Hygroscopic nature of non-volatile, water-soluble crystalline substances can be com-pared in general by their critical relative humidity, which corresponds to the specific vapor pressure of saturated solution of that substance. The specific vapor pressure of saturated solution of mixture was calculated by hypothetical formula (3) or (5), from the coefficient calculated from molar concentration and specific vapor pressure of saturated solution of the component and from the saturation concentration of each solute in saturated solution of mixture. It was thereby found that the values agreed tolerably well with measured values. This has also proved that the hypothesis laid down by Elder that the “critical relative humidity of a mixture of several soluble solids is equal to the product of the critical relative humidity of several components” applies when the concentration of each solute in water does not differ greatly between saturated solution of a single substance and of a mixture.
The method of determining the critical relative humidity of a water-soluble crystalline substance includes that of calculating from the humidity equilibrium curve of its dry powder and that of calculating from the vapor pressure of its saturated aqueous solution. The values obtained by these two methods usually agree. In some cases, the values do not agree and experiments were conducted with samples in the following cases as giving disagreeing results: (1) When the substance takes water of crystallization; (2) when the substance contains an impurity; (3) when the substance undergoes change during determination; and (4) when such is the specific property of the substance. It was thereby considered that the dry powder method is suited for measuring the critical relative humidity of the substance itself, while the saturated solution method is suitable for finding a theoretical critical relative humidity of the substance in general.
Attempt was made to synthesize 11β-hydroxyprogesterone (Va) from 11α-hydroxyprogesterone (Ia) by the route indicated in Chart 1. The intermediate, 9α-bromo-11β-hydroxyprogesterone (IVa), was debrominated by copper-plated zinc and ethanol, palladium-carbon, or Raney nickel, but the objective (Va) was not obtained. Reduction of (IVa) with copper-plated zinc and ethanol afforded (IIIa) and a small amount of (Va), while that with palladium-carbon gave (VI). It is rather interesting that the Raney nickel treatment of (IVa) resulted in the formation of 11-oxoprogesterone (VII).
2-Methyl-3-alkylpyridines (I) were synthesized from allyl alcohol, methyl alkyl ketone, and ammonia at 375-400°, using a catalyst of cadmium phosphate and activated Fuller's earth. The alkyls in (I) were propyl, isopropyl, butyl, sec-butyl, isobutyl, and isopentyl. (I) was also synthesized from ethyl 2-alkyl-3-aminocrotonate (III) and diethyl malonate through several steps. The reaction hardly progressed by either routes when the alkyl was isopropyl or sec-butyl, giving the objective compounds in a very low yield.
Phenylpyridines were synthesized in good yield by the catalytic vapor-phase reaction of allyl alcohol, aromatic ketones, and ammonia. 2-Phenylpyridine (I) was obtained from allyl alcohol, acetophenone, and ammonia, 2-phenyl-3-methylpyridine (II) from allyl alcohol, propiophenone, and ammonia, and 2-methyl-3-phenylpyridine (III) and a small amount of 2-benzylpyridine (IV) from allyl alcohol, 1-phenyl-2-propanone, and ammonia. Of these, (II) and (III) are new compounds. Ultraviolet absorption spectra of phenyl- and methylphenylpyridines were measured and the effect of the position of phenyl and methyl groups in the pyridine ring was examined.
Trypsin digestive rate was examined with milk coagulated by enzymes, rennin and pepsin, and by acids, hydrochloric and lactic acids. The digestive rate with trypsin was greater in enzyme-coagulated milk than the acid-coagulated, while no difference was found in the digestive rate with milk coagulated by rennin or pepsin, and between that by hydrochloric or lactic acid. Trypsin digestive rate of rennin-coagulated milk was low by the addition of metallic ions, such as calcium, magnesium, and manganese, that accelerates milk coagulation, but high when added with metallic ions like cobalt and nickel that suppress coagulation of milk by rennin. The reason for such a phenomenon is now under examination.
It was found that the hydrogenation of 2, 3-dimethyl-5, 6-dihydropyrazine to form 2, 3-dimethylpiperazine resulted in the selective formation of only one of cis- or trans- isomers according to the kind of the reduction agent used. Reduction with sodium and ethanol only afforded the trans compound, while that with lithium aluminum hydride gave the cis compound alone. Catalytic reduction with Raney nickel, platinum oxide, or palladium-carbon chiefly afforded the cis compound, with a minute amount of the trans compound. Both cis and trans compounds, and their derivatives agree with Auwers-Skita's law.
Reëxamination was made on the fact that the reaction of aromatic ethers and diazonium salts sometimes affords azo compounds in which a part or whole of the alkyl or aryl groups had been lost. It would seem more understandable to consider the formation of a quinonoid adduct as an intermediate in this reaction since the ease or difficulty of the formation of azo compounds of phenol, naphthol, and 9-an-throl systems is parallel to the stability of these quinones. Diphenyl ether, hydroquinone dimethyl ether, and methyl phenyl ether, and catechol methyl phenyl ether, and sterically hindered laudanosine and 1-(3, 5-dimethoxybenzyl)-2-methyl-6, 7-dime-thoxy-1, 2, 3, 4-tetrahydroisoquinoline do not form azo compounds. It was found that the dealkylation and dearylation in these series of reactions was dependent in part on the pH of the reaction system, and the ratio became larger as the acidity decreased.
It was observed that tannin and allied substances inhibited the decarboxylation of basic amino acids by Escherichia coli. The inhibition by tannin is comparatively weak and this is probably due to the permeability of cell membrane. Phenolcar-boxylic acids have stronger inhibitory action than polyphenols lacking carboxyl group and this activity of the former is decreased by esterification. This shows that the presence or absence of a carboxyl group has a great effect on the degree of inhibition. This inhibition is not antagonistic to coenzymes, is not recovered by cysteine, and is not competitive with the substrate.
Thirty-six kinds of 2-alkylbenzimidazole derivatives, including 14 new compounds, were prepared and they were submitted to screening test of their antitumor effect using solid tumors obtained by the subcutaneous injection of Ehrlich ascites sarcoma in the inguinal region of a mouse. It was found that 2-propylbenzimidazole was effective and that this effect could be increased by the introduction of a nitro group in its 6-position.
Viscosity of non-saturated and supersaturated solution of diphenylhydantoin sodium was measured and plotting of its log η-1/T on a graph gave two straight lines that crossed at the temperature of saturation. The slope of the straight line for supersaturated solution is larger than that of non-saturated solution and activation energy also increases with supersaturation. The density-temperature curves of non-saturated and supersaturated solutions also showed a discontinuity at the point of saturation temperature.
Reduction of 4-nitropyridine 1-oxide and 4-nitro-2-picoline 1-oxide with hydrazine hydrate in the presence of copper powder was examined. When 4-nitropyridine 1-oxide is heated with hydrazine hydrate in ethanol, in the presence of copper powder, it is reduced to 4, 4′-azoxypyridine 1, 1′-dioxide and to 4-aminopyridine 1-oxide by longer heating. If heated in diethylene glycol at a higher temperature of 180-200°, it forms 4-aminopyridine. It was assumed that this deoxygenation chiefly concerns the pyrolysis of 4-aminopyridine 1-oxide by copper catalyst. Under similar conditions, 4-nitro-2-picoline 1-oxide was reduced to 4, 4′-azo (2-picoline) 1-oxide, 4-amino-2-picoline 1-oxide and to 4-amino-2-picoline.
Dihydroxyaluminum aminoacetate (DAA) possesses the action of insolubilizing inorganic phosphate in vitro by precipitating it as AIPO4. Since it is nontoxic, it can be mixed with animal diet by which it will insolubilize phosphoric acid in the diet suppress absorption of this acid through the digestive tract, and give the effect of experimental diet containing a small amount of phosphorus component. After two days of pretreatment period, mice were fasted for 5 hours and injected subcutaneously with 0.1 μc of 90Sr (+90Y) as an aqueous solution (0.1cc.). All the animals in the control and treated groups were respectively fed with 500mg. of normal diet and that added with 30mg. of DAA, three times during the 24-hour period after injection of 90Sr. All animals were then sacrificed, excreta and carcass were ashed, and the ash, dissolved in dil. nitric acid, was measured for radioactivity. It was thereby found that the radiostrontium remaining in the body after 24 hours was 49% and that in the excreta 48% in the animals given a diet containing DAA, while these were 70% and 28% in those in the control group. Stimulative effect of DAA in excretion of 90Sr was thereby found to be of the similar magnitude of order of other chemical agents tested. The nontoxicity of DAA and simplicity of its use suggest its practical usefulness as a protection of men and animals from the effect of radiostrontium.
A series of experiments were carried out to test several chemicals that might interfere in the absorption of 90 Sr from the intestinal tract. In an in vitro experiment using isolated small intestine of male rats, with apparatus shown in Fig. 1, both magnesium and sodium sulfate were found to be ineffective, although MacDonald reported that these salts were effective in stopping absorption of non-radioactive strontium. Sodium phytate was very effective in a similar in vitro experiment. The inability of these inorganic salts to prevent absorption of radiostrontium may have been due to the low concentration of the strontium used and non-laxative action of the isolated intestines. Similar results were also obtained for these salts in experiments with intact mice, although the absolute activity of sodium phytate was smaller than that in in vitro experiment. This was probably due to the biological decomposition of the phytate and interference of the reaction between the phytate and radiostrontium by intestinal content.
Condensation of 1-bromo-2-hexene and ethyl 3-formylpropionate by the Reformatsky reaction afforded ethyl 4-hydroxy-trans-6-decenoate, whose methyl ester was reacted with N-isobutylamine to form the amide. Its dehydration and column chromatography through alumina layer to remove trans-4, trans-6-decadienamide, with ultraviolet absorption maxima of 225 and 270mμ (petr. ether, b.p. 60°) as the criteria, afforded the objective. The infrared absorption spectrum of this amide was similar to that of natural spilanthol from Spilanthes oleracea JACQ., but there were some shifts and the synthesized amide had only weak acid taste and paralytic action.
In order to confirm the theory of Crombie regarding the relationship between steric structure of conjugated double bonds and infrared absorption spectra, N-isobuty-4-ethyl-2, 4-octadienamide was prepared by the condensation of 2-ethyl-2-hexenal and ethyl bromoacetate by the Reformatsky reaction and reaction of the ester so obtained with isobutylamine. This amide formed an adduct of m.p. 164° with maleic anhydride and exhibited only one band at 968cm-1 in 950-1000cm-1 region of its infrared absorption spectrum, confirming Crombie's theory.
Examinations were made on the effect of phenyl thiolbenzoate (Fig. 1), thiophenol ester of fatty acids (Fig. 2 and Table I), and thiophenol ester of aromatic and heterocyclic carboxylic acids (Table II) on the mycelium and spores of Aspergillus niger. It was found that the intensity of the effect of phenyl thiolacetates against mycelia and spores (Fig. 3) by the introduction of methyl or bromine in the para-position of thiophenol ring was in the order of bromine >hydrogen >methyl, in parallel with their acyl migration reactivity (Fig. 4) under organic chemical experimental conditions. It was observed that the antispore effect of phenyl thiolacetate tended to become stronger by the addition of pyridine (cf. Fig. 5).
A process for synthesizing 2, 3-cycloalkenopyridine by catalytic vapor-phase reaction from allyl alcohol, alicyclic ketone, and ammonia was found. The use of cyclopentanone, cyclohexanone, and cycloheptanone as the alicyclic ketones gives the corresponding cyclopenteno- (II), cyclohexeno- (I), and cyclohepteno-pyridines (III) in a good yield. As by-products of this reaction, 3-picoline and a minute amount of 3, 5-lutidine are formed, while quinoline (IV) is formed in a small amount in the case of (I). Since quinoline can be obtained by dehydrogenation of 2, 3-cyclohexeno-pyridine (I), the effect of activity of various catalysts and their concentration, reaction temperature, molar ratio of starting materials, and flow rate on the yield were examined from the point of industrial manufacture.
Starting with 10-thiaxanthenyl-cyanoacetic acid (IV), obtained by the condensation of 10-thiaxanthenol (I) with malonic acid or cyanoacetic acid, 10-thiaxanthenylacetic acid (III) was prepared via 10-thiaxanthenylacetonitrile (V). Several alkamine esters of (III) and (IV) were prepared and toxicity, anticholinergic, antihistaminic, and antibarium chloride activity of the hydrochlorides of these esters were comparatively examined. The anticholinergic activity of these compounds seemed to be weaker than that of corresponding 9-xanthenylacetic acid derivatives.
Mutual solubility of hexylamine-water system was measured at temperatures between 0° and 70° and characteristic solubility curves were obtained. The solubility curve of an amine layer has a maximum point at the amine concentration of approximately 10% and a temperature of 22.5°, and a minimum point at the amine concentration of approximately 30% and a temperature of 18.7°. When 10-60% aqueous solution of hexylamine is cooled to below 10°, it forms an optically anisotropic jelly-like solid. Solid-liquid equilibrium of this state was examined, its transition and melting curves were obtained, and the presence of a hexylamine hexahydrate was assumed from the shape of these curves.
Reëxamination of acylation of thiosemicarbazide in acetone showed that 1-isopro-pylidene-2-acylthiosemicarbazide (II) forms as an intermediate, which undergoes hydrolysis and rearrangement of acyl group by the action of hydrochloric acid, formed as a by-product during heating in the final step, to produce 1-acylthiosemicarbazide (I). Therefore, presence of a dehydrochlorination agent, such as sodium carbonate, may stop the reaction at the stage of (II), while its absence will afford (I). Benzoylation and phenylacetylation of thiosemicarbazide by the Schotten-Baumann reaction showed that the amount fo sodium hydroxide affected formation of the reaction product. In the benzoylation, yield of 1-benzoylthiosemicarbazide was poor when the molar ratio of thiosemicarbazide to sodium hydroxide was 1:1, affording several kinds of a by-product, while the amount of by-products decreased when the molar ratio became 1:2, and the yield of the 1-acyl compound became 61%. However, these conditions failed to suppress side reactions in the case of phenylacetylation.
1) Benzoylation of 4-phenylthiosemicarbazide (I) in acetone invariably afforded 1-isopropylidene-2-benzoyl-4-phenylthiosemicarbazide (IV) in the presence of sodium hydrogen carbonate, and (IV) and a small amount of 1-benzoyl compound of (I) in the absence of the alkali. Benzoylation of 1-phenylthiosemicarbazide (VI) in acetone and in chloroform afforded 1-benzoyl compound (VII) in a good yield. 2) Benzoylation of 1, 4-diphenylthiosemicarbazide (VIII) in benzene afforded 2-anilino-4, 5-diphenyl-5-chloro-1, 3, 4-thiadiazole (XI) and 1-benzoyl compound (X) of (VIII). Both (X) and (IX) forms the cyclization product (XI) of (X) by the action of alkali that the benzoylation of (VIII) in alkaline solvent was found to give (XI) and (X) could not be isolated. The substance of m.p. 161°, isolated during the acetylation of 2, 4-diphenylthiosemicarbazide (XII) in acetone was determined as 1-isopropylidene-2, 4-diphenylthiosemicarbazide. 3) 1, 2, 3-Triphenyl-Δ3-1, 2, 4-triazoline-5-thione (XIII) was obtained by the reaction of hydrazobenzene and benzoyl isothiocyanate and its desulfurization afforded the corresponding triazolone (XIV).
From the whole herb of Euphorbia maculata L. (Euphorbiaceae), besides β-sitosterol, a new alcohol of m.p. 197-198°, [α]D10 +32.18°, C30H50O, giving crimson coloration by the Liebermann-Burchard reaction, was obtained and was designated as maculatol. It formed an acetate of m.p. 223-223.5°, [α]10D +27.7°, and a benzoate of m.p. 227-228°, [α]D12 +25.5°.
Taraxerol and taraxerone were isolated and identified from the whole herb of Euphorbia pilurifera L., and it was considered that taraxerol might be identical with euphosterol isolated from this plant by Power and others.
It was found that tannin and allied substances inhibited the decarboxylation of lysine and arginine by acetone-dried cells of Escherichia coli. The inhibition by gallotannin is far more marked in acetone-dried than intact cells and this seems to confirm the fact that the apparent weak inhibition is due to the difficulty of penetrating the cell membrane. Other substances had the same tendency to inhibit with acetonedried as with intact cells. This inhibition was not recovered by pyridoxal.
Quercetin, m.p. 315°(decomp.), was isolated and identified from the leaves of Pirola japonica SIEB., as well as β-sitosterol of m.p. 137°, [α]D9 -38°, and ursolic acid of m.p. 286-288°, [α]D10 +72°. The sterol and the acid were identified by mixed fusion with authentic specimens of acetate and benzoate of β-sitosterol, and acetate, methyl ester, and methyl ester acetate of ursolic acid. Oleanolic acid was also isolated in a minute amount and identified by mixed fusion of the free acid and the acetate with authentic specimens. Further, a substance of m.p. 67-69°, assumed to be hentriacon tane, and of m.p. 146-147°, [α]D22+5.2°, assumed to be α3-sitosterol, were also isolated. The acetate and benzoate of the latter approximately agree with corresponding derivatives of α3-sitosterol.
Taraxerol, m.p. 269-271°, [α]D22+12.7°(CHCl3), and β-sitosterol, m.p. 138-139°, [α]D15 -39°(CHCl3), were isolated from the rhizome of Pirola incarnata FISCH., and were identified by comparison with authentic specimens of their acetates and benzoates. p-Methoxycinnamic acid, m.p. 171-172°, was also isolated and identified. Another component, 2, 7-dimethylnaphthoquinone, m.p. 112.5-113.5°, also isolated was proved to be chimaphilin, widely distributed in Pirolaceous plants. The presence of a minute amount of homoarbutin was also observed.
1-Acyl-2, 5-dithiobiureas were prepared by the acylation of 2, 5-dithiobiurea (I) by the Schotten-Baumann reaction and by the reaction of thiosemicarbazide and acyl isothiocyanate. These acyl compounds were reacted with sodium hydroxide solution and 3-aryl(alkyl)-1H-1, 2, 4-triazole-5-thiol, (I), and the corresponding carboxylic acid were obtained. By the reaction of 1-acyl-2, 5-dithiobiureas with conc. sulfuric acid, 2-acylamido-5-amino-1, 3, 4-thiadiazole and 2-acylamido-1, 3, 4-thiadiazole-5-thiol were obtained, and the reaction of 1-acyl-2, 5-dithiobiureas and acetic anhydride afforded 2-acylamido-5-acetamido-1, 3, 4-thiadiazole.
Sixteen kinds of compounds including 2-(2, 4-dihydroxy-6-methylbenzylidenehydr-azono)-4-thiazolidone and 2-(2, 4-dihydroxy-3, 6-dimethylbenzylidenehydrazono)-4-thiaz-olidone were synthesized by reacting thiosemicarbazones with ethyl chloroacetate and sodium acetate in ethanol. A total of 27 kinds of compounds including these and other known compounds were submitted to antibacterial tests against human type tubercle bacilli H37Rv and following conclusions were drawn: 1) As the ring bonded to the =N-N=CH- in 2-position of 2-arylidenehydrazono-4-thiazolidone, benzene has the strongest antibacterial activity, as was stated by Taniyama and others, and the presence of one hydroxyl in the ortho-position of such benzene ring showed the strongest activity. 2) Alkoxycarbonyl group increased antibacterial action. 3) Introduction of a chlorine generally tended to increase the antibacterial action. In 2-(2, 4-dihydroxy-5-alkylbenzylidenehydrazono)-4-thiazolidones, the antibacterial activity was in inverse proportion to the length of the alkyl chain.
A mixture of aminopyrine and barbital, in a molar ratio of 1:1, and their molecular compound were administered to rabbits and blood level and action of both components were comparatively examined. It was thereby found that the administration of the mixture and molecular compound effected lowering of initial blood level and decrease of toxicity in aminopyrine, and lowering of initial blood level, rise of final blood level, and prolongation of anesthetic action in barbital, as compared to the administration of each drug alone. No significant difference was observed in the blood level and physiological action between the said mixture and molecular compound.