboflavin Derivatives. III

Leucoriboflavin Acyiates

Yasuo Sumi

1961 Volume 81 Issue 5 Pages 647-651
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_647

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Leucoriboflavin, reduced form of riboflavin, is easily oxidized to riboflavin when shaken with air. To retain the leuco state, riboflavin was reduced with sodium dithionite or with zinc in acid solution to the leuco compound and its acylation with acetic anhydride or benzoyl chloride gave leucoriboflavin acylate. These compounds were stable in solid state but were easily decomposed to riboflavin acylate on exposure to sunlight or by heating, regaining the yellow color. Several decomposition products of leucoriboflavin acylate are described.

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Studies on Riboflavin Derivatives. IV

Leucoribofavin 5′-Phosphate Acylates

Yasuo Sumi

1961 Volume 81 Issue 5 Pages 652-655
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_652

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Leucoriboflavin 5′-phosphate derivatives were prepared by reductive acylation of riboflavin 5′-phosphate. These compounds were rather unstable and were easily hydrolyzed to riboflavin 5′-phosphate derivatives, regaining the yellow color. On heating with 17% hydrochloric acid, leucoriboflavin 5′-phosphate tetraacetate and monoethylformate yielded riboflavin 2′, 5′-anhydride, m.p. 300-302°. This substance was sensitive to light and formed lumichrome as the photo-decomposition product on exposure to light.

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Studies on the Paper Chromatography. II

Characteristics of Filter Paper

Hitoshi Hasegawa

1961 Volume 81 Issue 5 Pages 656-658
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_656

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In a previous paper, seven factors were cited as the reasons for variation of Rf values in partition-type paper chromatography and some brief mention was made of the characteristics of filter paper as one of the factors. In the present series of work, the characteristics of filter paper were divided into two, the amount of moisture retained according to relative humidity and the rate of void space. Relationship between atmospheric moisture and water content of the paper was examined by drawing adsorption and desorption isotherms of vapor, using Toyo Roshi No. 51 filter paper. It was thereby revealed that this No. 51 is a filter paper suitable for paper partition chromatography, that the theory of BET and of capillary condensation, applicable to powder, are also applicable to filter papers, and that the weight of filter paper at the time of absolute dryness, G₁ (necessary when using Zaffaronitype impregnated filter paper), can be derived from equation (1) or from the adsorption isotherm (Fig. 1).
It was considered that the formation of a hysteresis loop by the desorption isotherm is an indication of the presence of a bottle-neck type capillary and that the approximate identity of the Kelvin radius calculated from the equilibrium vapor pressure of the starting point of hysteresis with theoretical value shows there was only a small experimental error.

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Studies on Pharmacological Action of 2-Aniirnoacetamide Derivatives

Hajime Fujimura, Katsuya Ohata, Hideaki Hikida, Akira Nomura, Suetaka ...

1961 Volume 81 Issue 5 Pages 659-663
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_659

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Screening tests were carried out, with special emphasis on toxicity and analgesic action, on numerous 2-anilinoacetamide derivatives, prepared for the purpose of decreasing the toxicity and increasing solubility of acetanilide and acetophenetidine with increase or retention of their pharmacological effect. Two compounds were found to satisfy these objectives; GB-105 and GB-302.

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Studies on the Molecular Compound Formation of Xanthine Derivatives. I

Solubilizing Action of Sodium Salts of Substituted Benzoic Acid on Caffeine

Keiji Sekiguchi

1961 Volume 81 Issue 5 Pages 664-669
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_664

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Solubilizing action of the sodium salt of benzoic acid, o-, m-, and p-hydroxy-, methoxy-, amino-, nitro-, and chloro-benzoic acid, and nicotinic acid on caffeine was determined and the effect of the kind and position on the solubilization was examined. The solubilizing action was found to be in the descending order, in molar equivalent of the salt, of salicylate≅m-chloro-, p-chloro-, m-hydroxy-≅p-hydroxy-≅m-methoxy-≅p-methoxy-, m-nitro-, p-nitro-, o-amino-, and p-amino-benzoate, benzoate, m-aminobenzoate, nicotinate, and o-chloro-, o-methoxy-, and o-nitro-benzoate. The solubilizing action of these benzoates is assumed to be not due to formation of a complex of established composition but due to the formation of a hydrogen bond between caffeine and benzoate, with the water molecule of the solvent acting as the hydrogen-bond donor.

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Studies on the Molecular Compound Formation of Xanthine Derivatives. II

Thermal Analysis of Binary System composed of Anhydrous Caffeine and Various Organic Acids

Keiji Sekiguchi

1961 Volume 81 Issue 5 Pages 669-674
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_669

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Thermal analysis was carried out on 26 kinds of binary systems, having caffeine as one component and various carboxylic acids as the other. Molecular compounds were formed by caffeine with o-, m-, and p-hydroxybenzoic acid, gallic acid, m-me-thoxybenzoic acid, m-nitrobenzoic acid, o-, m-, and p-aminobenzoic acid, phenylacetic acid, malonic acid, oxalic acid dihydrate, and maleie acid. Caffeine did not form a molecular compound with benzoic and phthalic acids. Comparison of the result of thermal analysis and the report of Higuchi and others regarding caffeine complex in aqueous solution suggested that there is some difference in the behavior of caffeine between anhydrous state and in aqueous solution.

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Studies on the Molecular Compound Formation of Xanthine Derivatives. III

Thermal Analysis of Binary System composed of Anhydrous Theophylline, Theobromine, and Various Organic Acids

Keiji Sekiguchi

1961 Volume 81 Issue 5 Pages 675-680
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_675

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Thermal analysis was carried out on 39 kinds of binary system, consisting of theophylline, theobromine, or 2, 3-dihydroxypropyltheophylline as one component and benzoic acid, substituted benzoic acids, nicotinic acid, phenylacetic acid, or dicarboxylic acids as the other component. Theophylline formed a molecular compound with benzoic, phthalic, m-chlorobenzoic and p-nitrobenzoic acids, with which caffeine does not combine. Theobromine formed a molecular compound with o-, m-, and p-hydroxybenzoic acid, gallic acid, and malonic acid. Thermal analysis with 2, 3-dihydroxypropyltheophylline as one component failed to give distinct phase diagram but it seemed that the compound formed a molecular compound with m- and p-hydroxybenzoic acid.

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Studies on the Molecular Compound Formation of Xanthine Derivatives. IV

Thermal Analysis of Binary System composed of Anhydrous Methylated Xanthines and Phenols, Aromatic Amines, or Substituted Benzoic Acid Esters

Keiji Sekiguchi

1961 Volume 81 Issue 5 Pages 681-686
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_681

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Thermal analysis was carried out on 32 kinds of binary system consisting of caffeine, theophylline, or theobromine as one component and phenols, aromatic amines, or substituted benzoic acid esters as another. These methylxanthines form molecular compounds with phenols easily but does not with aromatic amines, except only nitroaniline and benzidine form binary compound with caffeine. There seemed to be no affinity with esters and only theophylline formed a molecular compound with ethyl p-aminobenzoate. It was assumed from the present series of results that two carbonyls take part in caffeine while only one takes part in theophylline and theobromine, and that the combination seemed possible with the NH group at 7-position in theophylline.

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Studies on the Molecular Compound Formation of Xanthine Derivatives. V

Thermal Analysis of Binary System composed of Anhydrous Methylated Xanthines and Acid Amides, Imides, or Pharmaceuticals

Keiji Sekiguchi

1961 Volume 81 Issue 5 Pages 687-692
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_687

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Thermal analysis was carried out on 36 kinds of binary system with caffeine, theophylline, or theobromine as one component and acid amides, imides, pyrazolone derivatives, sulfanilamides, or ammonium benzoate as the other. None of the combinations of caffeine examined seemed to form a molecular compound except in the binary system of caffeine and iodoform. Theophylline formed a molecular compounds with benzamide, nicotinamide, phthalimide, and dimethylglyoxime, while theobromine did not show any tendency to form such a binary system.

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Chemicopharmacological Studies on Antispasmodic Action. XIX

Syntheses of the Derivatives of ω-(Diphenylmethoxy) alkylamines and their Antispasmodic Action on Smooth Muscle of Uterus

Kyo Fujie

1961 Volume 81 Issue 5 Pages 693-698
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_693

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Seven derivatives of 2-diphenylmethoxyethylamines and six of 3-(diphenylmethoxy)-propylamines were synthesized and their papaverine-like antispasmodic activity was tested on some smooth muscle preparations such as rat uterus, mouse intestine, and guinea pig tracheal muscle. The index of thermodynamic activity of these compounds was obtained from the potency ratio and solubility of the bases in water. The ω-(diphenylmethoxy) alkylamines would belong to the second group of antispasmodics, which are strong bases, having pKa larger than 8, and act as cation on smooth muscle of ileum. Larger variability of the thermodynamic activity of these compounds might perhaps depend on the facts that they irreversibly inhibit the motility of smooth muscles, that the free bases easily decompose in aqueous solution, and that the preparation of saturated solution of the bases is very difficult.
The smooth muscles of uterus would be similar to small intestines rather than to tracheal muscles from the mode of action of several antispasmodics and the ω-(diphenylmethoxy) alkylamines.

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Chemicopharmacological Studies on Antispasmodic Action. XX

Relationship between Phase-boundary Potential and Acetylcholine-like, Atropine-like and Papaverine-like Activities

Kyo Fujie

1961 Volume 81 Issue 5 Pages 699-703
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_699

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Out of six N, N-dimethyl-2-alkoxyethylamines, only 2-ethoxy derivative exhibits acetylcholine like action and, among methyl, ethyl, and propyl ethers of choline, which have cholinomimetic activity, the ethyl ether has the maximum activity. These facts agree with the five-atom chain rule of Ing on cholinergic action. The higher members of these two series showed atropine-like activity and no partial agonist was found. The phase-boundary potential was estimated for the above alkoxyalkylamines, three N, N-dimethyl-ω-(diphenylmethoxy) alkylamines, five alkyltrimethylammonium salts, isopentyl phenylacetate, and potassium bromide. Definite relationship, as stated by Barnes and Beutner, was not found between the phase-boundary potential and acetylcholine-like activity, but it was found that the potential increases within homologous series of increasing molecular weight. It was concluded that the phase-boundary potential is no more than an expression of physicochemical properties of a molecule.

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Studies on the Alkaloids of Magnoliaceous Plants. XXVI

Alkaloids of Michelia compressa MAXIM. (2). Structure of Michepressine

Kazuo Ito

1961 Volume 81 Issue 5 Pages 703-707
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_703

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Presence of water-soluble quaternary bases was examined in the trunk bark of Mechelia compressa MAXIM. (Magnoliaceae) (Japanese name ‘Ogatamano-ki’) and a new base, named michepressine, was isolated as its iodide. Its chemical structure was established as l-1, 2-methylenedioxy-10-hydroxyaporphine (l-O-demethyllaureline methiodide), formulated as (VI).

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Synthesis of N¹-4-Pyridazinylsulfanilamide and its Derivatives

Mitsuji Yanai, Tsukasa Kuraishi, Toshio Kinoshita

1961 Volume 81 Issue 5 Pages 708-711
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_708

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Starting from 3, 4, 6-trichloropyridazine, 4-pyridazinyl- (V), 3-methoxy-4-pridazinyl- (VIIIa), 3-ethoxy-4-pyridazinyl- (VIIIb), and 3, 6-dimethoxy-4-pyridazinyl-sulfanilamide (XIX) were prepared. (VIIIa) was also obtained from the 4-amino derivative formed by nitration of 3-methoxy- or 3-ethoxypyridazine through their 1-oxide and final reduction.

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Studies on Fluidity of Powders. VI

Effect of Particle Size and Surface Pugosity on Fluidity of Powders

Eiichi Nakajima, Tadashi Morioka, Yoshihiko Ikegami, Ikuo Tanaka

1961 Volume 81 Issue 5 Pages 712-716
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_712

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Fluidity of powdered pharmaceutics was examined from their sliding angle. Sliding angle becomes greater as the diameter of a granule becomes smaller and the degree of this change becomes more drastic. Sliding angle also increases with increasing rugosity. When two kinds of samples with different granular diameter are mixed, sliding angle increases in proportion to the mixing ratio until the ratio of granules with smaller diameter reaches a definite value and the value becomes constant after reaching the same value as the sliding angle of granules with smaller diameter, as indicated by equations (7) and (8). When more than two kinds of powder are mixed, sliding angle becomes greater, the smaller the average diameter of granules in the mixed sample and greater the range of distribution. Empirical formula indicated by equation (13) is established for relationship between these values.

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Studies on Fluidity of Powders. VII

Fluidity of Powders mixed with Glass Beads

Eiichi Nakajima

1961 Volume 81 Issue 5 Pages 717-723
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_717

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Sliding angle and flow rate from an orifice were measured in a mixture of glass beads with lactose, anhydrous dibasic calcium phosphate, talc, titanium oxide, magnesium oxide, starch, calcium p-aminosalicylate (PAS-Ca), and calcium carbonate. In general, mixing of powders resulted in greater sliding angle and smaller flow velocity, and this tendency was especially marked in magnesium oxide, calcium carbonate, and PAS-Ca, and smaller in titanium oxide, talc, and starch. The degree of this change became greater as the diameter of granules decreased. Apparent specific volume of a mixture seemed to suggest that mixing of powders resulted in aggregation of glass beads and formation of some kind of an internal structure in the mixture. A correlation was found to exist between the value obtained from equation (2), which is thought to indicate the degree of aggregation, and the sliding angle and flow velocity. Therefore, changes in fluidity, as indicated by sliding angle and flow rate, by mixing of powders is thought to be due to aggregation caused by binding of glass beads themselves by mixed powders.

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Studies on the Dibenzo-p-dioxin (Diphenylene Dioxide) Derivatives. XXX

Synthesis of 1, 2, 3, 6, 7, 8-Hexamethoxydibenzo-p-dioxin and 1, 2, 3, 6, 7, 8-Hexamethoxy-4, 9-diethyldibenzo-p-dioxin

Masao Tomita, Shin-ichi Ueda

1961 Volume 81 Issue 5 Pages 724-728
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_724

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Tomita had discovered that all substances possessing a dibenzo-p-dioxin skeleton (XVI) gave blue to bluish green coloration with conc. sulfuric acid and potassium nitrate or other oxidation reagents and this is utilized for qualitative reaction of such compounds as the diphenylene dioxide reaction. However, octachlorodibenzo-p-dioxin (XVII) and octabromodibenzo-p-dioxin (XVII) prepared by the present author and others do not undergo this coloration reaction. In order to examine whether this failure is due to the insolubility of (XVII) and (XVIII) in conc. sulfuric acid or because these compounds cannot take the quinoid form required for coloration reaction in general by substitution of all the hydrogens in the benzene ring with halogen atoms, 1, 2, 3, 6, 7, 8-hexamethoxydibenzo-p-dioxin (VIII) and 1, 2, 3, 6, 7, 8-hexamethoxy-4, 9-diethyldibenzo-p-dioxin (XIII) were prepared by the route shown in Chart 1. Of these compounds, (VIII) naturally colored bluish green to this reaction but (XIII) colored violet, contrary to the usual coloration of blue, bluish green, or green in this reaction. Consequently, the reason for failure of the octahalogen derivatives (XVII and XVIII) to show this diphenylene dioxide reaction is due to their complete insolubility in conc. sulfuric acid.

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The Chromatographic Analysis of Opium Alkaloids. IV

Quantitative Separation of Codeine or Hydrocodeine from Ephedrine or Methylephedrine

Sadayuki Kori, Mitihumi Kono

1961 Volume 81 Issue 5 Pages 728-732
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_728

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Narcotic preparations often contain ephedrine or methylephedrine and separatory determination of these and codeine or hydrocodeine is generally difficult. Quantitative separation of two kinds of alkaloids was effected in four combinations of codeine and ephedrine, hydrocodeine and ephedrine, codeine and methylephedrine, and hydrocodeine and methylephedrine by partition column chromatography through Celite, using citrate buffer of pH 5.3 as the stationary phase and chloroform and ammonia-saturated chloroform as the mobile phase.

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Studies on the Alkaloids of Menispermaceous Plants. CLXXXI

Optical Resolution of dl-Magnoflorine by Paper Chromatography

Ikuo Kikkawa

1961 Volume 81 Issue 5 Pages 732-735
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_732

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Tomita and Kikkawa some time ago synthesized d-magnoflorine, a phenolic aporphine-type quaternary base contained in Menispermaceae plants and allied species, and d-laurifoline, a similar base contained in Cocculus laurifolius DC., both as racemic bases, the former as an iodide (I) and the latter as a chloride (II). The racemic bases of (I) and (II) produced two spots with different Rf values on paper chromatogram, one of which was in agreement with the spot of natural dextrorotatroy base. It was assumed from these evidences that optical resolution of the racemic compound had occured during paper chromatography.
In the present series of work, a large quantity of the synthesized racemic compounds of the two bases were submitted to chromatography. The separated two spots were each extracted and the two were isolated and identified as dextro- and levorotatory magnoflorine iodide (Table I) and laurifoline chloride (Table II). This has given experimental evidence that the two racemic compounds underwent optical resolution by paper chromatography.

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Analysis of Opium Alkaloids. X

New Color Reaction of Narcotine and its Application to Colorimetric Determination

Hiroshi Sakurai, Masuo Umeda

1961 Volume 81 Issue 5 Pages 736-740
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_736

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Reaction of narcotine and Chloramine-T, in dil. hydrochloric acidity, and adjustment of the solution to pH 6.8 with sodium sulfite results in red coloration. This coloration does not occur with morphine, codeine, or thebaine, but papaverine colors yellowish brown by the reaction. Limit of detection by the spot test is 0.8γ/0.05cc. and the reaction can be utilized for colorimetric determination of narcotine. The presence of one of morphine, codeine, and thebaine, in an amount below that of narcotine, has no effect but the presence of papaverine interferes in this reaction. The determination, therefore, is carried out after simple procedure for separation of papaverine. The determination is carried out as follows: To 1cc. of the test solution (60-600γ/cc.) placed in a 10-cc. measuring flask, 1cc. of 2.4N HCl is added and the mixture is maintained at 20° for 5 minutes. To this mixture, 1cc. of 1.2% Chloramine-T solution is added, mixed well, and maintained at 20° for 15 minutes. This mixture is again shaken vigorously. To this mixture, 3cc. of 20% Na₂SO₃ is added under vigorous shaking, shaking continues for further 30 sec., then 5% Na₂HPO₄ solution is added to bring the whole volume to 10cc., and optical density of the solution is measured at 515 mμ within 5 minutes. A control test is carried out with the same reagents and in the same manner, using 1cc. of ethanol in place of the test solution.
In the presence of papaverine pretreatment of the sample with alkali and shaking with isoamyl acetate is carried out to separate papaverine, and the aqueous layer is rendered acid with HCl. This acid solution is basified, narcotine is extracted with CHCl₃, and ethanol is added to the residue obtained on evaporation of CHCl₃. This ethanol solution is used as the test solution.

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Chemicopharmacological Studies on Antitussives. I

Pharmacology of d-N, N, 1-Trimethyl-3-(ethylsulfonyl)-3, 3-diphenylpropylamine Hydrochloride as a Long-acting Antitussive

Yoshitoshi Kasé, Tomokazu Yuizono

1961 Volume 81 Issue 5 Pages 740-747
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_740

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The pharmacology of d-N, N, 1-trimethyl-3-(ethylsulfonyl)-3, 3-diphenylpropylamine hydrochloride (A-5) was described in detail. A-5 showed a long-acting antitussive activity, duration of the effect being 18.9 times that of codeine (intravenous) and 13.5 times that of codeine (oral), though 50% antitussive dose is only 1.4 and 1.7 times that of codeine in dogs and cats, respectively. The site of action seemed to be the cough center per se. Toxicity in mice (subcutaneous) is 1.5 times that of codeine and 30% that of Methadone. No tendency to establish tolerance, cumulative action, or addiction liability was found by long-term administration. Analgesic action and other actions were discussed.

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Chemical Method for the Determination of Antibiotics. XII

Colorimetric Determination of Kanamycin

Kiichiro Kakemi, Takaichi Arita, Sada Ohashi

1961 Volume 81 Issue 5 Pages 748-750
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_748

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Potency determination of kanamycin solution was carried out as follows: To 5cc. of kanamycin solution in water, 0.5cc. of 20% sodium carbonate solution is added, followed by 0.5cc. of 1% solution of sodium 1, 2-naphthoquinone-4-sulfonate with cooling in ice water, and the mixture is allowed to stand at 0° to 2° for 20 minutes, protected from light. To this solution, 1.0cc. of acetone and 0.5cc. of 50% acetic acid are added and optical density of this solution, is measured at 420 mμ. As a control, the same procedure is carried out with distilled water in place of the sample solution. The potency of the sample solution is read from the calibration curve prepared with kanamycin of known potency.
The same determination was carried on samples boiled with acid or alkali, and samples left at various temperatures. Comparison of the values so obtained with the values determined by the cup method, stipulated in the antibiotics standard, showed good agreement.

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Studies on the Polarizational Titration by the Alternating Current. IV

Derivative Polarograghic Titration on Redox, Argentometry, and Neutralimetry by the Alternating Current with Platinum Electrodes

Katsuaki Morisaka, Takako Harada

1961 Volume 81 Issue 5 Pages 751-754
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_751

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A. C. constant-current titration was carried out as a modification of A. C. polarization titration using platinum electrodes. Similar to the A. C. constant-voltage method reported in previous papers, it is necessary to make the variation of polarization resistance at the electrode as large as possible in order to increase sensitivity of titration and the titration curve shows a type approximately reverse of that in the constant-voltage method. The solution resistance is neglected in the constant-current method and there is no necessity of considering polarization resistance and solution resistance at the same time, as is made in the constant-voltage method. In this sense, the A. C. constant-current method is easy, both theoretically and experimentally.

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Polymorphism of Long-chain Esters of Chloramphenicol. I

On Transition

Chihiro Tamura, Harumitsu Kuwano

1961 Volume 81 Issue 5 Pages 755-759
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_755

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It was found that chloramphenicol palmitate, myristate, and caprylate come in two kinds of crystalline form and one amorphous form. These compounds were prepared and their transition conditions were examined.
1) When the crystals is dissolved in a solvent and crystallized out, optional form of crystals can be obtained by controlling crystallization rate and this form is not affected by polarity or pH of the solvent. Crystals of α-form is obtained by rapid crystallization while the β-form is obtained by gradual crystallization. When a small amount is fused and cooled rapidly in a refrigerator, a vitrious substance is obtained.
2) Transition between the solids occur only in the direction of amorphous to α-form to β-form, and there is no reverse progress. The transition rate is faster, the nearer the melting point. The mechanism of such a transition is thought to be the transition to a stable form by the heat motion of the molecule itself. The transition rate becomes suddenly rapid after formation of β-form crystal and this is considered to be due to added effect of catalytic transition.

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Polymorphism of Long-chain Esters of Chloramphenicol. II

On Structure

Chihiro Tamura, Harumitsu Kuwano

1961 Volume 81 Issue 5 Pages 759-764
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_759

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From the consideration of X-ray diffraction, infrared absorption spectra, and various transition conditions of long-chain esters of chloramphenicol, and some assumptions were made on their crystal structure.
1) According to X-ray diffraction, all-trans configuration for the long-chain portion of the β-form molecule results in good agreement between the molecular models and the long axis by X-ray measurement. In the case of α-form, the long axis of the crystal cannot be explained unless the molecule is assumed to have some cis linkages or the long chain part is a trans structure but deeply twined with each other.
2) Infrared absorption spectra suggest that the α-form is closely resembled to a solution state and crystals with a cis configuration, having distorted molecule, may be assumed. The β-form is considered to have a higher order molecular arrangement as a crystal and it is convenient to assume an all-trans configuration by X-ray measurement.
3) Stability of the β-form can be assumed form the measurement of melting point and specific gravity. On the other hand, similarity to the α-form and solution state (or amorphous state) as found from transition conditions and these agree well with the above two measurements.

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Polymorphism of Long-chain Esters of Chloramphenicol. III

Determination of Polymorphism by X-Rays

Harumitsu Kuwano, Chihiro Tamura

1961 Volume 81 Issue 5 Pages 764-767
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_764

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Polymorphism of chloramphenicol was examined by the X-ray diffraction method and quantitative relationship between the two crystal forms was examined. In general, proportionation of concentration to diffraction intensity can be quantitated in polymorphs but the method was inconvenient for use with organic compounds due to strict packing conditions. In the binary system (α- and β-forms) of chloramphenicol palmitate, specific intensity and specific concentration of the component were in proportion and quantitative straight line independent of packing codition was obtained. This was found to be effective in the range of over 3% of the β-form and precision is within 1%. As the quantitative linear equation: the following was obtained: x_β/x_α=(0.347±0.005)⋅I_β/I_α, where x is the concentration of the component and I is the intensity of reflection.

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Studies on Syntheses of Coumarin Derivatives. XIII

On the Preparation of 7-Nitro-8-hydroxycoumarin-3-carboxylic Acids. II

Masataka Ichikawa, Yasushi Takaki, Hisashi Ichibagase

1961 Volume 81 Issue 5 Pages 768-771
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_768

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Nitration of ethyl 8-hydroxycoumarin-3-carboxylate (I) in glacial acetic acid solution affords ethyl 5-nitro-8-hydroxycoumari-3-carboxylate (III), m.p. 203.5-204°, and ethyl 7-nitro-8-hydroxycoumarin-3-carboxylate (IV), m.p. 201-202°. Methylation of (III) and (IV) with methyl iodide respectively gives 8-methoxy compounds, (VII) of m.p. 184-186°, and (VIII) of m.p. 152°, respectively. On the other hand, nitration of 3-methoxy-salicylaldehyde acetate (XVI) affords 4-nitro (IX), m.p. 92-93°, 5-nitro (X), m.p. 142°, and 6-nitro (XI), m.p. 104°, compounds. By condensation of (IX) and (XI) with ethyl malonate, in the presence of piperidine, the position of the nitro group in the foregoing (III) and (IV) was determined.
Hydrolysis of (I), (III), and (IV) with hydrochloric acid respectively afforded 8-hydroxycoumarin-3-carboxylic acid, m.p. 292-293° (decomp.), 5-nitro-8-hydroxycoumarin-3-carboxylic acid, m.p. 292-293° (decomp.), 5-nitro-8-hydroxycoumarin-3-carboxylic acid (V), 257-258°, and 7-nitro-8-hydroxycoumarin-3-carboxylic acid (VI), m.p. 246-248°.

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Studies on the Components of Panax Ginseng C. A. MEYER. I

On the Etheral Extract of Ginseng Radix Alha. (1). β-Sitosterol, its Glucoside and Others

Mitsuo Takahashi, Koichiro Isoi, Masahiro Yoshikura, Toshiaki Osugi

1961 Volume 81 Issue 5 Pages 771-773
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_771

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The essential oil of ginseng, the peeled and air-dried radix of Panax Ginseng, was fractionated by distillation and two kinds of oil of b.p₂ 71-74° and b.p₂ 110-120° were obtained. The former was the known panacen, which was found to have >C=CH₂ group. Presence of β-sitosterol glucoside was newly confirmed during separation of these oils and the glucoside was identified with daucosterin obtained from Daucus carota. Phytosterol described in the past literature was found to be β-sitosterol.

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Synthesis of Ferrous [⁵⁹Fe] D-Glucuronate

Minoru Kawada, Shigeru Takanashi, Yasuo Nakajima

1961 Volume 81 Issue 5 Pages 774-776
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_774

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Ferrous [⁵⁹Fe] D-glucuronate was prepared from glucuronic acid and ferrous [⁵⁹Fe] carbonate which was obtained from ⁵⁹FeCl₃. In this reaction almost the whole process was carried out automatically in nitrogen atmosphere. Determination of glucuronic acid in ferrous glucuronate by naphthoresorcinol picrate was not disturbed by the presence of radioactive ferrous ion.

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The Chromatographic Analysis of Opium Alkaloids. V

Quantitative Separation of Codeine and Hydrocodeine from their Mixture

Sadayuki Kori, Mitihumi Kono

1961 Volume 81 Issue 5 Pages 776-778
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_776

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Chromatographic separation of a combination of codeine and hydrocodeine was attempted in continuation of earlier works on codeine and ephedrine, codeine and methylephedrine, hydrocodeine and ephedrine, hydrocodeine and methylephedrine, and ephedrine and methylephedrine. The two bases were found to be separated quantitatively by the partition column chromatography over Celite, using phosphate buffer of pH 6.4 as the stationary phase and benzene-acetone mixture (50:1 by volume) and chloroform as the mobile phase.

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Studies on Carnitine. II

Synthesis of d -and l-Carnitine Hydrochloride

Akira Ayada

1961 Volume 81 Issue 5 Pages 778-783
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_778

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Resolution of dl-(2-hydroxy-3-cyanopropyl) trimethylammonium chloride (III) was carried out with d-tartaric acid or dibenzoyl-d-tartaric acid, and dextro- and levorotatory compounds of (III) were obtained. Hydrolysis of these optically active (III) with conc. hydrochloric acid by heating in a boiling water bath afforded the corresponding d- and l-(2-hydroxy-3-carboxypropyl) trimethylammonium chloride (VII). Of these, the levorotatory (VII) was found to correspond to the hydrochloride of natural carnitine (VIII). Infrared spectra of these compounds are given.

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Studies on the Stability of Drugs. I

Stability of Benzothiadiazines. (1). The Photometric Determination of 4-Amino-6-chloro-m-benzenedisulfonamide

Tsukinaka Yamana, Hiroshi Koike

1961 Volume 81 Issue 5 Pages 783-784
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_783

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Photometric method for the determination of 4-amino-6-chloro-m-benzenedisulfonamide, one of the hydrolysis products of benzothiadiazinines, was developed. The disulfonamide is determined by reaction with 4N hydrochloric acid and nitrous acid at 30°, and coupling of the diazonium compound formed with the Tsudareagent. The resulting red color which is read through a filter (535mμ) is linear in absorbance to the concentration of disulfonamide.

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Simultaneous Microdetermination of Organic Halogen and Sulfur in Gravimetric Method

Kazuo Imaeda, Yahyoe Kinoshita, Rokuro Mizutani

1961 Volume 81 Issue 5 Pages 785
Published: May 25, 1961
Released on J-STAGE: February 19, 2010

DOIhttps://doi.org/10.1248/yakushi1947.81.5_785

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