In order to test antibacterial activity, 36 kinds of 4-alkyl- and 4-arylthiosemicarbazones of pyridinealdehyde were synthesized, 2-Pyridinealdehyde 4-substituted thiosemicarbazones were prepared by application of 4-alkyl- and 4-arylthiosemicarbazides to pyridinealdehyde, while 3- and 4-pyridinealdehyde 4-substituted thiosemicarbazones were prepared by starting from nicotinic acid hydrazide and isonicotinic acid hydrazide, deriving them to 1-nicotinyl-2-benzenesulfonylhydrazine and 1-isonicotinyl-2-benzenesulfonylhydrazine, and application of 4-alkyl- or 4-arylthiosemicarbazide without forming the free aldehyde. Antitubercular tests of these compounds against human-type tubercle bacilli, H37Rv strain, gave following results: 1) Introduction of aryl group into nitrogen in 4-position of the thiosemicarbazono group (=N-NH-CS-NH2) showed stronger action than introduction of alkyl group. 2) Antibacterial activity of the 4-aryl- and 4-alkylthiosemicarbazones of 2-pyridinealdehyde was stronger than that of the original thiosemicarbazone, while those of 3- and 4-pyridinealdehydes were weaker than that of the original thiosemicarbazones.
Dehydroacetic acid monoimide reacts with cupric acetate in aqueous solution to form a copper chelate (DC-I). Such copper chelates are also formed by reaction with cupric chloride or sulfate. On the other hand, the product (DC-C) obtained by Collie by the addition of dehydroacetic acid to a mixture of conc. ammonia and cupric acetate seemed to have properties similar to those of the copper chelate (DC-I) obtained in the present series of experiments and therefore, comparative examination of these chelates was made. It was therefore found that (DC-C) is the same as the abovedescribed copper chelate (DC-I) and that they differ only in the amount of water of crystallization. The dried samples of (DC-I) and (DC-C) were identical. The one interesting behavior of this copper chelate is that the co-existence of this copper chelate with dehydroacetic acid in a solution results in the formation of dehydroacetic acid-copper chelate while dehydroacetic acid imide-copper chelate changes into dehydroacetic acid-copper chelate, showing that the so-called ligand exchange reaction had taken place.
Surface tension was measured with 0.0025M aqueous solution of N-acyl-4-acetamido-1-naphthalenesulfonamide, N-acyl-4-aminobenzenesulfonamide, and 4-(4-alkyl-benzenesulfonamido) benzoic acid. It was thereby found that compounds with a long carbon chain, above that of the capryl group, showed extremely low surface tension and that this was in parallel with their antiviral activity. Penetration of these compounds through mono molecular layer of cholesterol and lecithine was examined and antiviral N-lauroyl-4-acetamido-1-naphthalenesulfonamide increased surface pressure of the mono molecular layer of cholesterol and lecithine, and that this action is inhibited by serum albumin. The same experiment with sodium laurylsulfate showed that its action against mono molecular layer of cholesterol was also inhibited by serum albumin, this inhibition being stronger than in the case of the sulfonamide mentioned above. It was considered that this difference is controlled by the strength of bonding of these compounds with serum albumin and that this was one of the reasons why N-lauroyl-4-acetamido-1-naphthalenesulfonamide is not inactivated in vivo.
The racemic compound of bulbocapnine (I), the tertiary phenolic base of aporphine type obtained from Corydalis tuberosa DC. (Papaveraceae), was synthesized by the route shown in Chart 1. This dl-bulbocapnine (I), m.p. 213-214°, was derived to l-bulbocapnine d-tartrate by the application of d-tartaric acid, and l-bulbocapnine (Ib), m.p. 202-203°, was obtained in pure state from this d-tartrate. The application of l-tartaric acid to dl-bulbocapnine (I) gave d-bulbocapnine l-tartrate, from which pure d-bulbocapnine (Ia), m.p. 201-203°, was obtained. Application of methyl iodide to d- and l-bulbocapnines so obtained afforded the quaternary phenolic base of aporphine type, d- and l-bulbocapnine methiodides (XIa and XIb), m.p. 253-254° (decomp.), and the methiodides were converted by silver chloride into respective methochlorides (XIIa and XIIb), m.p. 226-228° (decomp.).
Thirty kinds of compounds with 2-amino-4-phenylthiazole as the parent compound were synthesized in three series of 2-acylamino-4-phenylthiazole with C2-C16 acyl group, 2-acylamino-4-(p-tolyl) thiazole, and 2-amino-4-(p-alkylphenyl) thiazole with C1-C12 alkyl group. None of these compounds had powerful antitubercular activity but 2-amino-4-phenyl-, 2-amino-4-(p-tolyl)-, and 2-amino-4-(p-decylphenyl) thiazoles showed weak activity in vivo against the Nakayama strain of Japanese B encephalitis virus.
A new tertiary non-phenolic base, thalicthuberine, was isolated as colorless silky crystals, m.p. 126-127°, from the root of Thalictrum Thunbergii DC (Ranunculaceae) from Tokushima. The composition and empirical formula of this substance corresponded to C21H23O4N=C16H9(OCH3)2(N(CH3)2)(-O-CH2-O-). Its ultraviolet spectrum suggested the presence of a phenanthrene skeleton. It was optically inactive. On the other hand, O-methyldomesticine was isolated from the commercial fruit of Nandina domestica and was derived to its methylmethine by Hofmann degradation. Comparison of this methine base and thalicthuberine by mixed fusion test, and their ultraviolet and infrared spectral analyses showed the two to be identical substances. Consequently, thalicthuberine was found to be 1-dimethylaminoethyl-3, 4-dimethoxy-6, 7-methylenedioxyphenanthrene (VII).
A new tertiary phenolic base, thalicberine, was isolated from the leaf base of Thalictrum Thunbergii DC. as colorless needles of m.p. 161° (sint. 155°), [α]D+231.2° (CHCl3), and a new tertiary non-phenolic base, O-methylthalicberine, as colorless needles, m.p. 186-187°, [α]D+265.9° (CHCl3). This latter base was also isolated from the leaf base of commercial crude drug, “Takatogusa.” On the other hand, thalicberine was O-methylated to form O-methylthalicberine and this was proved to be identical with natural O-methylthalicberine from elementary analytical values, optical rotation, mixed fusion, and by comparison of infrared spectra in Nujol. The composition and empirical formula of thalicberine are represented as C37H40O6N2⋅H2O=C32H24O2(OCH3)3(OH)(N-CH3)2⋅H2O, and those of O-methylthalicberine as C38H42O6N2=C32O24O2(OCH3)4(N-CH3)2. O-Methylthalicberine dimethochloride was submitted to the Hofmann degradation to be derived to the methylmethine which was oxidized with potassium permanganate to form 2-methoxydiphenyl ether-5, 4′-dicarboxylic acid (I). The experimental evidences, ultraviolet spectra (Fig. 1, A and B), and optical rotation suggest that both these are new bases closely related to the oxyacanthineberbamine series of the biscoclaurine-type bases.
In order to elucidate the structure of O-methyl thalicberine, cleavage reaction of it (I) with metallic sodium in liquid ammonia was carried out. It was thereby found that (I) is bisected almost quantitatively into d-O, O, N-trimethylcoclaurine (II) and d-N-methylisococlaurine (V). The same reaction of O-ethylthalicberine (VII) was also found to effect almost quantitative cleavage into d-N-methylisococlaurine (V) and d-O-ethylarmepavine (VIII). These experiments have proved that the one phenolic hydroxyl in thalicberine is present in the position ortho to the ethertype oxygen binding the benzyl groups (formula (VI)). Of the two phenolic hydroxyls in the bisected phenolic base, d-N-methylisococlaurine (V), one in the benzyl portion was naturally formed by cleavage of the ether linkage forming the diphenyl ether structure and the other hydroxyl in 6-position of the isoquinoline ring must also have been formed by cleavage of oxygen bridge forming the diphenyl ether since O-methylthalicberine (I) possesses four methoxyls. The other position at which this ether linkage is bonded was assumed to be 8-position in the isoquinoline ring considering biogenesis of the natural bases of this type and from all other bases of the oxyacanthine-berbamine series. Based on these and other experimental results, the formula (XVIII) is forwarded for thalicberine and formula (XIX) for O-methylthalicberine. It was later proved that the spatial arrangement (optical direction) of the two asymmetric centers in (XVIII) and (XIX) is (+, +) in both.
From the leaves of Neolitsea sericea (BLUME) KOIDZ., 3 kinds of phenolic base (I to III), 3 kinds of non-phenolic base (IV to VI), 3 kinds of water-soluble base (VII to IX) as styphnates, were isolated. Of these, boldine (I) and roemerine (IV) are structurally known bases. (II) and (VI) were thought to be new bases and were respectively named laurolitsine and litsericine. (III) and (V) were contained in the plant in trace amounts and were respectively designated as base-III and base-V. Molecular formulae presumed from their analytical values are as follows: Laurolitsine (II), C18H19O4N=C16H10(OH)2(OCH3)2(NH). Base-III, C19H19O4N=C16H10(O2CH2)(OH)(OCH3)(NCH3). Base-V (isolated as its hydrochloride), C19H17O4N⋅HCl. Litsericine (VI), C17H21O3N=C16H18N(O2CH2)(OH). (VII)-styphnate, C6H14(16)ON⋅C6H2O8N3. (VIII)-styphnate, C9H18ON⋅C6H2O8N3. (IX)-styphnate (choline styphnate), C5H14ON⋅C6H2O8N3.
The rearrangement of methylpyrazines N-oxides with acetic anhydride was examined to see whether this reaction goes in the analogous way as known in the case of 2-picoline 1-oxide. 2-Methylpyrazine 1-oxide, 4-oxide, and 1, 4-dioxide were subjected to this reaction and the following results were obtained. (1) 2-Methylpyrazine 1-oxide was converted through 2-acetoxymethylpyrazine to 2-pyrazinemethanol. (2) The reaction did not occur and the starting material was recovered in the case of 4-oxide. (3) 2-Acetoxymethylpyrazine, 2-acetoxymethylpyrazine 4-oxide, and 2-methylpyrazine 1-oxide were obtained from 2-methylpyrazine 1, 4-dioxide.
The hydroxymethyl groups in pyridoxine, pyridoxamine, pyridoxal, and their derivatives form deoxygenated derivatives of pyridoxine by catalytic reduction over palladium-carbon. Similarly, 2-, 3-, and 4-pyridinemethanols also form corresponding picolines by catalytic reduction. The presence of water is necessary as a solvent in the case of pyridoxine derivatives while the solvent is not required in that of pyridinemethanols. Since the acylation of the hydroxymethyl group in both derivatives results in more facile reduction to methyl group, this reaction was considered to be the direct hydrogenolysis.
Friedelin and epifriedelinol were isolated and identified from the dried root of Aster tataricus. Shionone, m.p. 158.5-159.5°, isolated and named by Nakaoki in 1932, was also obtained. It was assumed that this substance is a four-ringed triterpenoid, C30H50O, possessing one carbonyl. Besides these, a substance assumed to be astersaponin, isolated and named by Nakaoki in 1929, was also obtained.
The Meyer-Schuster rearrangement reaction of several kinds of acetylenic alcohol was examined and it was found that the compounds possessing hydroxyl group adjacent to one triple bond and the compounds possessing a hydroxyl between two triple bonds underwent normal Meyer-Schuster rearrangement reaction when refluxed for several hours in dioxane containing dilute sulfuric acid. By this reaction, 3-phenyl- and 3-(1-naphthyl)-1-propyn-3-ols, 1-phenyl-2-heptyn-1-ol, 1-phenyl-2-butyn-1-ol, and 1, 5-diphenyl-2, 4-pentadiyn-3-ol respectively formed cinnamaldehyde, 3-(1-naphthyl) acrolein, 1-phenyl-1-hepten-3-one, 1-phenyl-1-buten-3-one, and 1, 5-diphenyl-2-penten-4-yn-1-one. 1, 5-Diphenyl-1, 4-pentadiyn-3-ol was formed from phenylethynylmagnesium bromide and phenylpropargylaldehyde.
Reaction of phenylethynylmagnesium bromide with cinnamaldehyde and crotonaldehyde respectively forms 1, 5-diphenyl-1-penten-4-yn-3-ol (I) and 6-phenyl-2-hexen-5-yn-4-ol (II). Treatment of (I) with 16% sulfuric acid solution by shaking for 24 hours at room temperature results in recovery of the starting material and (I) does not undergo allyl rearrangement, while the heating of (I) in dioxane containing sulfuric acid for 7 hours results in normal Meyer-Schuster rearrangement and 1, 5-diphenyl-2, 4-pentadien-1-one is formed. (II) undergoes allyl rearrangement when shaken with 16% sulfuric acid solution for 24 hours at room temperature to form 6-phenyl-3-hexen-5-yn-2-ol which, when heated in dioxane with dil. sulfuric acid for 7 hours, changes into 6-phenyl-1, 3-hexadien-5-yne. Heating of (II) with dilute sulfuric acid in dioxane solution results in formation of 6-phenyl-1, 3-hexadien-5-yne and the product of normal Meyer-Schuster rearrangement, 1-phenyl-2, 4-hexadien-1-one. Oxidation of 6-phenyl-2-hexen-5-yn-4-ol and 6-phenyl-3-hexen-5-yn-2-ol with manganese dioxide affords the corresponding unsaturated ketones, 6-phenyl-3-hexen-5-yn-4-one and 6-phenyl-3-hexen-5-yn-2-one.
Attempt was made to determine the quantity of primary amine in aqueous solution of amines by the yellow coloration of the Schiff base formed from a primary amine and 3, 5-dibromosalicylaldehyde in ethanol. Determination conditions were established for methylamine hydrochloride, homosulfanilamide, aniline, and sulfanilamide. The best result was obtained by colorimetry at a wave length of 425mμ in pH 5.1 solution. This determination is not affected by the presence of secondary and tertiary amines, or ammonium salt in amount less than 200, 500, and 500γ/cc., respectively. The acid amide does not show this coloration.
Oxidation of pyridoxine 5-phosphite (IV), after acylation, with potassium permanganate and subsequent deacylation affords pyridoxine 5-phosphate (VII) in a good yield. Similarly, 4-N-benzoylpyridoxamine 5-phosphite (XII) affords its 5-phosphate (XIII) in 59% yield. Direct oxidation of (IV) with permanganate affords pyridoxal 5-phosphite (VIII) in 20% yield. Reaction of compounds allied to pyridoxine and diphenyl chlorophosphite was described.
Condensation of 2-methylbenzothiazole, having one active methyl group, with six kinds of primary amines substituted with methyl, methoxyl, ethoxyl, isopropoxyl, propoxyl, and butoxyl, in the presence of sulfur, was carried out. Although the yield was different, two forms of thioanilide and bis-benzothiazole were formed from each amine. The same reaction was carried out with nitrobenzene and six kinds of corresponding nitro compounds. Nitrobenzene gave both forms of the product while p-nitrotoluene formed the thioanilide alone. The reaction did not seem to proceed with other compounds probably due to the resistance of the nitro group to reduction to the corresponding amino compounds with nascent hydrogen sulfide produced in the first stage of this reduction. Therefore, electronic considerations were made on the six kinds of para-substituents on the nitro group based on the reduction potential of the nitro group by polarography at pH 4, 6, and 8. Finally, in order to clarify the difference in the chemical structure between the foregoing two forms, ultraviolet spectra of several compounds were measured.
The secondary cortex of the crude drug Phellodendron appears in its cross-section, as shown in Fig. 1, as fine squares formed by the crossing of numerous fiber bundles and medullary rays. Each of these squares was examined by three kinds of ratio, called fiber ratio; i.e. number of thin-walled cells to number of fibers, number of mucilage cells to number of fibers, and number of crystal cells around the fiber bundle to number of fibers. Statistical examination of these ratios showed that domestic Phellodendrons cannot be distinguished by plant anatomy alone and that these ratios seemed to vary greatly according to habitat and by each individual. The cortex of Phellodendron from Southern area is suitable as the material for crude drug or for manufacture of berberine while that from the North would be suitable for preparing aqueous extract.
In order to find synthetic anti-ameba agent, hydrogenated benzoquinolizines (A) with basic side chain of -(CH2)nN(CH3)2 type were prepared. The quaternary salt (I), obtained from nicotine monohydrochloride and 2, 4-dimethoxyphenethyl bromide, was oxidized to the pyridone (II), hydrogenated to the piperidone (III), and submitted to the Hofmann degradation to the methine base, which was fouud to have the formula (IV) from optical rotation, infrared spectrum, and behavior of its methiodide to oxidation with potassium permanganate or ozone. The second Hofmann degradation of (IV) was carried out to confirm the presence of trimethylamine and a butadiene compound (VI) was obtained. The permanganate oxidation of its butene compound (VIII) to the compound (IX) with carboxymethyl side chain, and its cyclization and reduction afforded the quinolizine ester (X). From its amide (XI), the amide (XIII) of (A) type with n=2 was obtained. Cyclization of the hydrogenated product (XIV) of (IV) with phosphoryl chloride afforded the amine (XV) of (A) type with n=4. The Hofmann degradation of (XIV) afforded an unsaturated neutral substance (XVI) whose structure was also confirmed. Oxidation of (XVI) with potassium permanganate gave a compound with -(CH2)2-COOH side chain and an amine (XX) of (A) type with n=3 was obtained from it by the same procedure as with (IX).
In order to obtain amebacidal agent, 2-dimethylaminoethyl-3-methyl-9, 10-dimethoxy-1, 2, 3, 4, 6, 7-hexahydro-11bH-benzo [a] quinolizine (IX) was prepared. Dieckmann con-densation of ethyl N-(3, 4-dimethoxyphenethyl)-N-(ethoxycarbonylpropyl) malonamate (I) afforded a β-ketoester (II), soluble in dilute sodium hydroxide solution and giving positive reaction to ferric chloride. Ketonic decomposition of (II) with 10% acetic acid followed by dehydrative condensation with ethyl cyanoacetate, and subsequent esterification, decarboxylation, and reduction afforded the carboxylic acid (VI). Cyclization and reduction of (VI) gave the quinolizine ester which was further derived to the amine (IX). The condensate (Xa) obtained from 3, 4-dimethoxyphenethylamine, 1, 1, 2-ethanetricarboxylic acid, and formaldehyde underwent automatic decarboxylation to form an aminodicarboxylic acid (XIa). Its esterification and condensation with ethoxycarbonylacetyl chloride gave the amide (XII) which was derived to the ketoester (XIV) as above, converted to the thioketal, and desulfurized and reduced to the homo acid (XVI). The use of 1, 1, 3-propanetricarboxylic acid gave an aminotricarboxylic acid (Xb) which was boiled with 60% acetic acid to effect decarboxylation and cyclization to form the lactam (XVIII) and its Arndt reaction gave the homo acid amide (XX). The compounds (XVI) and (XX) are intermediate for the preparation of the objective amine (A).
Ethyl 9, 10-dimethoxy-1, 2, 3, 4, 6, 7-hexahydro-11bH-benzo [a] quinolizine-3-acetate (I) was submitted to reduction with lithium aluminum hydride and the alcohol compound (III) so obtained was derived to the bromide (III). Heating of this bromide in benzene produced intramolecular ammonium salt and 1-aza-bicyclo [3.3.1]-type compound (IV) was obtained in high yield. Similar reaction, starting with quinoline ester (V) afforded 1-azabicyclo[2.2.2]-type compound (IX).
Presence of resveratrol and 3, 4-dihydroxyacetophenone in the Picea genus, Picea Glehnii, and four other kinds of plant leaves was examined and these components were found to be distributed widely in the leaves of Eupicea section plants. The components were isolated in crystalline state. Piceol was found only in Picea Glehnii.
Juniperic acid, the representative component of the estolide-type waxes of Coniferae, and several analogous compounds were prepared by the anodic synthesis. Juniperic acid was obtained from dimethyl thapsiate, which started from methyl hydrogen azelate, through methyl hydrogen thapsiate and ethyl 15-methoxycarbonyl-pentadecanthiol oate. Thapsic acid and 1, 16-hexadecanediol were prepared from dimethyl thapsiate. 1, 12-Dodecanedioic acid was prepared by mixed Kolbe electrolysis of methyl hydrogen sebacate and methyl hydrogen succinate. 1, 12-Dodecanediol was obtained by reduction of dimethyl 1, 12-dodecanedioate with lithium aluminum hydride. The purity of these synthesized acids was fairly high and the acids were considered to be very significant in the study of wax components of conifers.
Decomposition reaction of homoveratrylamine (I) and mescaline (V) with metallic sodium in liquid ammonia is comparatively difficult but their demethylation were effected and (I) afforded 3-hydroxy-4-methoxyphenethylamine (II) while (V) formed 4-hydroxy-3, 5-dimethoxyphenethylamine (VI) and a structurally unknown amine, which were obtained as their picrates. The same reaction of homopiperonylamine (III) was effected comparatively either with metallic sodium or lithium, with reductive proceeding solely to form tyramine (IV).
It had been found that epinephrine underwent decomposition with hydrochloric acid partially forming a compound having a dibenzocycloheptatriene ring. Ephedrinetype compound possessing alkoxyl in 3- and 4-positions of benzene ring was also expected to undergo the same reaction but its acid decomposition unexpectedly afforded 3, 4-dialkoxyphenylacetone as the main product. This shows that the reaction is no different from the so-called hydramine decomposition and a sevenmembered compound was not obtained in this reaction.
Colorless microneedles, m.p. 254-255°, were obtained from the fresh leaves of Circium microspicatum NAKAI, C. Otayae KITAMURA, C. Yoshizawae KOIDZ., and C. japonicum DC., and this substance was identified as pectolinarin (scutellarein 6, 4′-dimethoxy-7-rhamno-glucoside). The respective yields were 2%, 2.5%, 0.3%, and 2.1%. Colorless needles, m.p. 253-254°, were obtained from the fresh leaves of C. purpuratum MATSUMURA and this was identified as acacetin rhamnoglucoside. The yield was 0.3%.
Leaf wax of three plants of Picea genus and wax components of four kinds of Casuarina spp. were examined, and it was clarified that the leaf wax of Picea genus was all estolide type and that of Casuarina was a non-estolide type. Components of the leaves of the grafted plants of Taxodiaceae were examined and leaf waxes of the scion was found to be different types in deciduous and evergreen, and that the effect of stock was not evident in the leaf component of the scion. The latter fact was revealed through studies on leaf waxes and examination of flavonoid components.
Attempts were made to elucidate the action mechanism of INAH and several of its derivatives by the utilization of their action in inhibiting growth of Lactobacillus. All these substances were found to show marked inhibition in a concentration of 0.25×10-2M and the inhibition was completely reversed by pyridoxal and pyridoxamine. On keeping the aqueous solution of INAH-G in an incubator, its inhibitive activity became closer to that of INAH, the stronger the longer the period in the incubator. 1-Isonicotinyl-2-methylhydrazine which hardly forms INAH by hydrolysis, showed no inhibitive activity. It was assumed from these experiments that the antibacterial activity of INAH derivatives is due to that of INAH formed by hydrolysis and the antibacterial action of INAH is the result of inactivation by formation of Schiff base with pyridoxal.
Several compounds were found to have strong activity by the in vitro screening of 1, 300 kinds of organic compound against tumor by the cylinder-plate method. Antitumor activity of furan and thiophene derivatives among these compounds was tested against Ehrlich solid tumor in mice.
2-Oxo-2, 3, 4, 4a, 6, 7-hexahydro-5H-dibenzo [a, c] cycloheptatriene (II) and 3-oxo-11b-methyl-1, 2, 3, 6, 7, 11b-hexahydro-5H-dibenzo [a, c] cycloheptatriene (VI) were reduced with lithium aluminiumhydride to the corresponding alcohols (III and VII) and dehydrogenated to dibenzo [a, c] cyclohepta-1, 3-dione (IV). The result of these reactions has proved the structure of the product obtained by the Robinson-Mannich reaction of 5-methyl-5, 7, 8, 9-tetrahydro-6H-cycloheptabenzen-6-one to be (VI).
In order to examine the possibility of cultivating licorice in Hokkaido, Glycyrrhiza echinata, G. uralensis, and G. glabra were cultivated since 1955, and the state of growth and seeding were observed. The plants harvested in 1958 were examined for the content of extract and glycyrrhizin. It was found from the state of growth and content of glycyrrhizin that it is possible to cultivate licorice in cold area.