1) Reaction of 4-nitroquinoline 1-oxide with phosphorus bromide in chloroform or ethyl acetate proceeds in two directions, (A) and (B), in formula (III). It should be noted here that the N-oxide group is far more active than the 4-nitro group, the reaction chiefly going in the direction of (III-A) while cold and partly to (III-B) when heated. 2) The chief reaction in the desoxidation of 4-nitroquinoline 1-oxide with phosphorus tribromide would be represented by reaction (II) but a side reaction (III) was also found to take place. 3) Reaction of 4-nitropyridine 1-oxide with phosphorus bromide also afforded a small amount of 2-bromo-4-nitropyridine.
Coloration of aqueous solution of ascorbic acid was measured by the absorption spectral method in a definite concentration (50mg./cc.), pH (2.0), and amount of oxygen, at 45°, 60°, and 100°. The coloring process of the aqueous solution of ascorbic acid was found to result by the repeated maximum and minimum velocity of coloration and stepwise increase of optical density. The coloring was found to be composed of several steps represented by the formula for velocity of autocatalytic coloration dA/dt=kA1/2(a-A).
Phloroglucide was newly found in 5 kinds of ferns belonging to the Eudryopteris section and 2 kinds belonging to the Lophodium section in the Dryopteris genus. Subterranean portions of these ferns were examined microscopically and the important points of their discrimination were found to be the form of hypodermis and the number of its cell layers, form of internal glandular hair, presence or absence of a large tannin crystals, and the number of vascular bundles in stipe. The number of vascular bundles in the rhizome, to which a great importance had been attached in past literature, differs according to the position of the cross section and the form of internal glandular hair seems to have been insufficiently observed.
The presence of phloroglucide was newly found in 8 kinds of ferns belonging to the Polysticho-drys section and their internal morphology was examined. Majority of these ferns contains large crystals of tannin and this fact differs from the majority of ferns of Eudryopteris section. The form of their internal glandular hair allows discrimination of the Dryopteris varia, D. erythrosora, D. formosa, D. gymnosora, and D. gymnophylla groups. The ferns of the Polysticho-drys section, as those of Eudryopteris section, contain a large amount of phloroglucide. The use of D. pacifica TAGAWA in place of D. crassirhizoma NAKAI, prevalent in Shizuoka Prefecture, seems appropriate in the light of such results.
There are 29 kinds of domestic ferns which contain phloroglucide, effective for removing tapeworm. Of these, a large amount of phloroglucide is contained in Dryopteris crassirhizoma Nakai, D. polylepis C. CHRIST., D. cycadina C. CHRIST., D. dickinsii C. CHRIST., D. tokyoensis C. CHRIST., D. kominatoensis Tagawa, D. hondoensis KOIDZ., and D. gymnophylla C. CHRIST. These ferns may be discriminated by microscopic examination of their subterranean portions to see the number of cell layers in hypodermis (sclerenchyma), form of internal glandular hair, presence or absence of tannin crystals, and the number of vascular bundles in stipe. Difference in the form of internal glandular hair and presence or absence of tannin crystals are interesting characteristics in the classification of this section. These points are summarized in Table I.
Effect of nonionic surface active agents on the olive-oil decomposition with pancreatic lipase was examined. Of the agents used, both Brij 35 and Tween 80 activated the olive-oil decomposition in low concentrations but obstructed the decomposition in higher concentrations. Span 80 and 85 showed reverse phenomena, obstructing the decomposition in lower concentrations and activating in higher concentrations. This is chiefly due to the hydrophile-lipophile balance and this was evident from the results obtained by mixing Tween 80 and Span 85 to prepare mixtures of various hydrophile-lipophile balance. Activation agents with large balance activates the enzyme in lower concentrations and inhibits in higher concentrations, while the reverse is true of those with small balance. The same examination was made with anionic surface active agents, sodium dodecylsulfate, and carbowax, but all effected obstruction of decomposition and none showed any activation. The presence of calcium ion was found to make Brij 35 and Tween 80 inhibit enzymatic action even in lower concentrations, while the presence of dextrin and glucose had no effect on Brij 35 and. Tween 80 in an amount five times that of the enzyme. The concentration of Tween 80 in activating pancreatic lipase was found to be affected by the amount of the enzyme rather than that of olive oil.
Paper chromatography of crude insulin from a whale was carried out with developing solvent of acetic acid: butanol: water in various ratio. Optimal composition of the solvent for separating insulin alone was discovered. Using such a solvent, partition chromatography of crude insulin was attempted and a high-unit insulin of about the same quality as the crystalline product was obtained in one step in a high yield.
Because of the interest of changes in antibacterial power that might appear in the compounds formed by introduction of a second substituent, besides the hydroxyl group in the ortho-position of the benzene ring in 2-salicylidenehydrazono-4-thiazol-idone (I) and its 5-methyl derivative as compared to the original compound, compounds listed below were prepared and antibacterial tests with tubercle bacilli were carried out on these compounds. The compounds prepared were those possessing bromine atom in the positions meta and para to the hydroxyl group in the benzene ring, nitro group in the ortho, meta, and para positions, and another hydroxyl in the meta position. In vitro tests with tubercle bacilli showed that, even if the hydroxyl group was present in the orignal ortho position, the concurrent presence of another substituent resulted in the decrease of antibacterial power, as compared to the original (I), irrespective of the kind or position of the newly introduced substituent. The syntheses of these test materials were effected by boiling a mixture of respective thiosemicarbazone with a slight excess of ethyl chloroacetate or α-bromo-propionate, in the presence of sodium acetate in ethanol.
2-Salicylidenehydrazono-4-thiazolidone (I) and its 5-methyl derivative possess extremely strong antibacterial action against tubercle bacilli but their solubility in water and organic solvents is very small. In the present series of experiments, 2-α-methylsalicylidenehydrazono-4-thiazolidone (II) and its 5-methyl derivative (III), and 4 kinds of 2-α-methylarylidenehydrazono-4-thiazolidones, in which the hydrogen in α-position of salicylidene group had been substituted with a methyl radical, were synthesized as having improved solubility and the antibacterial activity of these compounds was compared with that of the original compound (I). It was found that the activity had decreased markedly in (II) and (III), indicating that the substitution of a methyl group in the α-position of salicylidene had clearly obstructed appearance of antibacterial activity. However, compounds containing the hydroxyl group in the ortho position, such as (II) and (III), were found to possess some antibacterial action, as compared to other substances not having such a group and this fact agrees with the relationship between chemical structure and antibacterial properties described earlier. The test meterial were prepared in the manner similar to those described in an earlier paper.
Using rabbit ear veins, reduction of bleeding time by 17 kinds of compounds related to adrenochrome, prepared by Iwao, was tested by the modified Duke's method. The compounds effective were 1-β-hydroxyethyl-3-hydroxy-5-(4′-β-hydroxyethyl-semicarbazono)-6-oxo-2, 3, 5, 6-tetrahydroindole (IV), sodium 1-methyl-5-semicarbazono-6-oxo-2, 3, 5, 6-tetrahydroindole-2-sulfonate trihydrate (VI), sodium 1-methyl-5-semicarbazono-6-oxo-2, 3, 5, 6-tetrahydroindole-3-sulfonate trihydrate (VII), and sodium 1-methyl-3-hydroxy-5-semicarbazido-6-oxo-2, 3, 5, 6-tetrahydroindole-5-sulfonate dihydrate (IX). Of these, (VII) was especially effective, with greater solubility in water, and effective in clinical tests, seemingly promising for practical use. Examination of a structure-activity relationship showed that compounds capable of forming an ortho-quinoid structure in 5- and 6-position of the indole ring possessed greater efficacy, while the introduction of a sodium sulfonate group increased solubility in water with increase in efficacy.
Reaction of methylmagnesium iodide with three isomers of methoxymandelonitrile affords methoxyphenylacetylcarbinol (I) and methoxyphenylmethylcarbinol (II) in all cases. The total yield of (I) and (II) are approximately the same in all three cases but the ratio of (I) and (II) differs in each case. From such a result, the formation of (I) and (II) was assumed to be a competitive reaction. By the comparison of the result from the present series of experiments and the reaction of mandelonitrile and methylmagnesium iodide, it was found that the -M (-E) effect of the methoxyl group in the aromatic ring of cyanohydrin, used as the starting material, was disadvantageous to the formation of (I) and advantageous for the formation of (II), while its +I effect had the reverse effect.
It was found that patulin colored orange yellow by reacting with phenylhydrazine and reddish brown by reacting with alkalis. Microdetection of this substance by paper chromatography, utilizing these reactions, and a method of its determination by photocolorimetry were established. Microdetermination by the use of antibacterial activity of patulin was devised by the cup method using Staphylococcus aureus. These methods are helpful in the microdetection or -determination of patulin from culture medium or wheat germs on which molds have grown. The limit of detection is 1-2γ, while the range of determination is 4-16γ/cc by the phenylhydrazine process, 0.2-0.8mg/cc with Staph. aureus.
Various conditions affecting the amount of patulin during the culture of Penicillium urticae BAINIER were examined. The amount of patulin produced increases with proliferation of the fungus but pH of the medium tends to alkaline side when the consumption of sugar source in the medium depletes beyond 1/4 of the original, and patulin produced in the medium was found to be decomposed. If sugar source is added during the rise of pH, such change of pH in the medium can be prevented and there will be no decrease of patulin. A large amount of ammonia was detected from the medium with increased pH and, considering the fact that patulin is easily decomposed in alkaline reaction and becomes detoxicated, one of the cause of decomposition of patulin in the medium may be taken as a simple chemical reaction of patulin with free ammonia.
The diol compound (VI), m. p. 152-153°, obtained by the reduction of desoxytetra-hydrosantonin with lithium aluminium hydride, was oxidized through its monobenzoate (VII) to a ketol compound (IX), in which the ketone group is in C5. Reduction of (IX) with either sodium and propanol or with sodium borohydride gave the same diol compound (XI), m. p. 99-100°, which is an isomer of (VT). A keto acid (XV) was prepared from tetrahydroalantolactone (XIV) and the reduction of unsaturated lactone (XVI) derived from (XV) with sodium amalgam afforded an isomer of (XIV). On the other hand, catalytic reduction of (XV) or its reduction with sodium borohydride followed by cyclization reverted the keto acid to the original tetrahydroalantolactone.
Engelitin (I) and isoengelitin (II) resist ordinary dehydrogenation to obtain flavonoid glycosides but undergo dehydrogenation by the method of Makesh and Seshadri using iodine and sodium acetate, forming a small amount of afzelin (kaempferol-3-L-rhamnoside) (III) from both (I) and (II). (III) remains inert in heating with 10% pyridine water or cold alkali, (III) being recovered entirely. However, the same treatment of structurally related (I) affords (II) and a new spot (IV) appeared on paper chromatogram, giving positive flavonoid reaction. On the other hand, the same treatment of (II) affords (I) and the same new spot (IV) on the paper chromatogram.
1) 2-Alkyl (or aryl) oxazolo[4, 5-c]pyridines were prepared by the dry-distillation of 3-acylamino-4-hydroxypyridines obtained by the application of carboxylic acid, acid anhydride, or acid chloride to 3-amino-4-hydroxypyridine. 2) 2-Thioxazolo[4, 5-c]pyridine was prepared by warming methanolic solution of 3-amino-4-hydroxypyridine and potassium methylxanthogenate and its reaction with alkyl halide, ethyl halocarboxylate, and alkyl β-bromoethyl ether afforded the corresponding thioethers. 3) Attempt to obtain 2-aminoxazolo[4, 5-c]pyridine by the application of aqueous ethanolic solution of cyanogen bromide to 3-amino-4-hydroxypyridine ended fruitless and only 3-cyanoamino-4-hydroxypyridine was obtained.
Synthesis of sulfanilamide derivatives of pyrazolone was attempted and five kinds of 3-arylsulfonamino-5-pyrazolone derivatives were obtained by the reaction of 1-(4-sulf onaminophenyl)-3-amino-5-pyrazolone and arylsulfonyl chloride. In this reaction, 2-mole acylated compounds were obtained but not 3-mole acylated compounds. Hydrolysis of such compounds afforded monoacyl compounds. Oxidative condensation of these 3-arylsulfonamino-5-pyrazolones with p-diethylaminoaniline afforded pyrazolone-azomethine dyes. The visible absorption spectra of these dyes were compared with those of dyes possessing no substituents in the phenyl ring bonded to the nitrogen in 1-position of the pyrazolone ring. The compounds possessing electron-attracting group, such as those listed above, generally show bathochromic shift of their first absorption band but there was found no regular changes in their second absorption bands. This fact is approximately the same as that described by Weissberger and others.
Seven kinds of phenylpyrazolone derivatives, substituted with p-acylamino- and dodecyloxy-benzenesulfonamido group in 3-position in the pyrazolone ring, were prepared, each was submitted to oxidative condensation with p-diethylaminoaniline, and derived to the corresponding pyrazolone-azomethines. The ultraviolet absorption spectra of these compounds were measured in methanol.
Hydrolysis of the new glycolipide, isolated earlier from soft tissues of an oyster, afforded a fatty acid with 16 carbon atoms and one double bond. Chromium trioxide oxidation of this fatty acid yielded succinic and azelaic acids. Infrared absorption spectrum of the acid suggested the presence of an isopropyl group and the acid was assumed to be 14-methylpentadecanoic acid with one double bond at C4 or C9.
Permanganate oxidation of methyl ester of the new unsaturated fatty acid obtained from the glycolipide afforded monomethyl succinate and 10-methylundecanoic acid, which were identified with synthesized specimens. The saturated acid obtained by the hydrogenation of the unsaturated fatty acid was found to be 14-methylpentadecanoic acid by identification with a synthesized product. As a result, this new unsaturated fatty acid was determined as 14-methyl-4-pentadecenoic acid.
Rats, 2-3 months old, were injected with 89Sr+90Sr (+90Y), without a carrier or with 0.5mg. of carrier-Sr, and then given repeated two injections without a carrier or seven (with carrier) injections of 50mg. of sodium rhodizonate. The animals were then sacrificed and excretion of radioactive strontium into urine and feces, and its deposition into the skeleton, kidneys, liver, spleen, lungs, and residual soft tissues were determined. (1) When radioactive strontium was injected with a carrier, with subsequent administration of rhodizonate, the excretion of radioactive strontium into urine and feces was inhibited and its deposition into all the body tissues increased, especially in the kidneys where 37 times that in the control had deposited. (2) When the radioactive strontium was injected without a carrier, with subsequent administration of rhodizonate, the excretion of radioactive strontium into the feces decreased and its deposition into the liver and kidneys increased. However, these tendencies were fairly limited and the distribution of radioactive strontium in the skleton, urine, and residual soft tissues excluding the kidneys and the liver, which determines the fate of the majority of radioactive strontium, was no different from that in the control.
Adrenochrome and the water-soluble sodium 1-methyl-5-semicarbazono-6-oxo-2, 3, 5, 6-terahydoindole-3-sulfonate trihydrate (AC-17) show antihyaluronidase activity but the insoluble adrenochrome monosemicarbazone (ACS) does not. While adrenochrome inhibits glycolysis, ACS and AC-17 do not, and AC-17 also does not affect the amount of liver glycogen. It seems, therefore, that adrenochrome cannot carry out its biochemical functions unless liberated. Both adrenochrome and ACS do not fluctuate the amount of adrenal ascorbic acid and in this respect, they do not seem to have any ACTH-like activity. The fact that the adrenochrome derivatives, irrespective of their solubility in water, are known to have very weak toxicity from their LD50, and activities on respiration, blood pressure, and on excised intestines.
Crystalline bases obtained from aconite plants collected in Nohmi, Kyoto Prefecture (Ochiai specimen No.24), Hanamiyama (Ochiai No.26) and Giboshiyama (Ochiai No.28), Okayama Prefecture, Dohgoyama, Hiroshima Prefecture (Ochiai No.27), and Kuzuresawa, Nagano Prefecture (Ochiai No.29), were analyzed and the results are listed in Table I. It was concluded that the specimens (Ochiai Nos. 2, 3, 22, 24, 25, 26, 27) which contain hypognavine as the chief component, lack aconitine-type strong poisons and ignavine, and contain some water-soluble bases are Aconitum sanyoense var. sanyoense NAKAI and that (Ochiai No.29) containing neither aconitine, ignavine, nor hypognavine, but with Ashio-base I, common with the foregoing specimens, as the chief component, and Kajigamori-base as the minor component is A. sanyoense var. tonense NAKAI. The specimen, Ochiai No.1, which contains ignavine and mesaconitine but not hypognavine, is not the former species.
The action of alkali on patulin, the toxic substance produced in the culture of Penicillium urticae BAINIER, isolated as the cause of feed poisoning, was examined. It was thereby found that the application of 3 moles of alkali to 1 mole of patulin resulted in complete decomposition of patulin, forming a brown powder which seems to melt slightly at 100° but the majority remains intact even above 300°. This powder is almost insoluble in many of the organic solvents but has become easily soluble in water, and has lost the antibacterial action or toxicity. Similar substance was obtained from the culture medium which had become alkaline and lost its toxicity. Paper chromatographic examination revealed that this substance is identical with that obtained from patulin by the application of alkali. These experimental results indicate that the cause of decomposition of patulin in the culture medium can be attributed to the change of pH.
The reaction of pyridine 1-oxide and tosyl chloride in boiling nitrobenzene affords N-(α′-pyridyl)-α-pyridone p-tosylate in 35% yield. The anhydrate of quinoline 1-oxide (I), when allowed to stand over night in chloroform solution with tosyl chloride, forms p-tosylate of (I) while the solution of the hydrate of (I) in chloroform, dried over sodium sulfate and refluxed with tosyl chloride, forms p-tosylate of carbostyril (II). Decomposition of its recrystallization mother liquor affords (II), 4-chloroquinoline, and N-(α′-quinolyl)carbostyril.
1) Two kinds of aconite plants (Ochiai No.3 and No.4) were collected near Jofukuji, Kajigamori, Kochi Prefecture, and their alkaloidal components were examined. Specimen No.3 yielded hypognavine as the chief component and a new Kajigamori Base as prismatic crystals of m. p. 107-110°, [α]D28 0±0.5° (CHCl3), C21H21-23O4N-(OCH3)2 (no ester group according to the infrared spectrum). Specimen No.4 contained mesaconitine as the chief component and a small amount of hypaconitine. These results revealed that the Kajigamori plants reported earlier had been a mixture of the Specimens No.3 and No.4. 2) Plants collected in the mountains of Katsuyama, Fukui Prefecture, were examined. a) The specimen (Ochiai No.2) collected around Wasadani yielded hypognavine, Kajigamori Base, and a new Katsuyama Base-I as prisms, m. p. 283-285°, [α]D24: +90.93° (MeOH), C22H27-29O3N (no ester group according to the infrared spectrum), indicating that the Wasadani and Kabeshita specimens reported earlier had been mixed with the Akakabe specimen (Ochiai No.1). b) The specimen (Ochiai No.22) collected around Ipponmatsu area yielded a new Katsuyama Base-II as needles, m. p. 243-245° (decomp.), C29H35O6N (presence of benzoyloxy and acetyloxy groups indicated by the infrared and ultraviolet spectra). 3) The aconite plants collected in Hieizan, Kyoto Prefecture, and Bunagatake, Shiga Prefecture, were found to contain ignavine and mesaconitine as the chief components and to be identical in componental makeup as the specimen (Ochiai No.1) collected in Akakabe, Katsuyama, Fukui Prefecture.
The alkaloids isolated to date from Coptis japonica MAKINO are berberine, palmatine, coptisine, and worenine and they are all berberine-type quaternary bases. An aporphine-type quaternary base, magnoflorine, was newly separated from this plant.
Components of the Chinese crude drug “Fang-chi” or “Fenfang-chi” were examined and it was found that the chief component is a bitter principle, besides starch, and only an extremely minute amount of a water-soluble, quaternary base alkaloid, magnoflorine, was detected. From the standpoint of alkaloidal chemistry, this crude drug probably originates from Stephania hernandifolia WALP.
The mycelium of Penicillium tardum THOM. cultivated on a Czapek-Dox medium containing 5% glucose at 25° for 14 days was treated as indicated in Chart 1 and rugulosin and skyrin were obtained. Rugulosin was found to have one-third the toxicity of luteoskyrin.
Antihistamine activity was examined with several compounds derived from chlorprophenpyridamine whose pyridyl group had been substituted with 4-(2-picolyl) or 4-(2, 6-lutidyl) group. A definite relationship was found to exist between chemical structure and antihistamine activity of these compounds. The effect was the strongest in 1-p-chlorophenyl-1-[4-(2-picolyl)]-3-dimethylaminopropane, the effect being 50% of that of diphenhydramine, while its intracisternal injection showed weaker suppressive action than diphenhydramine. The effect of this compound on blood pressure and respiration was about the same and surface anesthetic action was somewhat weaker.
Oxocarboxylic acids were obtained in a high yield by the Gilman's ketone synthesis. Reduction of these acids afforded straight-chain higher fatty acids, such as eicosanoic, docosanoic, tetracosanoic, hexacosanoic, octacosanoic, triacontanoic, and dotriacontanoic acids. Their properties are also described.
The aconite (Ochiai Specimen No.25) collected around Ashio, Kyoto Prefecture, was found to contain hypognavine and Ashio-base I (m.p. 142-145°; [α]D28: -5.45°; C24H37-39 O5N, with 3 OCH3, 1 NCH3 (or NC2H5)). It also contained a minute amount of a base occurring as prismatic crystals of m.p. 294-296° (decomp.) and a small amount of the following bases: Kajigamori-base, Katsuyama-base II, Ashio-base II (hydrobromide, m.p. 333° (decomp.); [α]D19: +97.69°; C29H33O6N⋅HBr; infrared spectrum suggests BzO-, AcO-, and >C=CH2 groups), Ashio-base III (m. p. 310-313° (decomp.); [α]D8:+48.04°; C27H31O6N⋅1/2H2O; its infrared spectrum suggests the presence of OH and BzO-groups), and Hanamiyama-base (m.p. 246-247°; [α]D28: +120.6°; its infrared and ultraviolet spectra suggest the presence of a BzO- group.
Since the experiments reported in the preceding paper had shown that the soy sauce, used as the medium for mold-prevention tests, could be substituted with the Henneberg medium (15% glucose, 0.5% peptone, 0.5% K2HPO4, 0.2% MgSO4, 3% NaCl) suited for the growth of Zygosaccharomyces salsas and Z. japonicus, 27 compounds were selected from those already tested with soy sauce and submitted to mold-prevention tests in this medium. It was thereby found that about one-half of the compounds gave the same results as before, while the others behaved differently. It had been concluded from earlier tests that with compounds of the same skeleton, the increase in the size of alkyl group and introduction of a halogen resulted in the increase of mold-preventing activity. From such a point of view, the present experimental results seem to be more correct than the past method.
Manometric assay of Gunsalus and others was carried out with Streptococcus faecalis (strain 10 Cl) and it was found that the ability of DL-dimethyldihydro-α-lipoic acid to oxidize pyruvic acid is much weaker than that of DL-α-lipoic acid.