Inhibitory activities of steroid hormones and their related compounds were tested on the contraction of isolated guinea-pig ileum induced by acetylcholine (ACh), BaCl2, histamine, 5-hydroxytryptamine creatinine sulfate complex, and bradykinin, and of isolated rat uterus by ACh, BaCl2 and oxytocin. Compounds tested were 3 androgens, 5 estrogens, 4 gestagens, and 5 corticoids. All of them, except pregnanediols, had more or less inhibitory action on the contraction of smooth muscles. Among them, androsterone, dehydroepiandrosterone, estradiol, synthetic estrogens, and deoxycorticosterone were stronger than others and had almost the same order of activity as that of papaverine on guinea-pig ileum. Estradiol, diethylstilbestrol, and hexestrol showed a specific inhibition on the oxytocin contraction of isolated rat uterus. These results suggested that androsterone, dehydroepiandrosterone, and estradiol among the metabolites of steroid hormones may be some of inhibitory principles in human urine.
The reaction of ethyl trans-α-phenyl-2-nitrocinnamate derivative (XI) with triethyl phosphite gave a mixture of indole, quinoline, and carbostyril derivatives which were separated. The formation of quinoline and carbostyril derivatives proved that this reaction proceeded through an intermediate, the configuration of which was reversed.
The quantity of Prostaglandin (PG) E group was determined as PGE1 and PGF group as PGF2α from normal plasma and seminal fluid of humans by a new method. Crude lipid extracts of samples obtained by the procedure of Folch were separated from nonlipid contaminants on Sephadex G-25 columns following the modified method of Wuthier. After evaporation of the eluted solution, the residue was dissolved in carbon tetrachloride and PGs were extracted with water. The aqueous phase was acidified with hydrochloric acid to pH 3.0. After extraction of PGs with ethyl acetate, the ethyl acetate layer was neutralized with ammonium hydroxide. After evaporation of the solvent, PG fraction obtained was separated by thin-layer chromatography (TLC) on silica gel HR. Final recovery of PGE1 or PGF2α after group separations by TLC was constantly about 80% (>2 ng) although the yield of PGA1 was low. The recovery of PG was examined at each step of the extraction and separation procedures and the factors which affect the rate of extraction were discussed. Antigen was injected three times to male rabbits. The first administration was subcutaneous injection and the second and third were intramuscular. Two kinds of antiserum for PGE1 and PGF2α were successfully obtained at 40th day after initial injection. Therefore, the radioimmunoassay was used for the determination of PGs. The sensitivity of the quantitative minimum detection of PGE1 was 40 pg, but the standard curve of the range from 200 to 800 pg of PGE1 or PGF2α was usually used for the measurement.
The Voges-Proskauer reaction using 1, 1-dialkylguanidines, diacetyl, and 1-naphthol, in the presence of alkali, gave A and B pigments, besides C and D pigments as by-products. Pigment A was isolated as crystals by column chromatography, and its structure was elucidated. The molecular formula of each of Pigment A were C17H17ON3 for 1, 1-dimethylguanidine (DMG), C20H21ON3 for 1, 1-pentamethyleneguanidine (PMG), and C19H19O2N3 for morpholinoamidine (MA). From NMR, IR, Mass and UV data, the structure of Pigment A was determined as 5-[2'-(1'-naphthonylidenmethyl)]-(2-dialkylamino-4-methyl)imidazole.
From the measurement of electric conductivity, binding of metal ion and aspartic acid was considered by the use of magnesium and potassium aspartate. This binding ability differs according to the equivalence ratio, R, between the metal ion and asparticacid, and the relationship between the equivalent conductivity and ionic strength of salt solutions with R=1 follows the Fuoss-Onsager and Robinson-Stokes formulae, indicating that such salts are strong electrolytes. In the case of magnesium salts, conductivity falls inversely when R becomes larger than 1, indicating that a conjugated compound has been formed. From the values of pH measured at the same time as the electric conductivity, the conjugated compound was assumed to exist in three types with the charge positive, negative, and zero. The same examinations were also made with barium, strontium, and calcium salts of aspartic acid and the ability of these metals to form the conjugates was found to decrease in the order of magnesium, calcium, strontium, and barium.
Aqueous electrolytic solution of a mixture of potassium hydrogen aspartate (KHAsp) and magnesium hydrogen aspartate [Mg(HAsp)2] was examined for the dispersion behavior of each ion and penetration through the vitreous capsule of bovine eye. Dispersion coefficient of K+ increased with increasing fraction of Mg2+ in the solution, indicating that Mg ion accelerated the dispersion of K ion, while dispersion coefficient of Mg2+ decreased with increasing fraction of K+, indicating that K ion retarded the dispersion of Mg ion. This tendency was also observed in a mixed solution of KCl and MgCl2 examined for the sake of comparison. Examination of the beavior of the solution with vitreous capsule indicated that the parameter f that expresses the interaction between the membrane and ion was greater in KHAsp-Mg(HAsp)2-H2O system than in KCl-MgCl2-H2O system, and there was a difference between K and Mg ions. It was found that the value of fMG of Mg ion increased in the presence of KHAsp.
The time-dependent changes in biological activities of mitomycin derivatives, demethoxymitomycin A (DMMA, 7-amino-N-methyl-isomitomycin B (NMMB), mitomycin C (MMC), decarbamoylmitomycin C (DCMC), 10-acethoxydecarbamoylmitomycin C (ADCMC), in rabbit blood serum and in 0.4% bovine serum albumin (BSA) aqueous solution at 37° were investigated in order to clarify the reason for difference in biological activities of these compounds in vitro and in vivo. In these compounds, both in rabbit blood serum and in 0.4% BSA aqueous solution, remarkable decrease in their biological activities were found for DCMC and ADCMC, the carbamoyl group at C-10 having been removed from Mitomycin or replaced by an acyl group. The observed effects were assumed to be due to the binding of these compounds with BSA. Further, to elucidate the thermodynamic mechanism of the binding of mitomycin derivatives with BSA, some stoichiometric investigations were made on the interaction between these compounds and BSA by an equilibrium dialysis procedure at 25° and 5°. All the compounds were found to be bound with BSA according to the Langmuir type interaction. The free energy changes of binding of both DCMC and ADCMC were larger than the others and these large values of energy changes were found to be due to large entropy changes. The possible mechanism of the interaction is discussed.
The phase transition temperatures in the solid, liquid crystal, and isotropic liquid states of four cholesteryl esters have been determined in the heating and cooling cycles by a polarization microscope at the crossed nicoles, and by the differential thermal analysis and the measurement of the dielectric constant and dielectric loss. Values of ε' and ε'' were found not to be the same in heating and cooling. Data of transition temperatures obtained from these various methods are generally in good agreement with each other, and are found to be useful for mesophase identification. The difference in dielectric properties has not been observed between the smectic phase and the cholesteric phase.
Heating of α-acyl-3-methylphenylacetonitriles (IIa, b, c) or α-acyl-3, 5-dimethylphenylacetonitriles (VIIa, b, c) with POCl3 and HCONH2 give following results. α-Formyl derivatives (IIa, VIIa) afforded 4-amino-5-arylpyrimidines (IIIa, VIIIa) and β-formylamido-α-arylacrylonitriles (Va, Xa). Under more drastic condition, Xa did not give an isoquinoline (XII) or a pyrimidine (VIIIa), but produced β, β'-iminodi-α-(3, 5-dimethylphenyl) acrylonitrile (XI). From α-acetyl derivatives (IIb, VIIb), 4-amino-5-aryl-6-methylpyrimidines (IIIb, VIIIb) were obtained. α-Benzoyl derivatives (IIc, VIIc) gave 4-amino-5-aryl-6-phenylpyrimidines (IIIc, VIIIc) and β-amino-α-arylcinnamonitriles (IVc, IXc). IVc, and IXc are intermediates of the pyrimidines (IIIc, VIIIc), because they respectively gave IIIc and VIIIc under more drastic conditions.
Besides the unchanged drug, two major metabolites were found from the urine of animals that received orally high doses of bromazepam, 7-bromo-1, 3-dihydro-5-(2-pyridyl)-2H-1, 4-benzodiazepin-2-one. The metabolites were purified by column chromatography on silica gel and recrystallization. From the spectral and elemental analysis data, the structure of these metabolites were identified as 2-amino-5-bromobenzoylpyridine and assumed to be 2-amino-5-bromo-3-hydroxybenzoylpyridine, the latter being excreted as its glucuronide in the urine. It may be concluded that bromazepam after opening of the diazepine ring undergoes a process of hydroxylation.
Bischler-Napieralski reaction of the phenolic bromo-amide (VII), which was prepared by the condensation of 4-benzyloxy-2-bromo-5-hydroxyphenethylamine (V) with methyl 2-bromo-4, 5-methylenedioxyphenylacetate (VI) and reduction with NaBH4 of the resultant benzyldihydroisoquinoline (VIII) gave 7-benzyloxy-5-bromo-1-(2-bromo-4, 5-methylenedioxybenzyl)-8-hydroxy-1, 2, 3, 4-tetrahydroisoquinoline (IX). N-Methylation of IX gave X. The Ullmann reaction of X in the presence of potassium carbonate and cupric oxide in pyridine gave 6-benzyloxy-4-bromo-1-methyl-9, 10-methylenedioxy-1, 2, 3, 12, 12a-pentahydrobenzoxepino [2, 3, 4-i, j] isoquinoline (XI). Subsequent debromination of XI with LiAlH4 gave XII and debenzylation of XII with hydrogen over 10% palladiumcharcol gave dl-cularicine (I). I was identified with natural cularicine by infrared and nuclear magnetic resonance spectral comparisons.
Effect of glucose, fructose, sorbitol, xylitol, citric acid, and gluconic acid on hydrolytic polymerization of iron was examined. 1) Fructose, sorbitol, or xylitol (20 mM each) added to 1 mM ferric chloride solution inhibited the polymerization of iron during alkaline hydrolysis process and gave a low molecular polymer. These facts were confirmed by measurement of polymer formation rate, elution pattern from Sephadex G-75, and sedimentation constant. 2) Citric acid and gluconic acid were also found by gel filtration to inhibit the hydrolytic polymerization of iron. These results suggest that the carbohydrates, polyols, and organic acids enhance the absorption of iron across the intestine by formation of low molecular polymers of iron.
A large number of metal complexes containing thiopyrine as a ligand was synthesized and their characteristics were clarified from the measurement of molar conductivity and molecular weight in nonaqueous solvent. Thiopyrine coordinates with metal ions, and in the presence of perchlorate ion, forms electrolyte complexes like [ZnT4](ClO4)2, [CdT4](ClO4)2, [CoT4](ClO4)2, [PbT4](ClO4)2, [HgT2](ClO4)2, [HgT4](ClO4)2, [CuT3](ClO4)2, [AgT] ClO4, and [AgT3]ClO4, where T stands for thiopyrine. In the presence of halogen and thiocyanate ion, MT2X2 type of nonelectrolyte complexes are formed from zinc (II), cadmium (II), mercury (II), and cobalt (II), ahd MT2X type complex from copper (I) and silver (I), Where T stands for thiopyrine, M for metal, and X is Cl, Br, I, or SCN.
Poured angles of repose of spray-dried agglomerated salicylic acid and sodium salicylate particles, prepared from slurries containing these materials and gum arabic, were measured and the effect of parameters consisting of slurries inflvencing on them was determined. Concentration of sodium salicylate was the most important factor affecting on free-flowing properties of agglomerated powders as well as that of gum arabic. Angles of repose (φs) of the products were related to their sphericity (ψ) and their relationship was revealed by equation (1), φ=18.2ψ+33.8, where 0<ψ<0.36, Angle of repose measured by pouring and revolving cylinder method was defined as static (φs) and kinetic (φk) angle of repose, respectively, and distinction between them was clarified by a physical method. A coefficient of cohesion(Cf) indicating the cohesive property of particles was proposed, definied by equation (2), Cf=f/mg=sinθ/cosφko, where φko is extrapolation kinetic angle of repose, with revolution rate of cylinder being zero, and θ is the difference between φs and φko. A calculating table of Cf was prepared, which is convenient to estimate the cohesive property of powder, based on the equation (2), and also cohesive and frictional forces of agglomerated particles were determined as 1.30×10-5 to 1.03×10-4 (dyne) and 1.39×10-5 to 1.77×10-4 (dyne), respectively. Examination of the relationshiop between these forces and sphericity showed that the larger the sphericity, the smaller were the forces.
The metabolism of l-ephedrine [α-14C] (I) in mice, rats, guinea pigs, and rabbits was studied by a tracer technique to clarify the species differences in metabolic pathways. I was subcutaneously administered in a dose of 5 mg/kg and the urine excreted during 24 hr after the administration was analyzed. In mice, the major part of 14C activity was excreted as unchanged I. In guinea pigs, a large quantity of norephedrine and considerable amounts of benzoic acid and 1-phenyl-1, 2-propanediol were excreted, but the amount of p-hydroxyephedrine and its metabolites was very small. In rats, the metabolic activity was low next to mice and the excretion of a considerable amount of substrate was observed ; the p-hydroxylation activity, however, was the highest in animals tested here, so that the main metabolites were p-hydroxyephedrine and its conjugated metabolite. In rabbits, both the N-demethylation and deamination activities were extremely high, and the major part of administered I was excreted as deaminated products. A remarkable amount of 1-phenyl-1, 2-propanediol and its conjugated metabolite were also detected in rabbit urine.
A total of 180 compounds, 54 kinds of 1-alkyl-3-(4'-alkoxycarbonyl-3'-hydroxyphenyl)-2-thiourea and 126 kinds of 1-aryl-3-(4'-alkoxycarbonyl-3'-hydroxyphenyl)-2-thiourea, were synthesized and their antibacterial activity was tested against human-type tubercle bacilli H37Rv strain. 1) None of the 1-alkyl derivatives showed stronger antibacterial activity than p-amino-salicylic acid (PAS) and 1, 3-di-(p-iso-pentoxyphenyl)-2-thiourea (DAT). 2) Among the 1-aryl derivatives, 1-(p-butoxyphenyl)-3-(3'-hydroxy-4'-isobutoxycarbonylphenyl)-2-thiourea and 1-(p-pentoxyphenyl)-3-(4'-ethoxycarbonyl-3'-hydroxyphenyl)-2-thiourea inhibited the growth of the bacillus in a concentration of 0.39 μg/ml, indicating antibacterial activity comparable to PAS or stronger than DAT. In addition, 1-(p-propoxyphenyl)-3-(3'-hydroxy-4'-methoxycarbonylphenyl), 1-(p-propoxyphenyl)-3-(4'-ethoxycarbonyl-3'-hydroxyphenyl), 1-(p-propoxyphenyl)-3-(3'-hydroxy-4'-propoxycarbonylphenyl), 1-(p-propoxyphenyl)-3-(4'-butoxycarbonyl-3'-hydroxyphenyl), 1-(p-propoxyphenyl)-3-(3'-hydroxy-4'-isobutoxycarbonylphenyl), 1-(p-butoxyphenyl)-3-(4'-butoxycarbonyl-3'-hydroxyphenyl), and 1-(p-pentoxyphenyl)-3-(3'-hydroxy-4'-propoxycarbonylphenyl) derivatives inhibited bacillary growth in a concentration of 0.78 μg/ml, a comparable effect as that of DAT. 3) Result of experiments on a part of 1-alkyl derivatives showed that some of these compounds had no cross resistance with PAS and had stronger antibacterial activity against resistant strains rather than sensitive strains.
The essential oils of Cymbopogon Goeringii A.CAMUS obtained from Kyushyu and Kinki district of Honshu in Japan were examined. The yield of the oil was 0.50-1.04% of the herbs according to their stages of vegetation. The main constituents are elemicine and trans-isoelemicine amounting to a total of 69.3-81.1% of the oils. A small amount of d-linalool, l-borneol, and l-bornyl acetate were also determined as the characteristic odoriferous components. Besides many other compounds, two new sesquiterpene ethers, ogarukaya ether A and B, both C15H26O, were recognized but their constitution and configuration are not yet perfectly clear. The phylogenetic position of this plant in thi C.Nardus series of the genus was shown as an end species of differentiation from the point of chemical systematics.
Chinese crude drug "She Huangzi ( ?? ?? ?? ), " which has previously been presumed to be the fruits of a species of Cnidium from the morphological investigation, afforded eight known coumarins, columbianadin (I), archangelicin (II), edultin (III), O-acetylcolumbianetin (IV), bergapten (V), isopimpinellin (VI), columbianetin (VII), and O-isovalerylcolumbianetin (VIII), together with two new products which were proved to be 2'(S), 3'-(R)-3'-isobutyryloxy-O-acetyl-2', 3'-dihydrooroselol (IX) and 2'(S)-O-isobutyryl-2', 3'-dihydrooroselol (X). The herbs and roots of Cnidium japonicum MIQ. contain I, IV, V, VI, VII, and X. These findings suggest that from the chemotaxonomical point of view, this crude drug can also be considered to be the fruits of Cnidium sp. The new product X was named cnidiadin.
Palmitic acid, stigmasterol, and L-aspartic acid were isolated from the roots and terrestrial parts of Oenanthe stolonifera DC., and seven kinds of amino acid were also detected. Four kinds of amino acid and two kind of amino sugar, glucosamine and galactosamine, were detected from the roots besides the foregoing components.
The following six species of Rutaceae were examined for fatty acid composition by gas chromatography : Zanthoxylum piperitum (seeds and peels), Z.ailanthoides (seeds and peels), Ruta graveolens (fruits), Phellodendron amurense var. lavalli (fruits), Citrus natsudaidai (seeds), and C.trifoliata (Poncirus trifoliata)(fruits). All samples mainly contained palmitic, stearic, oleic, linoleic, and linolenic acids. Neither new nor uncommon fatty acid was detected in these species.