The content of folic acid, as calculated from the growth rate of Streptococcus faecalis in a complete synthetic medium not containing folic acid, in unit gram of various parts of dried spinach was found to be largest in the root, followed by the mesophyll, and least in the petiole. However, folic acid was found to be contained largely in the fresh mesophyll. The acid content was also found to be larger in terrestrial portion, the content being 43.6 γ/100g. in the terrestrial, and 6.8 γ/100g. in the underground portion. Folic acid was found not to change by drying, either in the sun or at 40°. It follows, therefore, that this kind of drying would leave folic acid virtually intact and that the acid would be contained in the prepared crude drugs in the amount approximately the same as that in fresh plants. The content of folic acid was also found to be the same in Japanese spinach, irrespective of the place or season of collection, as long as the growth of the plant was about the same. The content of folic acid was found to be comparatively large in the flowers of dandelion which may offer a material for research on the tonic flower drugs. The content of folic acid in a few tonic drugs was found to be smaller than in spinach but they invariably contain folic acid or a substance which gives the same action as the acid on microörganisms.
Eight kinds of pollens collected from various domestic plants, and seven kinds of honeys originating from different domestic plants, were subjected to bioassay for the content of pantothenic and nicotinic acids. They were all found to contain these vitamins. Mean content of pantothenic acid, calculated from the growth rate of the microörganisms was 15.3 γ/g. in pollens and 1.15 γ/g. in honey, the figures being approximately the same as those described in foreign literature. Mean content of nicotinic acid was 180 γ/g. in pollens and 0.85 γ/g. in honey, the latter being more than twice the average amount in foreign honey as reported in literature.
By the application of 2 moles of aniline to benzylpenicillin, aniline salt of d-α-benzylpenicilloic acid α-anilide was obtained, which was easily converted to d-β-benzylpenicilloic acid α-anilide by boiling the first compound in methanol for 72 hours. Boiling of the benzene solution of benzylpenicillin methyl ester only gave β-methyl-d-α-benzylpenicilloic acid α-anilide, but the boiling of it in dioxane, and changing the time of boiling gave the above two α- and β-forms, as well as two kinds of compounds which was assumed to be the isomers of these compounds, although the yield of the two latter were very poor and their purification were difficult. No decisive evidence was obtained as to which of these two belonged to the γ- or δ-type.
Growth inhibitory power of 39 compounds against tubercle bacilli, in vitro, was tested. Sodium p-aminosalicylate, used as the control, was able to inhibit the growth in 160, 000 dilutions, while a better results were shown by the esters of p-aminosalicylic acid, p-tolyl ester being effective in 200, 000 dilution, o-tolyl ester in 800, 000 dilution, m-tolyl ester in 800, 000 dilution, 2-methoxyphenyl ester in 2, 560, 000 dilution. Others were all weak except vulpinic acid which effectively inhibited the growth of the bacilli in 128, 000 dilution.
1) Antifungal activity of decanoylacetaldehyde, isolated from Houttuynia cordata Thunb., was tested. Its maximum dilution was found to be 1:40, 000 against Aspergillus niger. 2) Decanoylacetaldehyde was found to have the strongest antifungal activity among the various acylacetaldehydes tested, possessing acyl group other than decanoyl. 3) In the Claisen condensation of methyl alkyl ketone and ethyl formate, methyl radical was found to have been attacked by ethyl formate when the alkyl radical possessed odd number of carbon atoms.
1) As a preliminary experiment, toxicity and analgesic effect (by the modified Haffner method) of dialkylaminoacylamino derivatives of p-phenetidine and antipyrine against mice were tested and it was found that 4-dimethylaminoacetylaminoantipyrine (V) and 4-α-dimethylaminopropionylaminoantipyrine (VII) possessed far stronger actions than the other compounds tested. 2) As a result of the determination of pain threshold in man with radiant heat apparatus, analgesic effect of (VII) was found to be stronger than that of (V) which possessed stronger effect than aminopyrine. 3) Neither (V) nor (VII) effected the lowering of body temperature in febrile rabbits and normal mice. 4) Effect on respiration and blood pressure of dogs was the weakest in (V), (VII) having weaker effect than aminopyrine. 5) Successive intravenous administration of (VII) for 5 days to rabbits failed to give any apparent effect on leucocyte counts. 6) Solubility of (V) and (VII) in water was over 30%. 7) The purpose of the preparation of the derivatives and observations of experimental results were made.
1) Boiling of 2′, 6-diaminopyrido-2, 3:4′, 5′-thiazole in diluted sodium hydroxide solution resulted in the formation of 2, 6-diamino-3-mercaptopyridine which underwent autoxidation and changed to 2, 2′, 6, 6′-tetramino-3, 3′-dipyridyl disulfide. With the intermediate 3-mercapto derivative as the material, 2′-methyl-6-aminopyrido-2, 3:4′, 5′-thiazole and methyl 2, 6-diaminopyridyl-(3) sulfone were prepared. 2) Application of dimethyl sulfate or methyl iodide to the sodium mercaptide of 2-mercapto-3-amino-6-chloropyridine resulted in the formation of structurally unknown crystals, m.p. 286°(decomp.). The 3-acetamino derivative yielded methyl 3-amino-6-chloropyridyl-(2) sulfone. 3) Application of dimethyl sulfate or methyl iodide to the sodium salt of 2-mercapto-3-amino-6-ethoxypyridine resulted in the formation of structurally unknown crystals, m.p. 203-204°, and 2-methylmercapto-3-amino-6-ethoxypyridine. Application of ethyl iodide to the free base of the above 2-mercapto derivative also yielded structurally unknown crystals, m.p. 160-161°, and 2-ethylmercapto-3-amino-6-ethoxypyridine. 4) Methyl 3-amino-6-ethoxypyridyl-(2) sulfone was prepared.
Respective application of chloroacetyl chloride, α-bromopropionyl bromide, and α-bromo-(normal and iso) valeryl bromide to α-aminophenylacetonitrile, in ether or chloroform solvent, yielded the corresponding α-(α′-haloacyl)-aminophenylacetonitriles. These were condensed with dimethylamine or diethylamine to the corresponding α-(α′-dialkylaminoacyl)-aminophenylacetonitriles. Application of β-diethylaminoethyl chloride to α-aminophenylacetonitrile in dehydrated alcohol or benzene yielded α-(β′-diethylaminoethyl)-aminophenylacetonitrile.
Of the four possible racemates of α-(3-keto-9-methyl-3, 5, 6, 7, 8, 9-hexahydronaphthyl-6)-propionic acid, three kinds with m. p. 164°, 155°, and 202°, were obtained starting from methyl α-(3-ketocyclohexyl)-propionate or diethyl (3-ketocyclohexyl)-methylmalo nate which were derived through the hydroxymethylene compound to the formyl methyl compound, condensed with acetone, cyclized, and saponified. The lower melting compounds were structurally confirmed by their dienone-phenol rearrangement and from this the difference in their structures at C11 was assumed. On the other hand, the position of the hydroxymethylene was directly confirmed by other methods.
The Ullmann condensation of o-bromophenol and 5-bromo-6-hydroxyquinoline gave diphenylene dioxide (III), 5, 6-phenylenedioxyquinoline (IV), and diquinoline 5, 6-dioxide (V). Of these products, (IV), colorless needles, m. p. 127-129°, is a new compound unknown to date in literature. The melting point of the pure diquinoline 5, 6-dioxide previously given was found to have been an error and it should be 317°.
Reactivity of carbonyl group was observed by the formation of azines. The activity of the ketone group is weaker than that of aldehyde group due to the +I effect of the alkyl radical. Although negative substituents increase the activity of the carbonyl, the effect of nuclear substituent is generally smaller than the activity increase by the catalytic action of proton, or the activity decrease due to +I effect of the alkyls and the +T effect of the phenyl group. The formation of thiosemicarbazones by the reaction of thiosemicarbazide on the azines is assumed to be anionic addition to the carbon atom of the azimethylene group but when there are strong negative substituents such as the nitro group in the azine, the nucleophilic acitivity of the carbon in azimethylene is decreased by the contribution of reversed polarity due to electron attraction of the nitro group.
Thiocyanation of azine compounds were attempted. Aldazines yielded mercapto-bitriazole derivatives by this reaction, and ketazines, ketone thiosemicarbazones. However lower aliphatic ketazines yielded both of these compounds. The mechanism of this reaction was observed through the activity center of the azimethylene group, stability and solubility of bitriazole derivatives, dissociation of azine compounds to monohydrazones, and steric hindrance during bitriazole cyclization. These mercapto-bitriazole derivatives gave negative iodine-azide reaction so that they may be bithiodiazole derivatives. However, since the derivatives are soluble in alkali hydroxides, give methylmercapto derivatives by methylation with diazomethane, and methylmercaptan was obtained by reduction of aluminum amalgam, the structure of these compounds are still believed to be that of mercapto-bitriazole.
A mixture of fatty acids of capric, palmitic, and stearic acids was obtained as the acid component of “Mogusa” wax, and hentriacontane, C31H64, was isolated as the neutral substance as well as tricosanol-(12) and arachinic alcohol. Oxidation of tricosanol-(12) yielded a ketone compound but the positition of its hydroxyl could not be clarified.
Following compounds were synthesized as the derivatives of coumarin- and 6-nitro-coumarin-3-carboxylic acid: 1) Isoamyl coumarin-, methyl 6-nitrocoumarin-, and ethyl 6-nitrocoumarin-3-carboxylates (Table I). 2) Anilide (I), anisidide (II), and phenetidide (III) of coumarin-3-carboxylic acid, and anilide (V), p-anisidide (VI), and p-phenetidide (VII) of 6-nitrocoumarin-3-carboxylic acid (Table II). 3) Aniline (IX), anisidine (X), p-phenetidine (XI), and ethyl p-aminobenzoate (XII) salts of 6-nitrocoumarin-3-carboxylic acid (Table II).
Solubility of 10 kinds of steroidal hormones in non-ionic surface-active agents, possessing polyhydroxyethylene group, was tested with the following results. 1) Solubility of testosterone propionate was approximately proportional to the concentration of surface-active agents. 2) Solubilizing efficiency of the above compound was better at a lower concentrations; 3) At a very high concentration ranges of the active agents, the solubilizing efficiency increased rapidly. 4) When compared at the same weight/volume concentration, the active agents possessing smaller number of hydroxyethylene group possessed better solubilizing efficiency. 5) In general, hormones with stronger hydrophilic properties were less soluble, although there were some exceptions. Some simple observations were made on the above characteristics.
Based on the experiments of Hazard that procaine acts as an antagonist in the bacteriostatic action of sulfanilamides and that these two substances antagonize in a definite ratio (procaine: sulfanilamide=1:6) in their actions on excised intestines and local anesthetic action, p-aminobenzenesulfonyl diethylaminoethanol, m.p. 105°, was prepared as the antagonist of procaine and its pharmacological action, especially the presence or absence of antagonism against procaine, was tested on mice. LD50 of the compound against mice is 24.2mg./10g. by subcutaneous injection, the symptoms being sedation, stoppage of voluntary motion, paralysis of hindlimbs, and respiratory paralysis. In the antagonism tests, either the absolute lethal dose of procaine, 9.0mg./10g., was subcutaneously injected into a mouse, and a definite amount of this compound administered after a lapse of definite time, or vice versa, or the mixture of both was injected after the mixture was allowed to stand for a difinite length of time, and antagonism was examined from general symptoms and mortality. When 13mg./10g. of the compound was mixed with 9.0mg./10g. of procaine, and the mixture injected after being stood for 30 minutes, all the mice remained alive, but when a mixture of 30mg./10g. of the compound and 18mg./10g. of procaine was injected 30 minutes after mixing, all the mice died although the time elapsed until death was extremely prolonged. It must be added that the compound synthesized also possessed a very weak local anesthetic action.
p-Aminobenzenesulfonyl diethylaminoethanol (I), m.p. 105°, an antagonist of procaine, was obtained by hydrolysis with hydrochloric acid of p-acetaminobenzenesulfonyl diethylaminoethanol, m.p. 77°, formed by the condensation of p-acetaminobenzenesulfonyl chloride, m.p. 149°, and diethylaminoethanol, b.p. 160-161°. (I) is extremely stable in acids and alkalis but when heated with conc. hydrochloric acid in a sealed tube for 1 hour at 140°, it decomposes into the two components, sulfanilic acid and diethylaminoethyl chloride hydrochloride, m.p. 202-204°. (I) cannot be obtained when diethylamine and p-acetaminobenzenesulfonyl chloroethanol, m.p. 138°, are heated in a sealed tube for 10 minutes at 130°, only giving the sulfanilate, m.p. 187-188°, of 3-diethylaminoethyl chloride, assumed to have been formed by the intramolecular rearrangement followed by decomposition of p-acetaminobenzenesulfonyl diethylaminoethanol hydrochloride.
Both acacetin (I) and its 7-methyl ether (II) formed resinous products by chloromethylation with formaldehyde and hydrochloric acid, but (II) gave crystalline chloromethyl compounds by the mild action of chloromethyl ether (III). When a mixture of the chloroform solution of (II), (III), and glacial acetic acid was warmed for 5 hours at 30-35°, and allowed to stand overnight, evaporation of the solvent under a reduced pressure, and recrystallization from acetone gave chloromethyl compounds, one sparingly soluble, m.p. 218° (decomp.), and the other easily soluble, m.p. 188° (decomp.). Both gave greenish violet-brown coloration with iron. Both series of compounds were consecutively cyanated, methylated, and saponified. Catalytic reduction in the presence of palladium-carbon gave nuclear-substituted methyl compounds of m.p. 226° and of m.p. 175°.
In order to determine the position of CH2Cl group in the chloromethyl compound (I), 8-methylacacetin-7-methyl ether (II), m.p. 226°, was prepared and this was found to be identical with the reduction product, m.p. 226°, of (I). This has shown that the position of the CH2Cl group in this compound (I) is at 8. (II) was obtained from 3-methyl-2-hydroxy-4, 6-dimethoxyacetophenone anisoate which was derived to a diketone compound with sodium amide, cyclized with sulfuric acid to 8-methylacacetin-5, 7-dimethyl ether, and finaly demethylated with aluminum chloride.
Titration of weak acids, chiefly carboxylic acids, was carried out with approximately 0.1N sodium methoxide with benzene-methanol mixture as the solvent. The titration curve was not necessarily in parallel with the acidity of the aqueous solution but titrations were correct in all except extremely weak acids such as phenol and glycine. Boric acid was titrated correctly by the addition of a few drops of ethylene glycol. Dibasic carboxylic acids in which the carbon atoms between carboxyls was one or two, and in cis-position (succinic, malonic acids, etc.), showed very characteistic titration curves. These curves showed the correct first and second equivalence points from which it was made possible to determine separately a mixture of this and other kind of acids, e.g. malonic and acetic acids. Carboxylic acid anhydrides were also determined as dibasic acids.
It had previously been found that benzaldehyde dimethyl acetal could be catalytically reduced, with palladium and barium sulfate as a catalyst, to toluene. In the present series of experiments, aromatic aldehyde acetals, (II) to (XII), in which benzene is directly bonded to the aldehyde acetal group, were reduced to the corresponding hydrocarbons by the absorption of two moles of hydrogen by the same precess, but aliphatic acetals, keto acetals, and aldehyde acetates, (XIII) to (XVIII), did not undergo such reduction. From the absorption time (volume of hydrogen absorbed/period required for absorption), it may be said that the reaction time of compounds (I) to (V) decreases with the increase of the number of carbon atoms in the acetal group and that the nature of the aromatic ring combined directly with the acetal group has some effect on the reaction. For example, naphthalene and tetralene rings tend to slow the reaction compared to the benzene ring, and the presence of chlorine, methoxyl, or methylenedioxy group in the benzene ring increases the absorption time.
The racemic compound of magnocurarine (IV), an alkaloid of Magnolia obovata Thunb. (Magnoliaceae), was prepared from dl-coclaurine (I), an alkaloid of Cocculus laurifolius DC. (Menispermaceae). Although l-magnocurarine itself had been isolated as crystals from a natural substance, the racemic compound colored during treatment and could not be obtained in a crystalline form. The picrate of the racemic base, however, was obtained as pale yellow needles, m.p. 174°, whose analytical values corresponded to C19H24O3N⋅C6H2O7N3⋅H2O of magnocurarine picrate.
Eleven kinds of 2-[2′-methyl-4′-aminopyrimidyl-(5′)]-methyl-formamino-5-hydroxy-Δ2-pentenyl-(3) alkyl disulfide (thiamine alkyl disulfide) (I) were prepared by the reaction of the aqueous solution of the sodium salt (III) of thiol form of thiamine and sodium alkyl thiosulfate (II) (Bunte's salt). When the alkyl was methyl, ethyl, propyl, or allyl, the reaction mixture was saturated with sodium chloride. This reaction occurred with ease at room temperature and the yields were generally 80-95%. Use of homothiamine instead of thiamine yielded five kinds of 2-[2′-ethyl-4′-aminopyrimidyl-(5′)]-methylformamino-5-hydroxy-Δ2-pentenyl-(3) alkyl disulfide (homothiamine alkyl disulfides). (I) can also be obtained by the reaction of alkyl mercaptan and oxidizing agent to (III) or by the reaction of (III) and alkyl thiocyanate, or by the application of two moles of hydrogen peroxide to the glacial acetic acid solution of dialkyl disulfide, and reacting thiamine to this solution at pH 8.
Attempt was made to obtain homogeneous vitamin B1 tablets by the improvement of manufacturing processes from finding the cause of variations in content of vitamin B1. As a result it was experimentally confirmed that the following equation is established σr2=σw2+σc2+σm2+2ρ⋅σw⋅σc when σr, σω, σc and σw respectively stand for the observed value, weight, content per unit weight, and standard deviation of determined value, and ρ, the coefficient of interdependence. From these findings, improvements were made on the mixing and granulation processes. Examinations were also made on the thiochrome process for determination of vitamin B1, conditions for direct absorption determination, and interdependence.
The diphenyl ether derivatives possessing α-ketonic acid group in the ortho position of ethereal oxygen linkage easily undergoes change to xanthones by the action of alkaline hydrogen peroxide and this was confirmed with 4, 4′-dimethyldiphenyl ether-2-glyoxylic acid. Reaction of 4, 4′-dimethyldiphenyl ether and acetyl chloride was reëxamined and the errors appearing in earlier literature were corrected. Methyl 2-phenoxy-4, 5-dimethoxybenzoate, m.p. 114-115°, was prepared and the application of methyloxalyl chloride or acetyl chloride to this compound in nitrobenzene, in the presence of aluminum chloride, was found to give quantitatively, in either case, 2, 3-dimethoxyxanthone, m.p. 164°.
Friedel-Crafts reaction of 2-methoxydiphenyl ether and 2-methoxy-4′-methyldiphenyl ether with acetyl chloride was carried out from which it was found that the acetyl group preferentially attacked the para position of the methoxyl group in both compounds. In the reaction of 2, 3-dimethoxy-4′-methyldiphenyl ether and acetyl chloride, structurally unkown crystals of m.p. 183° were obtained besides 2-methoxy-3-hydroxy-4-acetyl-4′-methyldiphenyl ether, m.p. 107-109°. The crystals were not identical with those of either 2, 3-dimethoxy-5-acetyl-or 2, 3-dimethoxy-6-acetyl-4′-methyldiphenyl ether prepared separately.
Action of 2-thiocoumarin against ascaris was examined with nerve muscle and muscle preparation of ascaris, and by the forward movement of ascaris, and following results were obtained: 1) After application of the compound to nerve muscle preparation of ascaris, increase in bending motion and tonus was observed (samples I and V), or the appearance of bending or curling motion (samples II and IIIA). 2) In muscle preparation (samples IIIB and IV), no change was observed after application of the chemical. 3) The forward motion of ascaris being observed in U-shaped glass tube disappeared shortly after application of the chemical, and the ascaris simply moved its fore portion, or curled itself. The curling motion was most prominent in 1, 000 dilution of the chemical. From the foregoing results, 2-thiocoumarin was assumed to stimulate the nerve system (including the nerve centers in the head region) of ascaris.
Action of 4-methylcoumarin, coumarin-3-carboxylic acid diethylamide, and sodium barbital against ascaris was observed with muscle nerve, muscle preparation, and the forward motion of ascaris in a glass tube, and following conclusions were drawn: 1) 4-Methylcoumarin gave a transitory stimulation, and then strong papalysis in samples. The stimulation is assumed to chiefly affect the nerve system, and the paralytic action chiefly the muscles. In higher concentration, striking paralytic action was seen to effect the forward motion of ascaris. 2) Coumarin-3-carboxylic acid diethylamide showed only a very weak paralytic action in samples and the locus of action seems to be chiefly in muscles. Practically no effect was seen in the forward motion of ascaris. 3) Sodium barbital showed a medium paralytic action in samples, which seems to be chiefly musculotropic.
Sandmeyer reaction of 2-amino-6-methoxy (or ethoxy)-benzothiazole (I) gave the 2-chloro derivative (II) which was condensed with dimethylamine to (III) and dealkylated to 2-dimethylamino-6-hydroxybenzothiazole (IV). The accompanying table shows the comparison of the melting points of the objective compound and the intermediates obtained during the course of the present syntheses with those described in existing literature.
3-Aminoflavanone (III) resists dehydrogenation by palladium black with dil. sodium hydroxide, dil. sulfuric acid, or cinnamic acid, or by chloranil. Flavonol (IV) was obtained in a poor yield by warming (III) with dil. sulfuric acid for 30 hours at 100°. Generally, 3-hydroxyflavanones are easily dehydrogenated at 2- and 3-positions by the above-mentioned reagents and form corresponding 3-hydroxyflavones (flavonols) but com-pared to it, 3-aminoflavanone shows an extreme resistance.
Condensation of glycine benzyl ester hydrochloride (I) and p-nitrobenzoyl chloride in benzene yielded p-nitrobenzoylglycine benzyl ester (II) which was catalytically reduced to the objective p-aminohippuric acid (III). The same condensation of glycine benzyl ester with p-nitrobenzoyl chloride gave benzyl p-nitrobenzoate (V). In a similar manner, glycine ethyl ester, either as the free ester or as a hydrochloride, yielded p-nitrobenzoyl-glycine ethyl ester.
From the seeds of Digitalis purpurea L., a new substance of m.p. 205° (uncorr.) was obtained. This substance gave positive Legal and Keller-Kiliani reactions, and its analytical values corresponded to C32H48O9, with one methoxyl group. This substance is pharmacologically inactive and its properties are very similar to the substance isolated from the seeds of Digitalis lanata Ehrh. by Reichstein and others.
7-Hydroxy-3-methylphthalide, an alkaline degradation product of terramycin, was synthesized. Its identity was proved, indirectly, because of being unable to compare it directly with the phthalide derived from natural terramycin, by preparing its derivatives and comparing their physical and chemical properties with those of the known compounds.