Antibacterial action of biphenyl ether derivatives and their allied substances was tested in vitro against Mycobacterium tuberculosis, Staphylococcus aureus, and Escherichia coli. The results are shown in Tables I to VIII from which it can be seen that none of the compounds tested showed any high degree of antibacterial power.
As a method for testing analgesics, apparatus for generating intermittent electric stimulation, using thyratron vacuum tube, was applied. Such electric stimulation was passed through the tail of a mouse, its resultant squeak was taken as the sign, and the efficacy of the analgesic was determined by the increase or decrease of the pain threshold. The stimulation was found to be the best when given once per second, lasting 1/25th second per stimulation and at 26 V. Efficacy of antipyretic analgesics was determined by this method from which salicylic N-dimethylamide was found to be the best. On the other hand, the molecular compound of pentobarbital and aminopyrine was found to give too much toxicity at an effective dose, and was inferior than pyrabital. This apparatus was confirmed to be well adapted for the determination of efficacy in analgesics of weak activity.
Various dialkyl disulfides were oxidized with hydrogen peroxide in glacial acetic acid, and the alkyl alkylthiosulfinates thereby formed was applied to thiamine at pH 8 from which 2-[2′-methyl-4′-aminopyrimidyl-(5′)]-methylformamino-5-hydroxy-Δ2-pentenyl-(3) alkyl disulfides (thiamine alkyl disulfides) were obtained. The alkyls used were methyl, ethyl, propyl, isopropyl, butyl, isobutyl, isoamyl, and benzyl. As a result of test in preventing thiamine deficiency in Uroloncha domestica, these compounds were found to possess efficacy almost equal to that of thiamine.
Schiff bases were obtained by the condensation of piperonal to 2-allylmercapto-6-aminobenzothiazole (I) and 2-chloro-6-aminobenzothiazole (II). Corresponding azo dyestuffs were prepared by the respective coupling of phenol, resorcinol, or hydroquinone to the diazonium salt of (I). Application of acyl chlorides to (I) and (II) respectively furnished 6-propionyl-(butyryl-, isovaleryl-, isocaproyl)-amino derivatives. Application of succinic anhydride and maleic anhydride to (I) and (II) furnished the corresponding benzothiazolyl-(6)-amide acids.
Twenty-one kinds of new aminovinyl compounds were prepared by the condensation of the quaternary salts of 2, 6-lutidine to 5, 5′-dichloro (dibromo-, diiodo)-2, 2′-dipyridylformamidines and 3, 3′, 5, 5′-tetrabromo-2, 2′-dipyridylformamidine by the fusion method. These compounds are said to decrease the flowing velocity of leucocytes and to show antitumorous action.
The fourth method of synthesizing p-aminobenzene sulfone N1-3, 4-dimethylbenzoylamide consists in treating 3, 4-dimethylbenzamidine with sulfanilamide by which the N1-amino group reacts preferentially giving p-aminobenzene sulfone N1-3, 4-dimethylbenzamidine, which is finally hydrolyzed to the objective compound.
Reactions whereby neocyanine and kryptocyanine type dyes are formed by the application of ethyl orthoformate to cycloammonium salts (ethiodides of lepidine, quinaldine, 2-methylnaphthothiazole, and 2-methylbenzothiazole) possessing active methyl group, in various solvents, were carried out. Various factors that affect this reaction, such as the reaction temperature and ratio of reactants, were examined. Formation mechanism of the two dyes was proposed and the intermediates formed in these reactions were assumed. From the results of analytical values of carbon of the neocyanine iodide, bromide, and chloride formed, and by the consideration of reaction mechanism, it was concluded that, of the three structures proposed for neocyanine, that of Brooker or of König was the correct one.
By reacting triphenylguanidine and quinaldine ethiodide in acetic anhydride, with cadmium carbonate as the addition agent, a new dye was obtained which showed a maximum absorption at 6500Å and whose analytical values of halogen and carbon corresponded to neocyanine (Hamer type). At the same time, white crystalline substance of m. p. 167-168° (decomp.) was obtained and its treatment with conc. ammonia resulted in its transition to the above-mentioned dye from which it was assumed that the crystalline substance is an intermediate of the Hamer-type neocyanine.
By the application of one of α-triphenylguanidine, carbon tetrachloride, or chloroform to lepidine ethiodide in acetic anhydride, in the presence of cadmium carbonate, a dye whose composition and absorption maximum corresponded with 1, 1′, 1″-triethyl-4, 4′-trimethine-10-lepidylquinocyanine diiodide and its intermediate, were obtained. Heating of these two substances with ammoniac water resulted in the transition to a dye whose composition corresponded to 1, 1′, 1″-triethyl-4, 4′-trimethine-10-lepidenylquinolinium iodide. Since the absorption maxima of the two dyes do not differ, the initially obtained dye was assumed to be the so-called Hamer-type neocyanine, or a compound with one mole of hydrogen iodide bonded to the latter dye. Although no final confirmation were obtained, the latter assumption seemed to be the most likely.
By the reaction of the anilide of thiocarbonyl tetrachloride and quinaldine ethiodide, a new dye, 1, 1′, 1″-triethyl-2, 2′-trimethine-10-anilinoquinolinium iodide was prepared. Application of another mole of quinaldine ethiodide to the latter gave 1, 1′, 1″-triethyl-2, 2′-trimethine-10-quinaldenyl-cyanine iodide, and application of lepidine or 2-methyl-benzothiazole ethiodide gave pinacyanol, with heterocyclic ammonium salt in the 10-position, i.e. a new trimethine dye with three different nuclei.
Some kryptocyanines and benzothiocarbocyanines with anilino group in the meso (10-position) were prepared by reacting lepidine or 2-methylbenzothiazole ethiodide with the anilide of thiocarbonyl tetrachloride. Further application of another mole of quinaldine ethiodide to these dyes gave unsymmetrical trimethine trinucleic dyes.
3, 4-Dimethoxy- (m.p. 99-100°) and 2-methoxy-diphenyl ether-4′-acetic acid (m.p. 108-110°) were prepared by the Willgerodt reaction, and these compounds were used in some attempted Friedel-Crafts reaction.
Casein, ovalbumine, edestin, γ-globulin, and gelatin were decomposed with pepsin or trypsin and the kinds of amino acids liberated during the process and the degree of liberation, were examined by two-dimensional paper chromatography. The results, as shown in Table III, confirmed the fact that the amino acids liberated by pepsin or trypsin were not limited to few kinds but were of large variety and that the liberation of acidic amino acids, i.e. aspartic and glutamic acids, was higher in the case of pepsin than with trypsin. These were found of interest in connection with the specificity and cosubstrate effect of enzymic activity in the hydrolysis of proteins.
The casein hydrolysate of pepsin was divided into the following fractions: Fraction I, neutral and basic portions not adsorbed by Amberlite IR-4B; Fraction II, acid portion adsorbed by Amberlite IR-4B and eluted by N acetic acid; and Fraction I′, separated from Fraction I as the strongly basic portion not adsorbed by Amberlite IRA-400. Each fraction was put to microelectrophoresis on filter paper and the results obtained are shown in Fig. 1. The strongly basic Fraction I′ was hydrolyzed with hydrochloric acid and its composite amino acids were analyzed by paper chromatography with results as given in Table I.
Growth inhibition against Micrococcus pyogenes var. aureus was found in 80, 000 dilutions of ethyl pulvate, vulpinic acid, 6-chloro-4-amylresorcinol, and 6-chloro-2-cyclohexylorcinol, in 160, 000 dilution of 6-chloro-4-hexylresorcinol, and in 320, 000 dilution of 6-chloro-4-heptylresorcinol. Growth inhibition against Bacillus subtilis was found in 80, 000 dilution of 6-chloro-2-cyclohexylorcinol, 160, 000 dilution of 6-chloro-4-hexylresorcinol, and in 320, 000 dilution of 6-chloro-4-heptylresorcinol. All the compounds possessed only a weak growth inhibitory action against Escherichia coli communior except 6-chloro-4-propylresorcinol which was effective at 20, 000 dilution.
Distribution of flavonoids in plants was examined with methanolic extracts of about 300 kinds of plant materials by the paper chromatographic method. As a result, it was found that the distribution of flavonoids in plants was very large, as reported by the Late Dr. Keita Shibata, and that a large number of plants contained flavonol. For example, the young green pod of Sophora japonica, measuring about 1-2cm. in length, was found to contain 44.4% of total flavonol which was almost pure rutin. This must be the highest content of flavonols or glycosides in plants known to date.
The fact that triterpenoid was the common constituent of plant cuticles was confirmed with several hundred plants. Thin pieces of pure cuticle was obtained by boiling the leaf of Ilex latifolia, which possesses the thickest cuticle, with hydrochloric acid solution of zinc chloride, with subsequent washing with water. As triterpenoids, 0.68% of ursolic acid was contained in this pure cuticle, together with 0.32% of melissyl alcohol, 38.0% of lignin, 10.2% of cellulose, 12.0% of fatty acids, 10.2% of resin, 2.0% of uronide, 6.0% of ash, and a trace of glycerol. Paper chromatography was used in determining the presence of glucose in cellulose using as a developing agent a mixture of collidine, phenol, acetic acid, and water in 4:2:3:1 ratio. It was also confirmed that the component of cuticle was very similar to the component of the cork of Quercus suber reported by Fierz-David.
Condensation of 2-methyl-4-amino-5-aminomethylpyrimidine (I), carbon disulfide, and methyl α-chloro-γ-ethoxypropyl ketone (II), in the presence of ammonia, results in the initial formation of α-aceto-γ-ethoxypropyl N-[2-methyl-4-aminopyrimidyl-(5)]-methyl-dithiocarbamate (VIII) which is very labile and immediately undergoes intramole-cular rearrangement to form its isomer, 2-methyl-2-ethoxytetrahydrofuryl-(3) N-[2-methyl-4-aminopyrimidyl-(5)]-methyl-dithiocarbamate (IX). This kind of condensation was not witnessed when cyclic isomer of (II), 2-methyl-2-ethoxy-3-chlorotetrahydrofuran (X), was used instead of (II).
1) As a color reagent for santonin, 2, 4-dinitrophenylhydrazone, 1% pure alcoholic solution of sodium hydroxide was used instead of 1% aqueous solution of sodium hydroxide used in the previous method. A reddish purple color appeared when the reagent was added to the acetone solution of the hydrazone and the light absorbency (e) of the colored solution of different concentrations (γ) was measured by the Beckman spectro-photometer (λ=550mμ). From these experimental data (n=18), the following equation was calculated by the method of least squares: γ=1365e+6.51. 2) The standard deviation, σ, is 0.0168, and the concentration limit corresponding to 2σ limit is ±57.3γ. 3) Results obtained from the determination of pure santonin by this method agreed with the expected values. 4) The influence of bisatin on this method was found to be negligible. 5) Test conditions were found for colorimetric assay of santonin using 1g. of crude drug (Artemisia maritima). 6) Data obtained by the baryta method, 2, 4-dinitrophenylhydrazone gravimetric method, and the present colorimetric method were compared.
Ergotamine tartrate, kindly supplied by Dr. A. Stoll of Basel, Switzerland, and ergotoxine ethanesulfonate of Wellcome & Co., England, were used as standards in the determination of ergot alkaloids. A blue color with absorption maximum at 550mμ appeared when p-dimethylaminobenzaldehyde test solution (J. P. VI or U. S. P. XIV) was added to the solution of these standards. Light absorbency (e) at 550mμ in different concentrations (γ/10cc.) was measured by the Beckman spectrophotometer and the following two equations were calculated by the method of least squares from the experimental data obtained: Ergotamine tartrate γ=1246e+0.32 (γ<1000 in 10cc.), Ergotoxin ethanesulfonate γ=1397e+0.13. Values obtained (as ergotamine) by this method using 1g. of ergot agreed well with those obtained by other methods.
Dried rhizome of Bupleurum falcatum L. was extracted with hot alcohol and purification of the neutral portion of the non-saponifiable matter yielded a sterol of m.p. 166-168°. This sterol and its acetate, benzoate, and p-nitrobenzoate, coincided well with spinasterol and its derivatives. Its steryl acetate was catalytically reduced in an acid medium to stenyl acetate and, from the stenol and stenyl benzoate derived from it, the original sterol was confirmed as α-spinasterol.
For the purpose of preparing antitubercular chemotherapeutics with thiazole nucleus, 2-substituted 5-formylthiazole derivatives were prepared by the condensation of acetyl-, benzoyl-, phenylacetyl-, phenyl-, acetaminobenzenesulfonyl-, or aminobenzenesulfonyl-thioureas, thioacetamide, and diphenylthiourea with bromomalonic dialdehyde. Reaction of thiosemicarbazide with these compounds yielded eight kinds of corresponding thiazole-aldehyde thiosemicarbazones. Antitubercular action of 2-acetaminothiazole-5-aldehyde thiosemicarbazone and 2-benzoylaminothiazole-5-aldehyde thiosemicarbazone was tested using Tibione as the control from which it was learned that the former possessed about an equal efficacy as Tibione and the latter, about one-half the efficacy.
Condensation of α, β-dichlorovinyl alkyl ethers, where the alkyl is ethyl, butyl, or hexyl, and phenylthiourea results in the formation of 2-phenylimino-4-thiazolidone in all cases. As a result of detailed examination of this cyclization, it was assumed from experimental results that S-[β-chloro-β-alkoxyvinyl-(α)]-phenylisothiourea is formed as an intermediate which underwent liberation of alkyl chloride when heated with water to a ketene compound and changed finally to 2-phenylimino-4-thiazolidone.
That the structure of the condensation product of β-naphthol and maleic anhydride, by heating at 220-240°, was represented by (I) was confirmed by derivation from the naphthalene-maleic acid adduct. In the present experiment, naphthalene-maleic acid adduct, m.p. 139°, unknown to date in literature, was isolated and its properties were studied.
Alkyl ethers of α- and β-naphthols undergo coupling with diazonium compound obtained from 2, 4-dinitroaniline and form corresponding azo compounds of naphthols in approximately quantitative yields. Application of the foregoing diazonium compound to the phenyl ether of naphthols results in the formation of the azo compounds of α- and β-naphthols and of phenol, the formation rate decreasing in the order of α-naphthol, β-naphthol, and phenol. In the case of the phenyl ether of α-naphthol, a compound formed without the cleavage of ether linkage, i.e. 4-azo compoumd, is also formed. Application of the said diazonium compound to α, β-dinaphthyl ether results in the chief formation of azo compound formed by coupling without cleavage of the ether linkage, followed with 4-azo compound of α-naphthol, and a small amount of the azo compound of β-naphthol.
Diethylaminoisopropyl (I), 1, 3-bis (diethylaminoisopropyl) (II), 3-diethylamino-2-hydroxypropyl (III), and diethylaminopropyl (IV) groups were introduced into the amino radical of 8-amino- and 6-methoxy-8-aminoquinolines. The compounds were purified by derivation to crystalline picrates. In the above case, 3-diethylamino-1, 2-dihydroxy-propane was reduced with hydriodic acid and red phosphorus and reacted with the aminoquinoline, in order to obtain (I), but a mixture of approximately equal amounts of the iso compound (I) and normal compound (IV) was obtained. These two were easily separated by deriving them to respective monopicrate.
Hydrolysis with sodium hydroxide of 10kg. of the distillation residue of crude butanol, obtained by butanol fermentation, yielded 4050g. of neutral portion and 3200g. of acid portion. The neutral portion gave 135g. of trimethyleneglycol monobutyl ether from which 6-methoxy-8-(γ-diethylaminopropyl)-aminoquinoline was prepared.
Two simple synthetic procedures for N-(2-diethylaminoethyl)-p-aminobenzamide (Procainamide), effective as a therapeutic for irregular pulse, are described. One is the condensation of p-nitrobenzoyl chloride with diethylaminoethylamine, high pressure reduction of the condensation product with nickel catalyst, and low pressure distillation. The other is the condensation of p-nitrobenziminoether hydrochloride and diethylamino-ethylamine to N1-(2-diethylaminoethyl)-p-nitrobenzamidine, which is hydrolyzed with 50% methanol to N1-(2-diethylaminoethyl)-p-nitrobenzamidine. The determination of the hydrolysis was made by paper chromatography.
By the application of the hydrochloride of ethyl formimidoether or formanilide to quinaldine ethiodide and 2-methylbenzothiazole ethiodide, corresponding aminovinyl compounds or carbocyanine dyes were prepared. Trinucleic dyes, i.e. β-quinadenylcarbocyanines, were prepared by the application of diethyl imidocarbamate, phenyl isocyanate, or bromocyanide to quinaldine methiodide or ethiodide.
By the application of orthoformic ester and barbituric or thiobarbituric acid to α-picoline, 2, 6-lutidine, quinaldine, and 2-methylbenzothiazole, corresponding merocarbocyanine dyes containing barbituric acid were prepared.
In order to examine efficacies as anthelmintics against ascaris, 3-hydroxy-7-methoxy-and 3-hydroxy-7-methoxy-6-nitro-2-(2-furyl)-chromones were synthesized from the corresponding ω-furfurylideneacetophenones by heating in alcoholic potassium hydroxide solution with hydrogen peroxide. These 3-hydroxy-furylchromones and their O-methyl derivatives had no anthelmintic action in vitro in concentration of 1:1000.