Condensation of 2, 6-dimethyl-3-nitropyridine (I) and substituted benzaldehydes in acetic anhydride affords 2-substituted styryl-6-methyl-3-nitro-pyridines (II). Conversion of II to 2-substituted phenethyl-3-amino-6-methylpyridines (IV) was carried out in the presence of Raney-nickel of palladiumcarbon catalyst and hydrogen. 2-Substituted phenethyl-3-[(N, N-dialkyl- or N-cycloalkyl) aminocarbonylethyl] amino-6-methylpyridines (V) were prepared by the condensation of IV with N, N-dialkyl- or N-cycloaklyl-acrylamides in the presence of a catalyst such as acetic acid in nitrogen gas. Pharmacological screenings, such as the effect of the spasmus induced by serotonin, antibarium, antiacetylcolinegic, antihistamine, analgesic, prolonged effect on sodium barbiturate sleeping time, anticonvulsant, antipyretic, depressive action on spontaneous motility, locomotion test, and antihypertensive activity, were employed, whose results are shown in Table VIII. The structure-activity relationship was not clear, but compounds No. 23, 23-1, and No. 25 and 26 of V were found to have an effect on spasmus induced by serotonin and prolonged effect on sodium barbiturate sleeping time, respectively.
Effects on the cardiovascular system of new 17 derivatives of benzodioxane were studied in anesthetized dogs. 8-[(1, 4-Benzodioxane-2-yl) methyl]-3-oxo-1-thia-4, 8-diazaspiro [4, 5] decane (I), 4-methyl (XI) and 4-tolyl (XIII) substituted derivatives on I have a potent increasing activity in the femoral blood flow. These compounds showed less active in the coronary blood flow, systemic blood pressure, heart rate and respiration. I was found the most desirable compound as a peripheral vasodilator with low toxicity amoug these derivatives.
Alkylthiochalcones (IV-LIV) were synthesized by the condensation of alkylthioacetophenones (I-III) with aromatic aldehydes for the purpose of screening their antibacterial activity in vitro. Of these chalcone derivatives tested, 18 compounds (IV, VI, XII, XIII, XVI, XIX, XX, XXII, XXIII, XXVIII, XXX, XXXI, XXXII, XXXVI, XXXVII, XXXIX, IL, and LIII) showed a relatively intense antibacterial activity against Bacills subtilis NRRL, and VI was also effective against Escherichia coli O-55. XXXVIII revealed antibacterial action only against Staphylococcus aureus 209 P.
Tritium-labeled compound of a new benzodioxane derivative, 8-[(1, 4-benzodioxane-2-yl) methyl]-3-oxo-1-thia-4, 8-diazaspiro (4, 5) decane maleate (Y-3506), was administered to rats orally, intraperitonealy, intravenously or intramuscularly. About 50% and 40% of the administered radioactivity (3H) were excreted in the urine and feces, respectively, by any route within 3 days. Following oral administration, 57% of the dose was also excreted in the bile during 24 hours. The highest concentration of 3H in most organs was found from 0.5 to 1 hour after oral administration, and the levels of 3H in the liver, adrenals, kidney, and serum were high, but those in the adipose tissue and brain were relatively low. Concentration of 3H in the adipose tissue was high in the case of intravenous administration. Protein binding of 3H in the serum was 15%. About 70% or more of 3H in the tissues other than the liver was attributable to S-oxide of Y-3506, one of the metabolites of Y-3506, and less than 20% to the unchanged Y-3506, 30 min after oral administration. On the other hand about 50% of 3H was found to exist as the unchanged compound in the blood and liver, 15 min after intravenous administration. Y-3506-S-oxide was identified as the major metabolite in 24-hour urine. Urinary excretion of the unchanged compound in the case of intravenous administration was more than that in the case of oral administration.
Reduction of the Schiff base (XVIII), obtained by the condensation of 2-amino-4, 5-dimethoxyphenethyl alcohol (XII) with 6-nitroveratraldehyde, afforded 2-(4, 5-dimethoxy-2-nitrobenzylamino)-4, 5-dimethoxyphenethyl alcohol (XIX). Cyclization of XIX with thionyl chloride, followed by the reduction of 2, 3-dihydro-5, 6-dimethoxy-1-(4, 5-dimethoxy-2-nitrobenzyl) indole (V) with zinc powder, gave the corresponding 1-(2-amino-4, 5-dimethoxybenzyl)-2, 3-dihydro-5, 6-dimethoxyindole (VI).
2-Trimethylaminoethyl-1'-methylisothiuronium bromide hydrobromide (MTMA) was found to produce an increase in blood pressure and contraction of the nictitating membrane in cats. These effects were either blocked or reduced by guanethidine, hexamethonium, phentolamine, tetrodotoxin, reserpinization, or by bilateral adrenalectomy but were not appreciably affected by hemicholinium, atropine, or spinal section. Ganglion stimulating action was confirmed when the compound was injected directly to the superior cervical ganglion in cats. The stimulating action on the parasympathetic ganglia though weaker, was also observed in dogs. Hemicholinium was unable to block the contraction of the cat nictitating membrane in response to MTMA and 1, 1-dimethyl-4-phenylperazinium iodide (DMPP) administered directly to the superior cervical ganglion at a time when it had blocked the contraction of the membrane elicited by preganglionic sympathetic nerve stimulation. This observation indicated that MTMA acts on the ganglion cell at the postsynaptic cholinoceptive site.
Plant tissues are completely ashed at ordinary temperature by very reactive oxygen stream excited in a high-frequency electromagnetic field under a low pressure, preserving mineral microstructures precisely identical with the original tissue matrices. Microscopic examinations of the mineral structures of the ashed tissues readily suggested their valuable contribution to plant taxonomical and morphological studies, as well as in identification of original plants for crude drugs. Systematic studies on mineral microstructures of medicinal plants were taken up and, as the first step, leaves of Cassia angustifolia VAHL and Camelia japonica L., both involving calcium oxalate crystals, were examined through surface and cross-sectional views of the ashed tissues. The results thereby obtained are summarized as follows, in comparison with the conventional Molisch's high temperature ashing method. 1) The low-temperature ashing preserves the mineral microstructures better than the high temperature ashing method and crystals in the ashed tissues retain their original location and shape. 2) Calcium oxalate crystals forming both clustered and solitary bodies are non-reactive with the oxygen plasma so that their geometric constitutions and optical properties of the crystals can be studied well in the ashed tissues, while with the high-temperature ashing the calcium oxalate crystals are considerably destroyed by thermal decomposition during ignition. 3) Cell membrane, nuclei, chloroplasts, leucoplasts, and some other small grains are ashed as they were in the original tissues, suggesting that certain mineral constituents were present in these materials.
N-Benzylideneaminopyridinium salt (II), prepared from N-aminopyridinium salt (I) and an aromatic aldehyde, was reacted with potassium cyanide in aqueous solution to afford a novel compound, "iminonitrile" (III). III is labile and is converted to the nitrile (IV) by dehydrocyanation. II was partly hydrolysed by potassium cyanide in less than equimolar amount to the aldehyde which, when further reacted with III, produced competitively 2, 4-diaryl-5-aminooxazole (V) and its arylidene derivative (VI), together with main products, III and IV. III was isolated from the reaction mixture in a good yield, and reacted with an appropriate aromatic aldehyde in organic solvent to produce V and VI in a good yield, or with an aliphatic aldehyde to produce 2, 4-disubstituted 5-oxazolone (VII). These procedures offer a simple and convenient route to a wide variety of compounds of V, VI, and VII series.
Gas chromatography of the aporphine-type alkaloids and their trimethylsilyl derivatives was carried out on OV-17 and XE-60 as the stationary phases. The relationship between the molecular structure of alkaloids and their retention time was discussed.
A low-temperature oxygen plasma generated in a high-frequency electromagnetic field under a low pressure was applied to plant tissues on a slide glass for removing organic matrices but perfectly preserving the shape and arrangement of calcium carbonate crystals in the specimens. The observation of ashed tissues of leaves of Ficus elastica ROXB. revealed details of cystolith deposited in the epidermis which seemed to be clustered crystals having optical properties of either isotropy or anisotropy. Calcium oxalate crystals were also observed along the vein in extremely high density. An ashed leaf of Himulus japonicus SIED. et ZUCC. was highly characterized by short hair of single cell which had semispherical base consisting of several cells encircling a cystolith ball inside. Justicia procumbens LINN. left slender cystolith in the ashed tissue irregularly arranging near the vein.
The low-temperature ashing with oxygen plasma excited by a high-frequency electrodeless discharge was successfully applied to leaves and stems containing silicon bodies, and microscopic observations of their shape and arrangement gave valuable contributions to plant taxonomical and morphological studies. An ashed tissue of Bambusa multiplex Raeuschel exhibited regular linings of silicon bodies along the vein. Each silicon body was characterized by a dumb-bell shape and deposited a dark nuclear point at an eccentric position. A stem of Equisetum hyemale LINN. was ashed both for surface and cross sectional views. Details of the silicon bodies depositing outside the stem and their surrounding sclerenchyma were studied. Using a specimen of Equisetum ramosissimum DESF. var. japonicum MILDE, a comparison of mineral microstructures was made with the Equisetum hyemale LINN.
In order to solubilize the sparingly soluble hydrocortisone, 16 kinds of its 21-hemiester derivative were systematically synthesized and their apparent pKa values were measured. These derivatives were all found to be soluble in water and their behavior to hydrolysis in alkaline aqueous solution was examined kinetically. All the derivatives underwent apparent first-order hydrolysis, and the effect of substituents on their stability included not only their steric effect but the position of terminal carboxyl group was found to be important. From the pH profile of the decomposition rate constant in an alkaline range, these derivatives were assumed to be decomposed by the catalytic effect of the hydroxyl ion. Effect of inoic strength and temperature on the decomposition rate constant was examined with several of the derivatives.
Eleven kinds of water-soluble hydrocortisone 21-aminoalkylcarboxylates were synthesized and their apparent pKa values were measured. Kinetic examinations were made on the behavior of these derivatives to hydrolysis reaction in an acid aqueous solution. These derivatives were found to undergo hydrolysis by the first-order reaction. At pH 3.0 and 100°, there was a correlation (r=-0.883) between the logarithm of the decomposition rate constant of these derivatives and their apparent pKa value, and it was assumed that pKa values had a more important effect on stability than their steric effect. Comparison of pH profiles of the decomposition rate constant in the range of pH 1-5 indicated two kinds of pattern according to the chemical structure of the substituents. It was assumed that these derivatives were decomposed by the catalytic effect of the hydroxyl ion in the range above pH 3. Examinations were also made on the effect of ionic strength, temperature, and buffer on the decomposition rate constant of several of these derivatives.
Hydrocortisone 21-o-sulfobenzoate (II), hydrocortisone 21-m-sulfobenzoate (III), and hydrocortisone 21-sulfate (IV) were synthesized. II is solubilized in an alkaline region, while III and IV are solubilized over a wide range of pH. Kinetic examination of the hydrolysis reaction of II and III in an aqueous solution indicated that both undergo decomposition of the first order. The pH profile of the decomposition rate constants of these derivatives showed that, in the alkaline region, decomposition reaction due to the catalyst effect of the hydroxyl ion is the most dominant. III is the most stable at around pH 3. The rate constant of IV was found to be the minimum at around pH 5-6 from the pH profile of its decomposition rate constant. Effect of ionic strength and temperature on the hydrolysis rate constants of these derivatives were examined, and pharmacological activities of 12 kinds of hydrocortisone 21-ester were compared.
Water-soluble prednisolone 21-hemisuccinate (I), prednisolone 21-hemiphthalate (II), and prednisolone 21-hemimaleate (III) were synthesized, and hydrolysis of I, II, III, and prednisolone 21-phosphate (IV) in aqueous solution was kinetically examined. Alkaline hydrolysis of I, II, and III progresses by the apparent first-order reaction, and these reactions were found to be catalyzed by a hydroxyl ion from the examination of pH profile of their decomposition rate constants. Effect of ionic strength and temperature on the hydrolysis rate constant of I, II, and III was examined. Hydrolysis of IV progresses by the apparent first-order reaction and, from the pH profile of its decomposition, IV was found to be more stable in the alkaline than in acid region. Further examinations were made on the effect of ionic strength, temperature, and buffer concentration on the hydrolysis rate constant of IV.
Binding of corticosteroid 21-ester derivatives with serum protein was examined by the equilibrium dialysis method. For serum proteins, bovine serum albumin, bovine serum α-globulin, rabbit serum, and human serum were used. Parameters for the binding of 18 kinds of derivatives with bovine serum albumin were examined under the condition of 15° and pH 7.4, and all the derivatives were found to follow the Langmuir-type binding formula. In the case of hemiester derivatives, a correlation was found to exist between the binding constant, K, and apparent pKa value, suggesting that electrostatic binding is dominant in these cases. In general, binding rate was found to be greater in carboxylic acid derivatives than in amine derivatives. Examinations were also made on the binding rate of these derivatives with bovine serum α-globulin, rabbit serum, and human serum, and the results therefrom suggested that these derivatives were chiefly bound to albumin in these sera. Effect of pH on the binding of some of the derivatives with bovine serum albumin was also examined.
The low-temperature ashing of plant tissues using high-frequency oxygen plasma, which gently removes organic matrices from the specimens preserving mineral microstructures existing in the original tissues, presents versatile applications in plant taxonomy, morphological studies, and identification of original plants. The present work has been carried out to refine the operative conditions for the ashing and the method of mounting the ashed tissues on glass slides using several specimens containing calcium oxalate and/or calcium carbonate crystals and silicon bodies. The results are summarized as follows : (1) Air preferred to pure oxygen as a plasma gas for ashing soft tissues and cross sections. (2) The ashed tissues are preliminarily impregnated by Canada balsam-xylene solution with low viscosity (25 centistokes), dried, and mounted by high viscosity solution (150 centistokes). The impregnation with organic resin highly improves light transmission through the ashed tissues resulting in clearer observations of the crystals. (3) The arrangement and shape of the crystals give a specific information on the individual species of the plants. (4) The method has revealed mineral constituents of cell membrane which was thought to be pure cellulose and at the same time various small particles probably resulting from chloroplasts, leucoplasts, nuclei etc., are found in the ashed tissues.
The structure of nornuciferine (I), an aporphine-type tertiary phenolic base isolated from the domestic lotus (Nelumbo nucifera GAERTN.) was proved to be correct by synthesis of 1-methoxy-2-hydroxyaporphine assumed as its structure. Synthesis of asimilobine (IX) was also attempted but cyclization to phenanthrene by the Pschorr reaction did not take place and only the corresponding deaminated compound (XII) and a hydrolyzed product (XIII) were obtained.
Saliva was collected from human subjects after intra-oral sterilization with tetracycline hydrochloride (Achromycin) or β-phenoxyethyldimethyldodecylammonium. bromide (Oradol) troche. Yield of Saliva-parotin-A obtained from the saliva was 0.35 g/liter after Achromycin, 0.31 g/liter for SPA, and 0.19 g/liter after Oradol. No difference was observed among three kinds of Saliva-parotin-A in their hypocalcemic, leukocytosis-promoting, and citrate-lowering activities. It does not seem likely that bacteria or their endotoxins would participate in the biological activities of Saliva-parotin-A.
Betulic acid, oleanolic acid, and ursolic acid were isolated from the leaves of Diospyros Kaki THUNB. These compounds were converted to their methyl ester acetates and identified with respective authentic samples.