Variation of repose angle was examined with a mixture of starch and salicylic acid, and it was found that the repose angle came to minimum at the mix ratio of 8 : 2 and to maximum at the ratio of 4 : 6. This trend coincided with the variation of cohesive force in all ratios of mixing. Assuming that the cohesive force between the starch grain and the salicylic acid particle is much larger than those between the same components, it was concluded that the values of repose angle depend on the microscopic structure of agglomerates.
According to theoretical calculations, particles with strong attractions between particles tend to become connected with each other to form a long chain or branched chains in the deposited layer and contact number of most of the particles would be 2. In contrast, particles with weak attraction tend to slip away when coming in contact with each other and their contact number would become more than 2, the particles forming a net work structure. Relationship between the mean contact number <q> and the porosity ε' is expressed by the following equations : <q>=1.61×ε-1.48 (ε⪈0.92) <q>=4.28.10-3×ε-17.8+2.00 (ε>0.82) The fractional rate of area Φ not covered by the particles will be -InΦ=f (3/4)(1-ε)h/γ-Inε where f is the parameter expressing the deviation from the ratio Φπγ2/S to be covered, γ is the radius of the particle, and h is the thickness of the layer. When the interparticle attraction (δ/γ) is zero and adhesive probability (p) is 1, f is 1, but when (δ/γ) is greater than zero, the particles will pile up on one another and the value of f will become smaller than 1. When p is smaller than 1, the particles will fill up the empty spaces and f becomes greater than 1.
Nitration of 2-chloro-and 2-bromo-quinoline 1-oxides with 80% sulfuric acid-potassium nitrate results in formation of 2-chloro-and 2-bromo-4-nitroquinoline 1-oxides (I and II) in a good yield but the use of 95% sulfuric acid was found to drastically reduce the yield. Reaction of I and II with some acylation agents was examined. Reaction of I with phosphorus tribromide and that of II with phosphorus trichloride in the cold respectively afforded II and I. Reaction of I with acetyl chloride and with benzoyl chloride afforded 1-acetoxy-(III) and 1-benzoyloxy-carbostyril (V), while the reaction of I or II with acetic anhydride-potassium acetate gave 4-nitrocarbostyril 1-oxide (VII). Since the reaction of 2, 4-dichloroquinoline 1-oxide (VI) and benzyl chloride-silver nitrite resulted in the formation of V, formation of III and V passed through the formation of VI from I, and the acyl nitrite formed as a by-product of VI reacts further to produce III and V.
Rearrangement reaction of 2-methoxy-, 2-ethoxy-, 2-allyloxy-, and 2-benzyloxy-quinoline 1-oxides was examined and the corresponding 1-alkoxy-2 (1H) quinolones were obtained by heating. Reaction of 2-chloroquinoline 1-oxide and sodium cinnamylalkoxide failed to produce the anticipated 2-cinnamyloxyquinoline 1-oxide and its rearranged product, 1-cinnamyloxy-2 (1H) quinolone was obtained.
S-(1-Oxido-4-quinolyl) cysteine (I) was prepared by the reaction of 4-nitroquinoline 1-oxide with cysteine, while 4-(2-aminoethylthio) quinoline 1-oxide hydrochloride (III) was also obtained as I with cysteamine. The rearrangement of I to N, N'-bis (1-oxido-4-quinolyl) cystine (II) and that of III to N, N'-bis (1-oxido-4-quinolyl) cystine (V) occured by the treatment with alkali. However, 4-(β-acetamidoethylthio) quinoline 1-oxide (VII) did not undergor earrangement under the same condition as for I.
4-(2-Aminoethylthio) quinoline dihydrochloride (I) was perpared by the reaction of 4-chloroquinoline with cysteamine. When I was treated with alkali, it underwent rearrangement to N, N'-bis (4-quinolyl) cystamine, which was much slower than that in the case of the corresponding N-oxide. However, 4-(o-aminophenylthio) quinoline 1-oxide (X), which is one of the typical aromatic aminothiol derivatives, unexpectedly did not undergo rearrangement under the same condition as for the former.
Mechanism of antioxidation of tocopheronolactone, isolated as the quinonoid metabolic product of α-tocopherol, was examined. Tocopheronolactone was as effective as α-tocopherol in inhibiting the increase of TBA value during the in vitro incubation of α-tocopherol-deficient mouse liver homogenate, but the production of peroxide from unsaturated fatty acids irradiated with ultraviolet ray was not depressed by the sole addition of tocopheronolactone. Reduced tocopheronolactone depressed TBA value during the irradiation of unsaturated fatty acid with ultraviolet ray and reacted with the stable free radical α, α-diphenyl-β-picrylhydrazyl, but tocopheronolactone was not active. Reduced tocopheronolactone was oxidized to tocopheronolactone by free radical products of heme-catalyzed decomposition of cumene hydroperoxide. Tocopheronloactone in cytoplasm was reduced in 9000×g supernatant fraction but not in mitochondria, so that mitochondrial peroxidation was not inhibited by tocopheronolactone itself. Antioxidativeeffect of tocopheronolactone seems to appear after the biochemical reduction of the tocopheronolactone in vivo, followed by the reaction with free radicals and peroxides.
In order to study the antiviral activity of benzimidazole derivatives, 2-(hydroxymethyl)-, 2-(α-hydroxyethyl)-, 2-(α-hydroxypropyl)-, 2-(α-hydroxybenzyl)-, 2-(β-hydroxyethyl)-, and 2-(β-hydroxypropyl)-benzimidazole and their 5 (or 6)-methyl, -chloro, -nitro, and -methoxy derivatives were sythesised by refluxing o-phenylenediamine, or either one of its 4-methyl, 4-chloro, 4-nitro, and 4-methoxy analogs with glycolic, lactic, α-hydroxybutylic, β-hydroxybutylic, mandelic acid, or cyanoethanol in 4N hydrochloric acid. The antiviral activity of these compounds on polio virus and adenovirus replication was examined by tissue culture method. The cytophathic effect and multiplication of polio virus was inhibited by 2-(α-hydroxybenzyl) benzimidazole derivatives, 2-(α-hydroxyethyl)-5 (or 6)-methoxy-, 2-(α-hydroxypropyl)-5 (or 6)-methoxy-, 2-(β-hydroxyethyl)-5 (or 6)-methyl-, and 2-(β-hydroxypropyl)-5 (or 6)-chlorobenzimidazole. Cytophathic effect of adenovirus was clearly inhibited by 2-(α-hydroxypropyl)-5 (or 6)-methyl-, 2-(α-hydroxypropyl)-5 (or 6)-nitro-, and 2-(α-hydroxybenzyl)-5 (or 6)-methylbenzimidazole.
Effect of complex formation on the absorption of drugs was investigated after oral administration to rabbits and the results were compared with those in the previous report using perfusion method by rat small intestine. Blood concentrations of antipyrine (salicylic acid), salicylamide (nicotinamide), aminopyrine (salicylic acid), salicylic acid (antipyrine), and salicylic acid (aminopyrine) were compared with or without drugs in parentheses after oral administration in solution or suspension. It was found that (a) the results after oral administration coincided well with those using the perfusion method, (b) salicylic acid reduced the blood concentration of antipyrine during the first one hour, (c) as the blood concentrations of salicylamide with nicotinamide, aminopyrine with salicylic acid, and salicylic acid with aminopyrine were higher than those of control after oral administration in suspension, it may be a good method for increasing the initial blood concentration of very slightly soluble drugs after oral administration in solid with the solubilizing compounds, and (d) aminopyrine gave constant blood concentration of salicylates for 6 hours and this was explained by the correlation with the fraction eliminated as free salicylic acid in urine.
The infrared spectra of 18 different kinds of benzenesulfonamide derivatives were obtained in the region of 4000-650cm-1, and substituent effects on the characteristic infrared absorption bands were examined, comparing the compounds substituted in ortho, meta, and para positions. The SO2 frequency shifts had approximate linear correlation with Hammett's σ value for the chemical shifts of benzene derivatives.
In order to find effective treatment method for eliminating radioactive iodine, various thyroid inhibitors were examined. Male rats of Donryu strain were injected with 10-20 μCi of Na 131I intraperitoneally. Thyroidal uptake of 131I was significantly decreased by single intraperitoneal injection of 3mg of 2-thiouracil, which was given 4 hours after 131I. This effect, however, was transient and several hours later the 131I uptake reached a higher level than that of the control group. Single intraperitoneal injection of a thyroid inhibitor, 3mg of 1-methyl-2-mercaptoimidazole, which was given 24 hours after the injection of 131I was ineffective for eliminating radioactive iodine from the thyroid gland. On the other hand, multiple injections of thyroid inhibitors, 2-thiouracil, 6-propyl-2-thiouracil, 1-methyl-2-mercaptoimidazole, or potassium perchlorate, 5 times at intervals of 6 hours resulted in significant decrease of thyroidal deposition of radioiodine, even if the first injection was given 24 hours after 131I. Moreover, no elevation in 131I uptake after the treatment took place. These results suggest that the decrease in the thyroidal deposition of radioiodine by multiple injections of thyroid inhibitors resulted from the blocking of reutilization of free iodine liberated from the thyroid into the blood. In parallel with the decrease in thyroidal deposition of 131I, significant increase of 131I level in blood was found. Possibility of the stimulation on liberation of radioiodine from the thyroid has been discussed. There was no synergistic effect of KClO4 promoting radioactive iodine removal from the thyroid by 1-methyl-2-mercaptoimidazole. Multiple administration of KSCN, T3, CoCl2, and NaI was ineffective for the elimination of radioiodine from the thyroid.
Measurement of sedimentation volume is often utilized for the study on the suspending state of particles. Attempts were made to calculate the sedimentation volume theoretically by assuming various degrees of attraction between the particles, in continuation of the theoretical calculation of the sedimentation volume of spherical particles of equal size reported in the preceding paper. In the present series of work, theoretical examinations were made on the sedimentation volume of a mixed system of spherical particles cohesive on contact of different sizes. It was thereby found that, in a mixed system of two kinds of particles whose sizes do not differ greatly, the number of contact of large and small particles is close to 2, these particles are lined like a chain, as in the case of particles of the same size, the small particles push in between large particles to extend the spaces, and the volume fraction, VF, probably becomes somewhat smaller than that in the case of particles of the same size. On the other hand, when the size of the smaller particles are far smaller than that of large particles, the number of contact of smaller particles becomes close to 1 and that of large particles becomes larger than 2, so that the small particles surround the large particle to fill up the spaces, and the volume fraction, VF, becomes larger.
Examinations were made on the chemical components of the rhizome of Ophiopogon japonicus KER-GAWLBR var. genuinus MAXIM. (Liliaceae). Four kinds of glycoside were isolated in crystaline form and were named ophiopogonin-A, -B, -C, and -D. Ophiopogonin-A formed colorless needles (from hydrated ethanol), mp 183°, [α]29.0D-98.8°(pyridine) ; ophiopogonin-B, colorless needles (from ethanol), mp 269-271°, [α]15.0D-105.5°(pyridine) ; ophiopogonin-D, colorless needles (from hydrated ethanol), mp 263-265°, [α]14.0D-107.9°(pyridine). Ophiopogonin-C formed colorless needles (from water-saturated ethyl acetate), mp 187° The genin portion of ophiopogonin-A, -B, and-D is ruscogenin in all. The sugar portion of ophiopogonin-B consists of fucose and rhamnose, and that of ophiopogonin-D, fucose, rhamnose, and xylose. Ophiopogonin-A was found to be the partially acetylated compound of ophiopogonin-B. In addition to these substances, the presence of β-sitosterol, stigmasterol, and β-sitosterol-β-D-glucoside in the ether-soluble portion was clarified.
trans-Ylidation was carried out between resonance-stabilized ethoxycarbonylmethylene-, cyanomethylene-, benzoylmethylene-, furoylmethylene-, and p-nitrobenzylidene-triphenylphosphorane and benzene-, p-toluene-, p-chlorobenzene-, p-bromobenzene-, o-nitrobenzene-, and p-nitrobenzenesulfenyl cholride These reactions were effected almost quantitatively and 21 kinds of novel phosphoranes were obtained in which o-or p-substituted phenylthio group was introduced into the carbon atom in α-position of the phosphorus atom in the starting phosphoranes.
Differential thermal analysis was carried out on synthesized zeolite to examine the relationship between the thermal properties and differential thermal curves of the crystal and the degree of crystallization. X-and P-type zeolites became amorphous first and then changed into nepherine at above 1000°. With the exception of P-type zeolite, crystal structure of all A-type, X-type, and analcite was not destroyed up to 800°. A correlation was found between the transition peak area and degree of crystallization. There is a proportionality between the dehydration peak area and water content. Some of the X-type zeolite showed two peaks in the dehydration differential thermal curve. These two peaks were considered to be due to the liberation of water from the water of crystallization and water adsorbed on the gel, and it was found possible to calculate the degree of crystallization from the ratio of the height of two peaks.
Examination was made on the extraction of caffeine from Japanese tea-leaves in water, assuming three mechanisms of extraction from plants ; washing extraction, diffusional extraction, and capillary extraction. It was concluded from the experimental results that these three mechanisms should exist together in the case of tea-leaves. Mass transfer coefficients for each case were determined at 37° under various agitation conditions and the values were : kw=2.07-6.57×10-7cm/sec for washing, KL=2.12×10-7cm/sec for diffusion, Kh=0.01-3.58×10-7cm/sec for capillary extraction.
Dried leaves of Acanthopanax sciadophylloides FRANCH. et SAV. were extracted with methanol and the water-soluble part of the extract was treated successively with solutions of lead acetate, basic lead acetate, and ammoniacal alkaline lead salt, as shown in Chart 1. myo-inositol, scyllitol, kaempferitrin, and antoside were isolated and identified. The constituents of these leaves were somewhat different according to the district where the materials came from. Utkin had suggested the structure of antoside as quercetin 3 (7)-glucosido-7 (3)-rhamnoside. Relative positions of glucose and rhamnose in the antoside molecule were now determined by enzymatic cleavage of rhamnose to give quercetin 3-glucoside (isoquercitrin) (Chart 2).
Reaction of 4-(methylsulfonyl) cinnoline (I) with various ketones (IIa to IIm) (Chart 1) in the presence of sodium hydroxide solution was carried out. Reaction of I with IIa and IIf gave IIIa and IIIf, respectively Reaction of I with IIb gave IVb, instead of IIIb The route of this reaction was assumed as shown in Chart 3. IVb is also obtained from the reaction of I with IIg or IIh. I and IIc afforded IVc by a similar route as above (Chart 4) and IVc is also obtained from the reaction of I with IIi. Ketones with branched alkyl chain, IId and IIe, did not react with I, while the methyl group in IIj and IIk reacted with I to form IIIj' and IIIk', whose hydrolysis afforded the same IVj (Chart 4). The same reaction had previously been carried out in the presence of sodium amide in benzene, and the same products obtained as in the present reaction were IIIa, IIIf, IV1, and IVm, and a difference in the reaction was observed in the case of other ketones when using sodium hydroxide solution.
Pharmacological properties of 2-(aminoethyl) isothiuronium (AET) derivatives were examined with 2-(aminoethyl) isothiuronium sulfate (I), 2-(dimethylaminoethyl)-N'-phenylisothiuronium bromide hydrobromide (II), 2-(2'-dimethylaminoethylthio) imidazoline bromide hydrobromide (III), 2-dimethylaminoethyl-N', N''-dimethylisothiuronium bromide hydrobromide (IV), 2-dimethylaminoethyl-N', N''-diethylisothiuronium bromide hydrobromide (V), 2-(2'dimethylaminoethylthio) benzimidazoline bromide hydrobromide (VI), 2-diethylaminoethyl-N', N''-dimethylisothiuronium bromide hydrobromide (VII), 2-diethylaminoethyl-N', N"-diethylisothiuronium bromide hydrobromide (VIII), 2-(2'-diethylaminoethylthio) benzimidazoline bromide hydrobromide (IX), 2-trimethylaminoethylisothiuronium bromide hydrobromide (X), 2-(2'-trimethylaminoethylthio) imidazoline bromide hydrobromide (XI), 2-(2'-trimethylaminoethylthio) benzimidazoline bromide hydrobromide (XII). II showed a hypertensive action and caused a prolonged contraction of nictitating membrane of the cat. None of the test compounds inhibited the pressor actions of noradrenaline and tyramine, or contraction of nictitating membrane evoked by preganglionic stimulation of the sympathetic nerve. I, III, IV, and V showed marked positive inotropic and chronotropic actions, but II, VII, VIII, IX, X, XI, and XII did negative inotropic and chronotropic actions on isolated heart of the guinea pig. On the other hand, X, XI, and XII showed marked positive inotropic and chronotropic actions on vagotomized open chest dogs. II, VI, IX, X, and XII possessed a muscle relaxing action on diaphragm of the rat and sartorius muscle of the frog. Activities of the test compounds on rat liver monoamine oxidase were investigated Only II inhibited monoamine oxidase and the inhibitory activity of II was weaker than that of phenethylhydrazine. Inhibitory activities of the test compounds on cholinesterase of mouse plasma and rabbit red blood cells were also investigated. II, VI and IX markedly inhibited plasma cholinesterase but these compounds did not inhibit red blood cells cholinesterase. Local anesthetic, and antispasmodic actions and acute toxicity were also tested.
From 3-coumarincarboxylic acid (I) and 3-coumarinacetic acid (III), 3-carboxamides and 3-acetamides were prepared by the use of pyrrolidine, piperidine, and morpholine. Nitration of I and III resulted in introduction of the nitro group into 6-position, the compounds were derived to amides, and reduced catalytically over palladium-carbon, affording 6-amino-3-coumarincarboxamides and -3-acetamides. Catalytic reduction of 3-coumarincarboxamides over platinum oxide resulted in hydrogenation of 3- and 4-positions and gave dihydrocoumarin derivatives. Toxicity of these amides was examined by measuring their SD50, HD50, and LD50 in mice, and it was found that the introduction of an amino group into 6-position of the coumarin ring and hydrogenation of 3-and 4-positions resulted in decrease of the physiological activity as well as the toxicity, that the 3-acetamides have weaker action and weaker toxicity than the 3-carboxamides, and that morpholide is weaker in action and toxicity than pyrrolidide and piperidide.
Viscosity and turbidity of a mixed solution of chondroitinsulfuric acid and cationic surfaceactive agent were examined. Addition of a univalent cationic surfactant increases turbidity but there is no change in the intrinsic viscosity of the aqueous solution of chondrointinsulfuric acid. This is an interesting phenomenon in contrast to the lowering of intrinsic viscosity of the aqueous solution of chondroitinsulfuric acid by the addition of inorganic multivalent cation. Even in the case of cationic surfactants, extremely low ionic strength resulted in the decrease of viscosity. Binding ratio was calculated from the maximum value of turbidity of a mixed solution of chondroitinsulfuric acid and cationic surfactant. It was thereby found that the binding ratio was dependent on the concentration of chondroitinsulfuric acid present, and the number of molecules binding at the time of 1 mmole/1 of chondroitinsulfuric acid was 2.7 moles of dodecylamine hydrochloride and 5.0 moles of trimethyldodecylammonium chloride. This fact shows that, even if the length of the main hydrocarbon chain is the same, ratio of binding with chondroitinsulfuric acid becomes greater when the total number of carbon atoms is larger.
The Diels-Alder reaction of 4-methylthio-2-oxopyrano-[2, 3-b]-indoles with maleic anhydride, dimethyl acetylenedicarboxylate, and maleic anilide afforded carbazole derivatives (II to V) (cf. Table I). The reaction of one of these products, IV with ethanolamine, diethylaminoethylamine, and aminoacetal gave the imide derivatives (VI) (cf. Table II). The reaction of IVb and morpholine gave V which was also obtained by the reaction of the indole compound with maleic anhydride. The reaction of one of the products, II, with amines gave the same inide derivatives (VI), and that of IIb and ethanolamine gave the products (VII and VIII) formed by substitution of the methylthio group.
Catalytic reduction of 2'-nitropapaveraldine methochloride (IX) in dehyd. ethanol, in the presence of a small amount of potassium hydroxide, over Raney nickel catalyst, resulted unexpectedly in abnormal fission of the carbon-carbon bond to produce the ester compound (X), isocarbostril compound (XI), and tetrahydroisoquinoline compound (XIIa). On the other hand, reduction of IX in a mixed solvent of methanol and ethanol (3 : 1), in the presence of a small amount of water and an excess of sodium borohydride, followed by immediate catalytic reduction of its product over Raney nickel catalyst afforded XIIa from the hexane-soluble portion. Treatment of the hexane-insoluble portion with acetic anhydride gave the diacetyl compound (XVII). This abnormal reaction mechanism was considered to be as depicted in Chart 4.
The combined effects of sulpyrin, N-acetyl-p-aminophenol and aspirin in analgesic action and acute toxicity or LD50 were studied, using male mice (dd strain), weighing 18-20g, as the test animals, fed on a solid diet and tap water given freely in an air-conditioned room of 22-23° and a relative humidity of 60%. A graphic method was used in order to analyze the combined effects. It was found that analgesic activity was potentiated but acute toxicity was considerably reduced by the combined administration of three analgesics. The graphic method described in this paper seems to be useful for analyzing the combined effect of drugs.
In order to examine their analgesic activity, a number of 2-phenyl-3 (2H)-pyridazinone derivatives were synthesized. Among the compounds tested, 2-phenyl-4-methylamino-5-methoxy-3 (2H)-pyridazinone (V : R=CH3), 2-phenyl-4-diethylamino-6-ethoxy-3 (2H)-pyridazinone (VIII) and 2-phenyl-4, 5-bisdimethylamino-3 (2H)-pyridazinone (XII) revealed about twice activity of that of aminopyrine.
From the ripe fruit rind of Citrus grandis OSBECK forma Hirado, a variety of a large Chinese citrus fruit, pompelmous, naringin, mp 80-83°, and rhoifolin, mp 262°, were isolated in respective yield of 0.1% and 0.01%. It is interesting from chemotaxonomic point of view that the fruit rind of this species of citrus always contains naringin as the main glycoside and rhoifolin as the secondary component.
The saw dust from the trunk of Lyonia ovalifolia var. elliptica was extracted with methanol. The extract was concentrated, treated with benzene, and the benzene layer was examined by alumina column chromatography. The presence of 2-nonacosanone, taraxerone, taraxerol, β-sitosterol, and ursolic acid acetate were detected.