The two hexasaccharides obtained by the application of amylase produced by Bac. Bacerans on starch were applied with periodic acid. Both consumed 1 mole each of periodic acid but did not form formic acid or formaldehyde which fact would coincide with the assumption of a ring structure as described in the previous report. The corresponding periodic acid oxidation products, the aldehydes, are also hexasaccharides, showing [α]D16-14.8° and [α]D16-7.5°, respectively, for those derived from hexasaccharide and Akiya-Watanabe's hexasaccharide. Hydrolysis after periodic acid oxidation yielded glyoxal and erythrose. Oxidation by bromine of the aldehydes obtained by periodic acid oxidation followed by hydrolysis yielded glyoxylic acid and erythronic acid.
As a novel synthetic procedure for thiazole nucleus, preparation of 5-arylthiazole derivatives was carried out by the cyclization of thioformamino ketone. Application of the aqueous solution of potassium dithioformate to the diluted alcoholic or aqueous solution of the hydrochlorides of ω-aminoacetophenone, desylamine, m-nitro-ω-aminoacetophenone and p-chloro-ω-aminoacetophenone yielded the corresponding thioformyl compounds and their treatment with concentrated sulfuric acid at a room temperature respectively yielded 5-phenylthiazole, 4, 5-diphenylthiazole, 5-m-nitrophenythiazole and 5-p-chlorophenylthiazole.
Following 4 kinds of α-amino acids possessing benzimidazole nucleus were prepared by the use of acetaminomalonic ester and acetaminocyanoacetic ester, as those compounds were expected to possess antagonistic action against tryptophane, purine and vitamin B12: β-(Benzimidazole-2)-alanine, β-methyl-β-(benzimidazole-2)-alanine, β-(5-methylbenzimidazole-2)-alanine and β-methyl-β-(5-methylbenzimidazole-2)-alanine. The first two were able to inhibit the growth of Leuconostoc mesentroides, and the last two, E. coli.
Studies were carried out to obtain water-soluble preparation of rutin for clinical purposes. An aqueous solution containing sodium hydroxide and boric acid in 1:1-2 molar ratio specifically dissolves rutin. The aqueous solution is stable in air and has a low pH but is affected by warming. The amount of sodium hydroxide and boric acid necessary to dissolve rutin is 1.5-2 moles each, but as long as the above ratio is adhered to, the presence of excessive amounts of these compounds is not interfering. There is no likelihood of the buffer action of the combination of sodium hydroxide and boric acid acting on this solution mechanism. A completely similar effect was found to exist with quercetin, an aglycone of rutin.
Methylation of rutin by diazomethane in methanol under the presence of 2 moles of NaH2BO3, followed by hydrolysis yielded quercetin monomethyl ether, m.p. 290-294°. Since this ether gave tetraacetate, m.p. 183-185°, and a triethyl ether, m.p. 106-108°, it was proved to be rhamnetin. Methylation of quercetin under the same conditions yields dimethyl ether of m.p. 232-235°, which forms a triacetate, m.p. 163-165°, which have not hitherto been seen in literature. The same methylation of pyrocatechol results in the recovery of this compound. It was therefore concluded that rutin and quercetin bonds with NaH2BO3 at two places.
It was assumed from the results of methylation that the specific solubilization of rutin in an aqueous solution containing sodium hydroxide and boric acid in 1:1-2 molar ratio was due to the formation of two kinds of boric acid complex salts, which exist as soluble salts in equilibrium, by the bonding of boric acids with the phenolic hydroxyls at 3′ and 4′ positions, and with the hydroxyl at 5-position and the carbonyl of the pyrone ring. The same explanation was assumed to be applicable in the case of quercetin. The dying ability of flavonols by the oxides of heavy metals are also due to the formation of complex salts but the complex salts are insoluble in this case whereas boric acid complexes of rutin become water soluble by the complex formation.
By utilizing the formation of a water-soluble boron complex salt of rutin, rutin was extracted from Flos Sophorae japonicae, a chinese crude drug of the flowers of Sophora japonica. By cold digestion with extracting solutions Nos. 1, 2 and 3, in which the molar ratio of sodium hydroxide: boric acid were 1:2, 1:1.5 and 1:1, respectively, extraction with No. 1, which corresponds to 4.5% aqueous solution of borax, gave the best yield of 13%, a slightly better yield than methanolic extraction of 12%. Digestion with application of heat gave a poor yield. The yield was compared with the crystals of m.p. 175-180° obtained after one recrystallization from hot water.
Coloration of hypnotics of the barbituric acid series, such as Veronal, Luminal, Prominal, Dial, Amytal, Cyclopan, and Adorm, by condensation with various aldehydes was examined as a means of their identification. The possibilty of a formation of complex salts with Co, Ni, Mn, Fe, Al, Cu, Zn and Mg, was also examined and it was found that the coloration occured only with Co and Cu. The complex salts of Prominal and Cyclopan, which have N-CH3 group, with Co were found to be unstable that gave an example of a steric hindrance.
Conditions for the coloration of hypnotics of the barbituric acid series, such as Veronal, Luminal, Prominal, Dial, Amytal, Cyclopan and Adorm, with selenous acid were examined and found that the identification of these drugs was possible when heated on a microburner for two minutes. Based on these and the previous experiments, a systematic identification for barbituric acid compounds was forwarded.
Six kinds of following 2-benzylaminopyrimidines were obtained by the respective application of 2-chloro- or 2-chloro-4-methyl-pyrimidine to benzylamine, p-methoxybenzylamine and o-methoxybenzylamine: 2-benzylamino-, 2-benzylamino-4-methyl-, 2-p-methoxybenzylamino-, 2-p-methoxybenzylamino-4-methyl-, 2-o-methoxybenzylamino- and 2-o-methoxybenzylamino-4-methyl-pyrimidine. 2-(N-benzyl-N-phenylamino)-4-methyl-pyrimidine was also obtained from benzylaniline and 2-chloro-4-methylpyrimidine.
Bromine addition products of benzothiazole were prepared by the application of bromine to N-(p-methoxyphenyl)-thiourea and N-(p-methoxy(ethoxy)-phenyl)-N'-mono(di)methylthiourea. These addition products were treated with sulfurous acid to yield 7-bromobenzothiazole derivatives. Bromination of 2-amino-6-methoxy-7-bromobenzothiazole here obtained gives 4, 7-dibromo derivative which can also be obtained by the application of (CNS)2 to 2, 5-dibromo-4-methoxyaniline. 2-Amino-4-bromo- and 2-amino-5-bromo-6-methoxybenzothiazoles were obtained by the application of bromine to N-(2, 6-dibromo-4-methoxyphenyl)-thiourea and N-(3-bromo-4-methoxyphenyl)-thiourea. 2-Amino-5-bromo-6-methoxybenzothiazole can also be obtained by the application of (CNS)2 on 3-bromo-4-methoxyaniline. Treatment of N-(p-methoxyphenyl)-N′-mono(di)methhyltiourea with sulfuryl chloride gives 2-mono(di)methyl-amino-6-methoxybenzothiazole.
Semicarbazone and thiosemicarbazone of 2-acetamino-6-formylbenzothiazole, 2-allylmercaptobenzothiazole, 2-allylmercapto-6-acetamino (carbamido and thiocarbamido)- and 2-(2′, 4′, 5′-trichloroanilino)-6-nitro (amino)-benzothiazoles were synthesized. By the respective condensation of p-acetaminobenzaldehyde with 2-chloro-, 2-(2′, 5′-dichloroanilino)-, 2-(2′, 4′, 5′-trichloroanilino)- and 2-allylmercapto-6-aminobenzothiazoles and 2, 6-diaminobenzothiazole, the corresponding Schiff bases were prepared. These compounds were synthesized in order to test their antibacterial action against tubercle bacilli.
Several kinds of aminovinyl compounds were prepared by the condensation of diphenylformamidine or 2, 2′, 5, 5′-tetramethylformamidine with alkyl (or allyl) halides of the heterocyclic compounds possessing oxazole, benzoxazole, thiazole, benzothiazole or quinoline nucleus and a methyl group in the 2- or 4-position. Fifteen kinds of trimethinecyanines were also prepared by the condensation of these aminovinyl compounds with alkyl or allyl halides of various heterocyclic compounds possessing methyl at 2-position under the presence of acetic anhydride and anhydrous sodium acetate.
The synthesis of piperonylethyl- and piperonylallyl-barbituric acids is described. Examination of their physiological actions upon mice revealed that both are of no practical value because of the proximity between the hypnotic and lethal doses.
The wax of Juniperus ridida Sieb. et Zucc. was found to contain caprylic, capric, lauric, palmitic and montanic acids in combination with ceryl and myricyl alcohols. Besides these constituents was found a compound of a large molecule (mol. wt. ca 2600) which by saponification produced an ω-hydroxytetracosanic acid. The authors assumed it to be a kind of “etholide” of Bougault and to be composed of seven molecules of the acid. The ω-hydroxytetracosanic acid itself easily polymerizes to a gummy substance by distillation.
1) Boiling 2′-aminopyrido-2, 3:5′, 4′-thiazoles with aqueous NaOH solution results in the cleavage of the thiazole ring to form 2-mercapto-3-aminopyridines. The portion of the 6-chloro derivative of the latter is oxidized to a disulfide. 2) A kind of azo dye was obtained by coupling β-naphthol to the diazonium chloride of 2′-amino-6-chloropyrido-2, 3:5′, 4′-thiazole. The decomposition of the diazonium salt yielded a 2′-hydroxy derivative. The latter can also be obtained by the action of phosgene on the alkali salt of 2-mercapto-3-amino-6-chloropyridine. 3) Application of the carbon dioxide gas saturated with carbon disulfide to the alkali salt of 2-mercapto-3-aminopyridine yields 2′-mercaptopyrido-2, 3:5′, 4′-thiazoles. The 6-chloro derivative of the latter can also be obtained by the application of thiophosgene to the alkali salt of 2-mercapto-3-amino-6-chloropyridine. This latter compound cyclizes to 6-chloropyrido-2, 3:5′, 4′-thiazole by the action of potassium cyanide and hydrochloric acid or formic acid and zinc.
The treatment of 2′-hydroxy(mercapto)-6-chloropyrido-2, 3:5′, 4′-thiazole with a mixture of phosphorus oxychloride and phosphorus pentachloride, instead of a 2′-chloro derivatives, bis-type oxides or sulfides are obtained. On the other hand, chlorination of 2′-mercapto-6-chloropyrido-2, 3:5′, 4′-thiazole with sulfur chloride yields a 2′, 6-dichloro derivative. 2′-Alkyl (allyl)-mercapto derivatives were obtained by the condensation of alkyl iodides or allyl bromides with sodium salt of 2′-mercapto-6-chloro(ethoxy)-pyridothiazole. 2′-Mercaptopyrido-2, 3:5′, 4′-thiazole was synthesized by the action of carbon disulfide and hydrogen sulfide on 2-chloro-3-nitropyridine under the presence of sodium sulfide.
1) Coriamyrtin possesses a methylene group at the terminal end of a molecule and when it is saturated to a methyl group, the compound formed is the dihydrocoriamyrtin. 2) Isohydrocoriamyrtin, C15H20O5, m.p. 141-142°, possesses one aldehyde group. By its catalytic reduction, two moles of hydrogen is absorbed to yield hexahydrocoriamyrtin, C15H24O5, m.p. 196-197°. 3) Oxidation of coriamyrtin with lead tetraacetate gives a neutral substance, C15H18O6. 4) Coriamyrtin is assumed to be an acetal type, possessing one lactone ring, and lacks any atomic grouping which would give an absorption in the ultraviolet range.
Tertiary carboxylic acids possessing benzene nucleus in the α-position are not oxidized by alkaline potassium permanganate but are oxidized by acidic permanganate, generates carbon dioxide and form corresponding tertiary carbinols. Aliphatic tertiary carboxylic acids do not possess such a property. This fact was confirmed by experiments with diphenylpropionic acid (I), ditolylpropionic acid (II) and diphenylethanetricarboxylic acid (III). (III) yields the corresponding tertiary carbinol, diphenylmethylcarbinol-p, p-dicarboxylic acid (IV) which, when heated above its melting point, liberates water to form diphenylethylenedicarboxylic acid (V). Benzilic and benzohydroltricarboxylic (VI) acids are also easily oxidized by acidic potassium permanganate. The compounds (IV), (V) and (VI) are newly synthesized substances.
Triphenylacetic acid is oxidized to triphenylcarbinol in acidic potassium permanganate but the same reaction does not occur in alkaline medium. Similarly, triphenylcarbinol is further decomposed by oxidation to benzophenone in acidic permanganate but not in alkaline medium. Phenylethylmalonic acid is also easily oxidized to propiophenone in acid but not in alkaline medium. Conversely, trimethylacetic, diethylmalonic and dibenzylmalonic acids which all do not possess benzene nucleus directly bonded at the α-position, do not suffer such oxidation even in an acid medium. Even compounds possessing benzene nucleus bonded at the α-position are not oxidized when they have been esterified. In order to explain these reaction mechanism, a tendency to dissociate into free radicals was assumed and with the help of the known hypothesis that a certain catalytic action that promotes dissociation is present in acidic permanganate solution, the foregoing reactions were ably explained.
Oxidation of β-phenyl-α-ditolylpropionic acid by alkaline potassium permanganate yielded β-ketotricarboxylic acid, C23H16O7, which, on further oxidation in acid permanganate, gave benzyl-p-carboxylic acid. The latter was identical with the crystals of the same melting point obtained by the oxidation of p-methylbenzoin by 20% nitric acid. Therefore, one benzene nucleus has been liberated by the acid oxidation with potassium permanganate. This reaction mechanism was considered by comparison with the results obtained by previous experiments.
2-Anilinopyrimidine (I) and 2-anilino-4-methylpyrimidine (II) were prepared by the respective application of 2-chloro- and 2-chloro-4-methylpyrimidine to aniline. (II) can also be obtained by the application of 2-methylmercapto-4-methylpyrimidine on aniline, or by the condensation of 2-methylmercapto-4-methyl-6-hydroxypyrimidine with aniline, converting the product, 2-anilino-4-methyl-6-hydroxypyrimidine, to its 6-chloro derivative and finally reducing it to (II). Condensation of aniline and 2-methylmercapto-4-methyl-6-methoxypyrimidine did not yield 2-anilino compound. 2-(4-Diethylamino-1-methylbutylamino)-4-methylpyrimidine was obtained by the condensation of 4-amino-1-diethylaminopentane and 2-methylmercapto-4-methyl-6-hydroxypyrimidine, after conversion of the product to its 6-chloro derivative, followed by reduction. This compoud can also be obtained from 4-amino-1-diethylaminopentane and 2-chloro-4-methylpyrimidine.
In order to determine the position of the sulfonic acid group bonded to the thiazole residue, sulfathiazole-NaHSO3 addition product was methylated with dimethyl sulfate. As the reaction product obtained by its treatment with conc. sulfuric acid happened to be 3-methylthiazolone-acetosulfanilimide, the adition product was proved to be 2-(p-aminobenzenesulfonamido)-thiazole-2-sodium sulfonate. Chemical properties of several sulfonamide-NaHSO3 addition products were also examined.
2-Aminothiazole-, 2-aminopyrimidine- and 2-amino-4-methylthiazole-2-sulfonic acids were obtained by the application of sodium bisulfite to the aqueous solution of 2-aminothiazole, 2-aminopyrimidine and 2-amino-4-methylthiazole with subsequent acidification or by the application of sulfur dioxide gas to these aqueous solutions.
Benzalmethylamine, benzalbenzylamine and hydrobenzamide react with formamide, when heated with it, to form N-formylbenzylamine and N-formyldibenzylamine with some by-products. Reduction of these imines at a high temperature and high pressure, under the presence of formamide, results in the conversion of benzal radical to N-formylbenzylamine in almost theoretical yield.
Morphological and anatomical examinations were made of the stolons and roots of the original plant for the liquorice root, Glycyrrhiza glabra L. and its variey, glandulifera Reg. et Herd., and G. uralensis Fisch. et DC. These were compared with the crude drugs from Spain, Russia, China, Manchuria and Japan, and specific characteristics of each were clarified.
The Japanese market products of liquorice root was morphologically and anatomically determined by comparison with the roots and stolons of the three kinds of Glycyrrhiza species mentioned in the previous report and those of G. echinata. The ratio of glycyrrhizin content of each species and commercial products was also examined. The difference in the amount of the component contained in the drugs of Spain and China with their respective skinned products was hardly noticeable in the Chinese but very marked in the spanish drugs. This fact seems to point that a certain unified forms should be designated for crude drug according to use and also from the point of drug component. The domestic market products, examined by the authors in 1950, purported to be North China liquorice root and the unskinned Fuchow products are mostly attributable to G. uralensis. However, they contain about 6% of glycyrrhizin and, as long as the roots are to be used for medicinal purposes for sweetening, they can be substituted for Spanish liquorice.
Experiments were conducted in order to obtain the erythro-type β-phenylserine but the attempt was not successful. However, observations on β-phenylserine and its derivatives, obtained during the course of this experiment, are shown by the schema giving changes of compounds (I) to (XV).
It was shown that the acetone-desiccated powder and its extract prepared from pituitaries of bonitos, i.e. Katsuwonus vagans, Katsuwonidae, were also effective as those from mammalian pituitary bodies in their oxytocic, vasopressor and antidiuretic activities. From 1000 pieces of bonito pituitaries, isolated 5 to 10 days after being caught, 3.02g. of the acetone-desiccated powder was obtained which was evaluated to possess an oxytocic potency of 0.2-0.3 I.U. per mg. The standardizations of oxytocic, vassopressor and antidiuretic activities were respectively made employing the guinea pig uterine method by Burn accompanied with Coon's chick depressor method, the spinal cat method, and Goodman and Gilman's method using rats.
In the high pressure carboxylation of hydroquinone in glycerol solution with potassium bicarbonate and carbon dioxide gas, not the increase of pressure but the prolongation of reaction time influences the yield of gentisic acid, although the yield is generally poor. The increase of reaction temperature, however, promotes the formation of by-product dicarboxylic acid, which was proved to be 2, 5-dihydroxyterephthalic acid by the comparison of its methylated product with an authentic specimen. The carboxylation by this process is assumed to be the rearrangement mechanism similar to Kolbe's reaction. The fact that the formation of dicarboxylic acid was not evidenced in the carboxylation of hydroquinone monomethyl ether endorses this assumption but the increase of reaction temperature rather decreases the yield of monocarboxylic acid.
By following the method of Villani and Lang (J. Am. Chem. Soc. 72, 2301 (1950)), Reimer-Tiemann reaction was carried out with hydroquinone monomethyl ether, carbon tetrachloride and 50% sodium hydroxide, in the presence of copper catalyst. Besides gentisic acid-5-methyl ether, m.p. 144°, a dicarboxylic acid, m.p. 223-225° (decomp.), insoluble in benzene, was obtained. By methylation of the latter, it was proved to be 2-hydroxy-5-methoxyisophthalic acid, which was also obtained by the Reimer-Tiemann reaction of gentisic acid-5-methyl ether under the same conditions. The copper catalyst can be substituted by cuprous chloride.
α-Naphthol was led to its ether, nitrated to p-nitro compound, and chloromethylated in glacial acetic acid solution to monochloromethyl compound, m.p. 107-108°. Its catalytic reduction and subsequent oxidation with potassium bichromate and sulfuric acid yielded yellow needles, m.p. 102-104°, which was proved by mixed fusion to be β-methyl-1, 4-naphthoquinone. This has confirmed the fact that the chloromethyl group was introduced into the ortho position of the ethoxy radical. Phthiocol was prepared by Anderson-Newman's method from β-methyl-1, 4-naphthoquinone.
2-Ethyl-α-naphthol was prepared from α-naphthol by acetylation, Fries'rearrangement and the Clemmensen reduction. This was led to an azo dye by coupling, reduced by hyrosulfite and oxidized by sodium bichromate to 2-ethyl-1, 4-naphthoquinone, m.p. 89°. The use of sulfanilic acid, rather than aniline, for diazonium salt, makes for a better reduction by hydrosulfite. The quinone compound was led to 2-hydroxy-3-ethyl-1, 4-naphthoquinone, m.p. 136-138°, by Anderson-Newman's method. This compound yields phthiocol by oxidation with potassium permanganate according to Hooker's method.
Mold preventing action of the following 13 compounds were tested against soy sauce: Thymol, p-nitrosothymol, p-nitrothymol, p-aminothymol hydrochloride, o-nitroso-m-cresol, m-nitroso-o-cresol, p-nitrosophenol, 2-nitroresorcinol, 4-nitroresorcinol, 2-aminoresorcinol hydrochloride, 4-aminoresorcinol hydrochloride, o-chloro-p-aminobenzoic acid and p-quinone dichloroimide. In contrast to the complete prevention of molding in a 5-day test period by propyl p-hydroxybenzoate, used as control, in 0.01% concentration, p-nitrothymol, in ca. 0.003% concentration, p-quinone dichloroimide, in ca. 0.005% concentration, and thymol, in ca. 0.007% concentration, were able to prevent molding during the same period. Other compounds were found to have no action of preventing molding of soy sauce.
Several N-derivatives of phenol sulfonamide-(4) and salicylic aid sulfonamide-(5) were synthesized and their effectiveness against the virus of Japanese encephalitis was examined. Antiviral action was tested in vitro and in vivo using mice as an experimental animal. The virus was inoculated intracerebrally and the compound samples were injected intraperitoneally. The compounds found effective in vitro were: 4-Hydroxybenzenesulfonamide, p-(4-hydroxybenzenesulfonamido)-phenethol, salicylic acid sulfonamide-(5), salicylic acid N-(4-sulfonamidophenyl) sulfonamide-(5) and salicylic acid N-(4-sulfophenyl)-sulfonamide-(5). Those found to possess curative effect by in vivo test were salicylic acid sulfonamide-(5) and salicylic acid N-(4-sulfophenyl)-sulfonamide-(5). Others were all ineffective.
Protective action of compounds related to sulfanilic and naphthionic acids against the virus of Japanese encephalitis was examined. Antiviral action was tested by the injection of an aqueous solution of the sample compound into the peritoneum of a mouse daily, for four to five consecutive days, and then the virus was inoculated intracerebrally. The results showed that naphthionic acid and Congo Red possessed over 50% protective effect. This is the first instance that a substance effective against such a small virus as those of Japanese encephalitis had ever been found.
Potentiometric titration of arsenious acid, arsenic acid and several organic arsenic compounds was carried out, using antimony-electrode method and following results were obtained: 1) The potentiometric neutralization of arsenicals can effectively be carried out with antimony electrodes without any disturbance of the arsenic compounds. 2) The potentiometric redox titration of arsenic compounds was successfully carried out with antimony electrodes.
3, 6-Dinitrophthalic acid was prepared in a comparatively good yield by boiling for a long period of time a mixture of 1, 5-dinitronaphthaline with fuming sulfuric and fuming nitric acids. Dehydration of this compound with acetic anhydride yielded 3, 6-dinitrophthalic anhydride. This reagent, when boiled for 2-3 hours with primary alcohols or 5-10 hours with secondary or higher alcohols in anhydrous benzene, or by reacting with alcohols in anhydrous pyridine, yields crystalline and easily purifiable semiesters (Table I). The reaction velocity of this reagent and the primary and secondary alcohols is approximately the same as that between 3-nitrophthalic anhydride and alcohols (Table II).
0.1 to 1.0mg. of alcohol is dissolved in 0.1-0.2cc. of anhydrous pyridine, excess of 3, 6-dinitrophthalic anhydride added, and the mixture is warmed for one hour, at 50° in the case of lower alcohols, at 100° in the case of higher and polyalcohols. The excess of the reagent is decomposed by the addition of one drop of water, 2-3cc. of ether added to the mixture and pyridine removed by extracting twice with 2-3cc. of 5% hydrochloric acid. The ethereal layer is dehydrated by sodium sulfate, ether distilled off, and the residue is dissolved in a small amount of butanol. Paper partition chromatography is carried out with this butanol solution by placing a drop on a filter paper, 2×40cm., and developed by butanol-acetic acid. By first spraying 1N-sodium hydroxide and then ethyl acetoacetate, orange red spots will appear. For the separation of lower alcohol, butanol saturated with 1N-acetic acid is satisfactory while for polyalcohol, 8:1:2 mixture of butanol, acetic acid and water, is found satisfactory. Methyl alcohol, in as small an amount as 10 γ, can be separated from about 100 times that volume of ethyl alcohol.
The antibacterial intensity of 5-nitrofuran derivatives is related to the increase in the number of conjugated double bonds in the molecule and the low reduction potential held by the nitro group compared to other nitro groups. In order to attain this end, 15 kinds of amines which would serve as the auxo-antibacterial group were condensed to 2-(5-nitro)-furylacrolein, m.p. 118°, as the antibacterial body. Of the compounds prepared, 2-(5-nitro)-furylacrolein. aminoguanidine hydrochloride, m.p. 262°, showed the minimum bacteriostatic concentration of the following order: Staph. aureus, 20, 000; Strept. haemolyticus, 80, 000; Gonococcus, 40, 000; E. coli (Boxhill No. 88), 50, 000; S. dysenteriae (Shiga), 50, 000; B. pyocyaneae, <10, 000; B. subtilis, 200, 000; V. cholerae, 200, 000.
The effect of the form and the volume of nitrogen in the fertilizer against alkaloidal content in the leaves of Datura Tatura L., is described, together with the results of examination of three nutrient principles when sodium nitrate is used as the source of nitrogen, and the effect of phosphate. The yield of the alkaloid increases in the order of NaNO3<NH4NO3<(NH4)2SO4, the maximum yield being obtained with (NH4)2SO4 when used in a ratio of N 5.0, P2O5 3.0, K2O 1.5. Interrelationship between the alkaloidal content and the amount of total nitrogen in the leaves was examined.
The color reaction of sym-trinitrobenzene with some cardio-active glycosides, such as digitoxin, ouabain and strophanthin, in alkaline solution was studied. A quantitative colorimetric method for such glycosides is as follows: 4cc. of the methanolic solution of the glycoside (1-10mg.%), 0.5cc. of 0.04% solution of sym-trinitrobenzene in methanol, and 0.1N-KOH aqueous solution are mixed and allowed to stand at a room temperature for 35 minutes. Readings are then taken on a colorimer with filter of 550mμ.
Syntheses of several derivatives of imidazoisoquinoline have been described in part I to IV of this report. It has been learned that one of these derivatives, 9, 10-dimetoxy-3-(p-aminophenyl)-5, 6-dihydrobenzoglyoxalocoline possessed a certain amount of emetine-like action and, therefore, imidazoisoquinoline derivatives possessing a basic group, such aspyridyl, in the 3-position were synthesized. The present report describes the synthesis of one possessing a nicotinyl group, i.e. 9, 10-dimethoxy-3-nicotinyl-5, 6-dihydrobenzoglyoxalocoline. Its physiological properties are being examined.
With the same objective as the previous report, 9, 10-dimethoxy-3-isonicotinyl-5, 6-dihydrobenzoglyoxalocoline was prepared. This was a syrupy substance and difficult to purify that it was confirmed as its picrate. Its hydrochloride was also difficult to purify because of its highly hygroscopic nature and, therefore, 0.8% aqueous solution of this caramel-like, crude hydrochloride was used for physiological tests.
With the same objective as before, preparation of 9, 10-dimethoxy-3-picolinyl-5, 6-dihydrobenzoglyoxalocoline was attempted by cyclization of (picolinylaminoaceto)-β-veratrylethylamide with phosphorus oxychloride. The product, however, remained syrupy and the compound could not be confirmed but a by-product was obtained during this reaction which was assumed to be dipicolinylaminoacetocarbamide, m.p. 171-172°. Of the three compounds possessing pyridyl in the 3-position of imidazoisoquinoline, those substituted in the α- and γ-positions of pyridine nucleus remained syrupy substances.
A compound possessing imidazoisoquinoline groups symmetrically in the 3-position, i.e. 9, 10; 9′, 10′-bis-dimethoxy-3, 3′-(5, 6-dihybrobenzoglyoxalocoline), was prepared because of the interest in its physiological properties since the compound would have several similarity with Pyman's formula of emetine and and to see if a bis-type acid amide would cyclize by liberating four moles of water. However, the yields of oxalylglycine ethyl ester and the free base obtained by the cyclization of acid amide were very poor. It seems that generally the cyclization of a symmetric acid amide does not give satisfactory result.
With the same objective in view, imidazoisoquinoline possessing a quinoline group in the 3-position, i.e. 9, 10-dimethoxy-3-cinchonyl-5, 6-dihydrobenzoglyoxalocoline, was synthesized. In this instance, differing from previous experiments, the azide, obtained during the preparation of cinchonyl-β-veratrylethylamide, is quite unstable and must be treated at once and also, if left in alkaline state, it rapidly becomes red colored. Addition of phosphorus oxychloride for its cyclization also results in its coloration to dark purple. The free base softens at 60° and decomposes at 85°, but its picrate and hydrochloride show definite melting points.
The imidazoisoquinolines reported to date have been those obtained by the cyclization of acid amides yielded by the condensation of compounds of hippuric acid series with homoveratrylamine or safrylamine. It seemed interesting to see if the same dehydrogenation-cyclization would take place when β-alanine was used instead of glycine in the preparation of hippuric acid compounds, cyclization was carried out with (benzoyl-β-alalanyl)-β-veratrylethylamide. As expected, (2′-phenyl-4′-hydropyrimidino)-1′, 6′; 1, 2-(3, 4-dihydro-6, 7-dimethoxyisoquinoline) was obtained which was confirmed as its picrate and hydrochloride.