4-Isoquinolinecarbonitrile (I) forms 1, 1'-bis(isoquinoline)-4, 4'-dicarbonitrile (II) by the action of a cyanide ion in dimethyl sulfoxide. Formation of II was assumed to be oxidation following a benzoin condensation-like reaction by the catalysis of the cyanide ion. On the other hand, 4-isoquinoline 2-oxide (III) formed 1, 4-isoquinolinedicarbonitrile (IV) by reaction with a cyanide ion in dimethyl sulfoxide, and the process of formation of IV was examined in comparison with that of II.
Unlike soda-lime glass powder, borosilicate glass powder fails to give homogeneous thin-layers when used as a binder for the preparation of silica gel sintered plates. Examination of pH of water suspensions of these two kinds of glass powder revealed that the borosilicate powder has lower pH than the soda-lime glass powder, suggesting that pH of the glass might affect the formation of thin-layers. Addition of sodium methoxide or ammonium hydroxide to the suspension of silica gel-borosilicate glass powder in various solvents was found to increase sedimentation volume of the glass powder. Among several kinds of solvent tested, acetone was the most effective in increasing the sedimentation volume. Thus, the silica gel-borosilicate glass powder suspension in acetone with sodium methoxide or ammonium hydroxide added gave, after usual processing, homogeneous thin-layer plates which exhibited normal chromatographic separation of various organic compounds such as alkaloids, estrogens, and other steroidal hormones. Addition of basic flocculants and use of acetone were also effective for the preparation of alumina-borosilicate and kieselguhr-borosilicate sintered plates.
The flocculation-deflocculation behavior of chloramphenicol (CP) in aqueous solutions of polyvinylpyrrolidone (PVP)/polyacrylic acid (PAA) mixture, which was quite different from the behavior in the solution containing each polymer separately, was studied by means of sedimentation measurements. At a low suspension pH below 5.5 a slow rate of setting and a low sedimentation height ratio (H/H0) were observed, and microscopic observations showed deflocculation of the CP particles. From pH 5.5 to 6.5 the rate of sedimentation and the sedimentation volume increased rapidly, i.e., the systems in this pH region showed the typical flocculated states. When, however, the suspensions were brought to a higher pH (7 and above) and also when the concentration of PAA was relatively high, the rate of sedimentation was reduced markedly and the values of H/H0 approached unity. The polymer molecules may be considered as producing a three-dimensional structure in which CP particles were supported and/or producing flocculation of the particles. Both the results of rheological measurements and the polymer adsorption measurements were compatible with the above concept. The effect of neutral salts on the stability of the structure formed in the suspensions was also examined.
Derivatives of 2-(phenoxy)isobutyric acid with phenoxy group substituted with 4-chlorobenzyl, 4-chlorobenzyloxy, 4-chlorostyryl, 4-chlorophenethyl, 4-chlorobenzoyl, α-hydroxy-4-chlorobenzyl, α-ethoxy-4-chlorobenzyl, 4-chlorophenylacetyl, and α-hydroxy-4-chlorophenethyl were prepared and assayed for their hypocholesteremic activity in rats. In general, 2-[4-(4-chlorobenzyloxy)phenoxy]isobutyric acid derivatives were found to possess significant activities.
The reaction of vitamins K with cysteine was studied by polarography in 90% ethanol. Vitamins K1, K2, and K3 exhibit well-defined polarographic reduction waves in this medium. In the presence of cysteine in solution, the addition of SH group takes place at 3-position of naphthoquinone ring in vitamin K3. As a result of this reaction, the diffusion current of vitamin K3 decreases markedly with the increasing concentration of cysteine, and new reduction waves appear at a more negative potential region. The change in the polarogram of vitamin K3 caused by cysteine is affected by oxygen dissolved in the solution. Possible reaction mechanisms in the presence and absence of oxygen were discussed. On the other hand, cysteine does not affect the polarograms of vitamins K1 and K2 because the formation of addition compounds is hindered by the alkyl groups in both 2- and 3-positions of these vitamins. Vitamins K cannot be determined simultaneously by the conventional polarography because of their very close half-wave potentials. The experimental results in the present work is applicable to the consecutive determination of vitamins K1 (or K2) and K3. The total concentration of vitamins K is easily obtained by the measurement of the height of the reduction wave. The diffusion current of vitamin K3 disappears completely within 20 min by the Addition of an excess amount of cysteine to the solution, while that of vitamin K1 (or K2) remains unchanged irrespective of cysteine concentration, and consequently, both the concentrations of vitamin K1 (or K2) and K3 are determined. This method has been applied to the mixed solutions of K1-K3 and K2-K3 with satisfactory results.
Treatment of dehydrodeoxomonoacetate (VIII) with 90% H2O2-(CF3CO)2O gave a lactone acetate and treatment of the α, β-unsaturated ketone (XIII) with 10% NaOH-MeOH gave the phenolic base. The structures of these two rearrangement products, the lactone acetate and the pheno1ic base were deduced as B : R=Ac and XIV, respectively.
When Japanese acid clay is dispersed in an aqueous medium, pH of the solution deviates to acidic because of dissociation of H+ from clay minerals. Addition of neutral salt to this solution decreases pH values further. The order of electrolytes having common anion, Cl-, to decrease pH of the solution was found to be Na+, K+, and Ba2+, the latter being the most effective. The pH value of final equilibrium, (pH)f, was found to be constant in the range of initial pH of medium, (pH)i, between 3 and 11, which is prepared by adding hydrochloric acid or alkali hydroxide tb the salt solution. It was, therefore, concluded that Japanese acid clay has both buffer function and ion-exchanging property. On the other hand, the amount of alkali adsorbed to this clay increases with the concentration of hydroxide in the medium, and KOH is absorbed more than NaOH. It was, therefore, concluded that ion-exchanging capacity for K+ is larger than that for Na+. The rate of reaction of alkali adsorption was measured at constant pH by using pH-statt. It was concluded from analysis of the amount of adsorbed alkali as a function of time, that there are two ion-exchanging mechanisms which are competitive; the one is on the outer surface and the other in the inner layer of the clay mineral. It was concluded that the capacity of ion-exchange, α1, and the rate constant, k1, of the former is larger than those of the latter.
In order to study the fate of sulfadimethoxine in the bile of a guinea pig, sulfadimethoxine was administered intravenously and unchanged sulfadimethoxine, its N4-acetate, N1-glucuronide, and N4-glucuronide were separately determined in the bile. About 40% of the administered dose was excreted in the bile in 5 hr as total sulfadimethoxine and about 20% as N4-glucuronide, which is the major metabolite if the bile. After the administration of sulfadimethoxine and its N4-glucuronide into the guinea pig duodenum, the blood level and the biliary excretion were quantitatively studied. These results suggested that N4-glucuronide is absorbed from the intestine as sulfadimethoxine after hydrolysis. It is obvious that the enterohepatic circulation of sulfadimethoxine is present in the guinea pig.
The present study was undertaken to standardize the assay method for the cathartic effect of rhubarb in mice. Examinations were made on the effect of administration time, age, sex, and body weight of mice, light, other drugs, fatigue and fasting of mice, temperature, and humidity. The ED50 value of rhubarb was affected by administration time. Three-week-old mice were less sensitive than 4- to 7-week-old mice. In a group of the same age, mice of heavy body weight were more sensitive than light ones. The ED50 values were also affected by lighting and simultaneous administration of some other drugs. Other factors were found to be insignificant.
Hexosamine-containing substances, acidic glycosaminoglycans and glycoproteins, extracted from carrageenin granuloma obtained from the rat 4, 6, 8, 10, and 16 days after the injection of carrageenin solution, were studied. Considerable changes were observed in both fractions; during the evolution of granulomatous tissue from 4th to 6th day of hexosamine and uronic acid content in glycosaminoglycans reached a peak and then decreased gradually whereas glycoproteins gradually increased from 6th to 16th day. The effect of anti-inflammatory drugs on the carrageenin granuloma was tested for their inhibitory action on the content of hexosamine-containing substances by means of their daily local injection into pre-formed granuloma pouch during 6th to 9th day. A steroidal drug, betamethasone, reduced the content of both hexosamime-containing substances, while non-steroidal drugs, phenylbutazone and D-penicillamine, did not reduce the content significantly. Chondroitin sulfate isomers were also analyzed by the chondroitinase method. Chondroitin sulfate-B decreased strikingly compared with chondroitin sulfate-A by the treatment of a rat with betamethasone. Effect of this steroidal drug on the metabolism of glycosaminoglycans labeled with 35S was investigated. Betamethasone markedly inhibited the synthesis of sulfated glycosaminoglycans and considerably inhibitid the degradation of glycosaminoglycans.
Absorption, excretion, distribution and metabolism of bis(3-methylsulfonyloxy-propyl)amine p-toluenesulfonate (864-T), a new alkylating agent, were investigated in normal rats using the tritium-labeled compound. Within 3 days after the oral or intraperitoneal administration of radioactive compound (3H-864-T), 80-90% of the given radioactivity (3H) was excreted in the urine and 1-10% in the feces. In addition, 4% of the given tritium was also recovered in the bile during 24 hr after the oral administration. The blood level of tritium reached the maximum at 2 hr after the oral administration, and then decreased at such a rate that the half-life time was 2 hr. The highest concentration of tritium was observed in the kidney, while relatively low lever were found in other tissues. There was no sign indicating that the given tritium was bound to the serum protein. Two kinds of metabolites were detected in the urine during 24 hr after the oral administration of 3H-864-T. These metabolites were isolated from the urine after the administration of non-labeled compound (864-T). One of them was found to be 2-oxotetrahydro-1, 3-oxazine-3-propanol and the other, 2-oxotetrahydro-1, 3-oxazine-3-propionic acid.
Five kinds of alkaloids were isolated from the root of Physalis alkekengi L.var.francheti HORT. forma bunyardii MAKINO besides 3α-tigloyloxytropane (I) which was formerly isolated.1) Alkaloids II, III, and IV were determined as tigloidine (II), tropine (III), and pseudotropide (IV). The structure of alkaloid V was confirmed as 3α-tigloyloxytropane N-oxide by both chemical reaction and synthesis. This N-oxide-type alkaloid has been unknown in natural tropane alkaloids. Alkaloid VI could not be clarified due to its small amount. A convenient synthetic method for nortropine from tropine N-oxide was also established.
This kinetic study dealt with the decrease of salicylic acid concentration in water phase by its uptake into goldfish, and with the effect of different pH of the water phase, addition of polyethylene glycol 6000, and urea derivatives on the uptake. Elimination of salicylic acid in water phase was assumed to be expressed by the following equation : dC0/dt=k0C1-k1C0, where C0, C1, are the concentration of salicylic acid in water phase and in goldfish, k0, is the outflux rate constant, and k1 the influx rate constant. This equation was proved to be consistent with the concentration of salicylic acid with time course. The value of k1 decreased with increase of pH value in water phase and, therefore, the rate-determining process of salicylic acid flux was thought to be like a lipid membrane. The addition of polyethylene glycol 6000 and urea at 20° had a suppressive and promotive effect on the k1 respectively. This effect of urea diminished at 10°. The two effects were additive. Both methylurea and dimethylurea were less effective than urea. From the effects of additives and pH in water phase on the k0, the rate-determining region for the outflux was found to be affected easily by the condition in the external water phase.
The metabolic fate of 5-fluorouracil (5-FU) after its oral administration was studied in comparison with its intravenous administration using normal rats and solid Sarcoma-180 bearing mice, and results are summarized as follows : 1) When 5-fluorouraci1[2-14C] was given orally to rats, it was readily absorbed from the small intestine and the radioactivity was detected in various tissues and organs. Particularly, a higher radioactivity was counted in the small intestine, stomach, liver, and pancreas after orally than intravenous administration in rats. 2) The rapid rate of the metabolic degradation of 5-fluorouracil was found by both routes. Within 4 hr after oral or intravenous administration, about 80% of the total radioactivity was excreted into the expiration and urine. 3) Slightly larger radioactivity in the expiratory CO2 and high concentration of the degradation products, such as urea and 2-fluoro-3-ureidopropionate, in the urine were observed after oral administration in than after intravenous administration in rats. 4) The blood and tissue levels of the degradative products in the tumor-bearing mice were found a little higher after the oral than intravenous administration. 5) Orally administered 5-fluorouraci1 seemed to be catabolized more extensively than that administered intravenously in both mice and rats. However, in both routes excessive dose of 5-fluorotracil produced a different excretion pattern and high urinary levels of 5-fluorouracil.
Examinations were made on the reaction of dimethyl 3, 4-diaroyloxy-2, 5-furandicarboxylate derivatives with hydrazine hydrate or ammonia, and few other reactions, and 6 kinds of novel 3, 4-diaroyloxy-2, 5-furancarboxylic acid hydrazide and 3, 4-dimethoxy-2, 5-furancarboxamide (V) were obtained. The acid hydrazides so obtained were reacted with several aldehydes and 28 kinds of hydrazones were obtained. Mass spectra were measured for dimethyl 3, 4-diaroyloxy-2, 5-furandicarboxylate derivatives and acid hydrazides, and their fission pattern was examined. Ultraviolet absorption spectra of dimethyl 3, 4-diaroyloxy-2, 5-furandicarboxylates and dimethyl 3, 4-dihydroxy-2, 5-furan-dicarboxylate were also examined.
Tertiary bases in Nandina domestica THUNB., and N. domestica var. levcocarpa MAKINO were examined by gas chromatography-mass spectra and it was found that the bases contained in these plants were very similar. Besides the bases confirmed to be present, N-nornantenine, hydroxynantenine, dehydronantenine, nuciferine (a non-phenolic base), and dehydroisoboldine (a phenolic base) were assumed to be present, but the presence of nandinine was not observed.
Ethylenation of catechol (Ia), pyrogallol (Ib), 1, 2-dihydroxy-3-methoxy-4, 5-methyl-enedioxybenzene (Ic), 1, 2-dihydroxy-4, 5-methylenedioxybenzene (Id), and 1, 2-dihydroxy-4-nitrobenzene (Ie) with ethylene chloride showed the effect of kinds of solvents and bases used, and yields varied greatly according to reaction procedures. It was found that ethylenedioxy derivatives can be obtained in a good yield from cheap ethylene chloride during a short, time, when the concentration of Ia-e was regulated below 1M in the reaction system (according to the authors' procedure).
Reaction of 4-cinnolinecarbonitrile (I) with active methylene compounds was carried out by (a) refluxing in toluene in the presence of sodium amide or by (b) heating in dimethyl sulfoxide in the presence of potassium cyanide at 100°. The reaction of I and phenylacetonitrile (IIc) by method (a) gave α-phenyl-4-cinnolineacetonitrile (IIIc) in comparatively good yield of 60%, but that of I and malononitrile (IIa) gave a minute amount (4%) of 4-cinnolinemalononitrile (IIIa), with majority of I recovered. Reaction of I and ethyl cyanoacetate (IIb) ended in the recovery of unreacted I. By the use of method (b), reaction of I and IIa gave IIIa in a relatively good yield (66%), and that of I and IIb gave ethyl α-cyano-4-cinnolineacetate (IIIb) in 42% yield, while that of I and IIc gave only a minute amount (7%) of IIIc.
The relation between pH stipulated in Japanese Pharmacopoeia VIII and Japan Industrial Standard (JIS), and pαH (pαH=-log αH, where αH is the hydrogen ion activities) was kinetically examined in organic solvent-water mixture using methyl acetate as a model compound. The results demonstrated that pH values differ from p αH by constant values which depend on the composition and nature of the mixed solvent, and that these values can be used to estimate the stability of drugs in organic solvent-water mixtures.
The quantitative analysis of phyllodulcin (I) in "Amacha" (sweet hydrangea) was performed by thin-layer chromatography using Silica gel G and CHCl3 : CH3OH (15 : 1) as a solvent. The fluorescent spot of I was eluted by benzene : CH3OH (3 : 1), which was estimated by ultraviolet absorbance at 314 nm. It was proved that this method is always applicable for quantitative assay of phyllodulcin content in "Amacha". Among several Japanese species or varieties, crumpled and dried leaves of "Ko-amacha" Hydrangea macrophylla SERINGE subsp. serrata MAKINO var. thunbergii MAKINO (II) showed the highest value (2.38%), while these of "Amagi-amacha" H. serrata subsp. angustata (FR.et SAV.) KITAMU. (III) a wild variety, the lowest (0.07%).
The permeation at the interface and in the membrane were studied by using two kinds of the measurement cells for permeation. Two kinds of gelatin membranes were used, which were cross-linked by different formaldehyde cross-linking process. KCl, tetra-alkylammonium chlorides and dodecylamine hydrochloride were used as solutes. The thickness of stagnant layer, δ, the rate constant of interfacial permeation, k, and the rate constant of permeation at the membrane surface, kS, were obtained under various conditions. Without stirring it was found that δ depended on the density of solution and kS depended on the diffusion coefficient, D, and on the interactions between gelatin and solute. Furthermore, kS was different for the membranes prepared by a different cross linking process. Permeability coefficient in the membrane phase, P*, decreased along a sigmoidal curve with increasing gelatin content. The apparent membrane constant, f*(=P*/D), was disscused by Wang's and Mackie's equation. f* depended on the radius of solute and the interaction between ge1atin and solute. In the case of KCl, these values agreed with the above equations.
Sulfur-containing substances in some vegetables often interfere in the analysis of residual organophosphorus insecticides by gas chromatograph equipped with a flame photometric detector. Elimination of such an interference required clean-up by Florisil column chromatography and selection of optimum flame condition for P mode flame photometric detector with least cross-interference. Recoveries of Diazinon, Ronnel, Malathion, Sumithion, and Parathion were from 74 to 106% for Japanese leek, onion, scallion, and garlic.
Solid nickel peroxide, readily obtainable by the treatment of nickel salts with sodium hypochloride in alkaline solution, has been proved to be a useful oxidizing agent for the preparation of some kinds of substituted aromatic α-diketones from the corresponding α-ketoalcohols in benzene or ether.
In order to investigate the antibacterial activity of acyltetrapeptides, some compounds similar to the partial structure of lysine-colistin were synthesized. Nα-Acyl-L-lysyl-Nε-(D-leucyl)-L-lysyl-L-threonine hydrochloride was synthesized by the acylation of tetrapeptide condensed by the stepwise method with dicyclohexylcarbodiimide. Acid chlorides of 6-methyloctanoic acid (a component of colistin) and seven other kinds of acid were employed as acylating agents. It was proved that antibacterial activity of two acyltetrapeptides of these compounds was one-eighth that of colistin sulfate against Shigella sonnei, and activities of the others were one-fifteenth to one-thirtieth.