Condensation of various 1-alkyl-3-aminoguanidine with 1, 5-bis(5-nitro-2-furyl)-3-pentadienone produced methyl, ethyl, propyl and dimethyl derivatives in better yields. Chemical properties of the compounds, as well as antibacterial activities against various bacteria have been studied. Especially, methyl compound, 1, 5-bis(5-nitro-2-furyl)-3-pentadienone N4-methylamidinohydrazone⋅HCl was found to show remarkable antibacterial activities against Gram positive bacteria, and also to show considerable activities against Gram negative bacteria. The compound with low toxicity was demonstrated to be absorbed into living body by oral administration and to activate urine.
Decomposition of 1, 5-bis(5-nitro-2-furyl)-3-pentadienone N4-alkylamidinohydrazone by heating in organic solvent, in the presence of a basic catalyst, resulted in the formation of a 1, 2, 4-triazine ring inside the molecule and a series of new compounds, 3-alkylamino-6-[2-(5-nitro-2-furyl)vinyl]-as-triazines, were obtained. These triazine derivatives had a wide antibacterial spectrum and were found to inhibit the growth of gram-negative bacteria (dysentery, typhoid, and coli bacilli) in a dilute solution of 10, 000, 000 to 40, 000, 000 dilutions. Moreover, these derivatives were found to have very low toxicity and their oral administration resulted in good absorption, with excretion of urine retaining marked antibacterial activity.
In order to examine the effect of metal salts on the blood level of chloramphenicol, oral administration of chloramphenicol solution, containing ferrous lactate, calcium lactate, magnesium oxide, or synthetic aluminium silicate, was made in rabbits and blood level of chloramphenicol was measured. In all of these cases, there was retardation of the time required until highest blood level is reached or clear indication of maximum blood level, compared to administration of chloramphenicol alone. Combined use of sodium ethylenediaminetetraacetate or sodium metaphosphate in this case showed the same blood level as that of chloramphenicol alone. Factors influencing blood level might also include crystal size, chloramphenicol crystals of various size were administered similarly. Measurement of blood level indicated that administration of fine crystals resulted in the highest blood level one hour after administration and this time required to reach the highest level lessened gradually as the crystal size became larger. However, there was no difference in the amount of total nitro compound excreted into the urine according to crystal size and this probably suggests that there is no difference in the absorption of chloramphenicol according to its crystal size.
Chloramphenicol undergoes marked biotransformation to become inactivated and in order to inhibit this inactivation, prolongation of its action was attempted by the following method. A method for measuring the rate of inactivation was devised by examination of various conditions using liver slice of a guinea pig and this rate was measured with addition of various compounds. Comparative examination with chloramphenicol concentration at 10-4M and additive concentration of 10-3 to 10-5M showed that dozens of chemicals, including phenothiazine and ethanolamine derivatives, had the effect of inhibiting this inactivation. Several of these chemicals were tested with rabbits and combined use of these chemicals was found to give longer duration of a high blood level than by administration of chloramphenicol alone.
Chloramphenicol is rapidly absorbed and attempts were made to prolong the duration of its action by controlling this absorption. Chloramphenicol was made into granules using a binder which would undergo disintegration in digestive tract and liberate chloramphenicol gradually, and this rate of dissolution was examined. Several kinds of granules showing different dissolution curve were selected and these were administered orally to rabbits to measure the blood level of chloramphenicol. It was thereby found that the blood level of chloramphenicol is low at the beginning but clearly showed longer duration and the dissolution curve in vitro was found to give a suggestion of duration of granules. In order to increase the initial concentration of granules, chloramphenicol crystal was administered orally at the same time and this was found to give a constant blood level for 10hours after the administration.
Two kinds of new flavone glycoside were isolated from the fresh leaves of Phegopteris polypodioides FÉE and they were named phegopolin (I) and phegokaempferin (II). (I) is obtained as yellow needle crystals of m.p. 203-204°, [α]D30 -31.64°, and its molecular formula corresponded to C22H22O10⋅H2O. Its hydrolysis yielded genkwanin and glucose but the properties of (I) were different from those of glucogenkwanin, coloring greenish brown to ferric chloride and its complete methylation being difficult, indicating the presence of a free hydroxy in 5-position. Consequently, the structure of genkwanin 4′-glucoside was given to phegopolin (I). (II) is obtained as pale yellow needle crystals of m.p. 190-191°, [α]D30 -65.33°, and its molecular formula corresponded to C26H28O15⋅H2O. Its hydrolysis yielded kaempferol, arabinose, and glucose. Complete methylation of (II) with diazomethane, followed by hydrolysis produced 3-hydroxy-4′, 5, 7-trimethoxyflavone, showing that the sugar is bonded to 3-position as a disaccharide. Consequently, phegogaempferin (II) would be kaempferol 3-glucoarabinoside.
Three kinds of new, natural xanthones, named athyriol (I), isoathyriol (II), and norathyriol (IV), were isolated from the acetone extract of fresh leaves of Athyrium mesosorum MAKINO, together with mangiferin (V) and hydroquinone (III). Norathyrial (IV) is obtained as pale yellowish brown needle crystals of m.p. above 320° and its molecular formula corresponded to C13H8O6. It was identified with 1, 3, 6, 7-tetrahydroxyanthone from its physical properties and the result of methylation. Athyriol (I) is obtained as pale yellowish brown needle crystals of m.p. 300° (decomp.), C14H10O6. Isoathyriol forms pale yellow needle crystals of m.p. 325° (capillary), C14H10O6. Both (I) and (II) had one methoxyl group, formed a triacetate by acetylation, and 1-hydroxy-3, 6, 7-trimethoxyxanthone by methylation. Therefore, they must be monomethyl derivatives of (IV), having a methoxyl group in 3-, 6-, or 7-position. (V) was identified with mangiferin from its physical properties and formation of norathyriol by the action of hydriodic acid.
The structures of both athyriol and isoathyriol have been investigated. Phloroglucinol and 2, 4, 5-trihydroxybenzoic acid was condensed, in a presence of zinc chloride and phosphorus oxychloride to norathyriol through a novel reaction applying the Grover method. Following the same route of reaction, 1, 3, 6-trihydroxy-7-methoxyxanthone (II) from 2, 4-dihydroxy-5-methoxybenzoic acid, as well as 1, 3, 7-trihydroxy-6-methoxyxanthone (III) from 2, 5-dihydroxy-4-methoxybenzoic acid were synthesized. Isoathyriol was identical with (III) and its triacetate was also identical with 1, 3, 7-triacetoxy-6-methoxyxanthone, therefore the structure of athyriol has been determined to be (III). As to the athyriol, it was identical neither with (II) nor (III) and the color reaction suggested a presence of free ortho-diphenolic structure, therefore, 1, 6, 7-Trihydroxy-3-methoxyxanthone has been determined as a structure of athyriol.
Total alkaloid assay in Rauwolfia serpentina root was modified to use petroleum ether for preliminary extraction, by which the emulsion was prevented and analytical procedure was improved. The total alkaloid content in domestic plant was measured by this modified method using individuals according to age of the plant and to month of the year. The relative content ratio of strong basic alkaloids was roughly estimated by using ultraviolet spectra of total alkaloids. The pattern on the paper chromatogram of the total alkaloid in the domestic plant was similar to that of the foreign origin. The low content of strong basic alkaloid in the domestic plant seemed to be the distinct difference from the plant of the foreign origin.
The modified Carol-Banes method for reserpine-rescinnamine assay was discussed. It was considered that such procedure would be unlikely to find favor as a routine work. The other recommended assay was proposed, in which the weakly basic alkaloidal fraction was separated by the extraction method, then hydrolysed to the acidic fraction and alkamine component. The ether-soluble acidic fraction, containing trimethoxybenzoic acid and trimethoxycinnamic acid exclusively derived from reserpine and rescinnamine, was determined spectroscopically. The content of these alkaloids in domestic plant was found to be as follows: Average content in first-year growth, 0.109, 0.044%; second-year growth, 0.088, 0.041%; third-year growth, 0.071, 0.040%; fourth-year growth, 0.083, 0.051%. The highest content of reserpine plus rescinnamine was observed in August and the lowest in December.
The Huang-Minlon reduction of sinomenine gives deoxosinomenine (VIII), together with demethoxydeoxodihydrosinomenine (II) as a byproduct. Reduction of methylsinomenine (XIV) with sodium borohydride gives methylsinomeninol-A (XV) and methylsinomeninol-B (XVI), which were found to be epimers originating in the hydroxyl at 6-position. Catalytic reduction of methylsinomeninol-A (XV) afforded methyldihydrosinomeninol-A (XVII) and demethoxy-methyldihydrosinomeninol-A [(+)-dihydrothebainol-A methyl ether] (XX). From the result of these experiments, direct correlation was established between sinomeninol-A (VI) and dihydrothebainol-A (XXI) with regard to the configuration of their hydroxyl at 6-position.
Dihydrothebainol-A methyl ether (XVI) is far more easily acetylated than dihydrothebainol-B methyl ether (XVIII). Catalytic reduction of dihydrothebainone 4-acetate (XXII) in glacial acetic acid over platinic oxide resulted in formation of dihydrothebainol-B 6-acetate (XXIV), besides dihydrothebainol-B 4-acetate (XXIII) which easily underwent acyl migration during alumina chromatography to transit to the 6-acetate (XXIV). These experimental evidences suggest that the hydroxyl group at 6-position of dihydrothebainol-B (XV) takes a configuration close to the hydroxyl at 4-position, i.e. axial configuration.
Acetylation of methylsinomeninol and methyldihydrosinomeninol was carried out with their respective epimers and it was found that the hydroxyl at 6-position with A-type configuration was far more reactive. This fact suggests that the hydroxyl at 6-position of methylsinomeninol-A (III) and methyldihydrosinomeninol-A (VI) takes the equatorial configuration. Sinomeninol-B 4-acetate (XII) undergoes acyl migration during alumina chromatography and forms sinomeninol-B 6-acetate (XIII). These facts suggest that the hydroxyl at 6-position of sinomeninol-B (XI) and methylsinomeninol-B (IV) takes axial configuration. The optical rotation of sinomeninol and methylsinomeninol shows greater degree of dextrorotation in A-type configuration, which is not inconsistent with Mills' rule.
Hydrolysis of methylsinomeninol-A and -B afforded the same (+)-6-hydroxy-7-oxo-3, 4-dimethoxy-N-methyl-D-morphinan The acetoxyketone compound of this morphinan derivative was derived to the thioketal by the Hauptman method and desulfurized with Raney nickel to D(+)-dihydrothebainol-A methyl ether (demethoxy-dihydromethylsinomeninol-A). These experimental evidences suggest that a part of hydroxyl at 6-position of methylsinomeninol-B undergoes inversion to take an equatorial configuration.
Derivation of dihydromethylsinomeninol-A (XIV) and dihydromethylsinomeninol-B (XVI) to their respective tosylates (XXIV and XXVII), and their treatment with 2, 4, 6-collidine afforded (-)-3, 4, 7-trimethoxy-N-methyl-Δ6-D-morphinan (XXVI) from (XXVII) and (XXVI) was proved by its hydrolysis (+)-7-oxo-3, 4-dimethoxy-N-methyl-D-morphinan (XXVIII) by treatment with dilute acid. (XXIV) failed to form the enol ether by treatment with collidine. These experimental evidences suggest that the methoxyl at 7-position in (XIV) and (XVI) takes the equatorial configuration (trans to the ethanamine chain at 13-position). It has thereby been clarified that, in the catalytic reduction of sinomenine derivatives, hydrogen adds stereospecifically from the less hindered side i.e. from the direction cis to the ethanamine chain at 13-position.
The periodate oxidation of new glucofructan “Sessilifolan, ” isolated from Lobelia sessilifolia LAMB. was found to consume one mole of periodate per hexoseunit (C6-unit) and no formic acid formation was observed in this reaction. Furthermore, neither glucose nor fructose was identified in the hydrolyzate of the oxidized product. These findings suggested that the structure of sessilifolan supposed to be nonbranched one, that two moles of glucose in the molecule situated in polysaccharide chain, not at the terminal forming 1, 4-linkage, and that, though fructose bound in 1, 2-linkage, the terminal fructose combined at the 2-position because sessilifolan did not reduce the Fehling's solution. Though sucrose was identified in the incomplete hydrolyzate of sessilifolan, any disaccharides composed from simply such glucose as maltose and cellobiose were not identified. This fact suggested that several molecules of fructose may intervene between two molecules of glucose in sessilifolan.
4-Quinolizidinone (IV) and ethyl oxalate were reacted to 3-ethoxalyl compound (V), and further hydrolyzed to α-ketonic acid (VI). The contactive reduction of ester (VII) of (VI) gave ethyl 4-quinolizidine carboxylate (XA) and (XB). In the latter, an absorption at 2700-2800cm-1, that is corresponding to trans-quinolizidine, has been observed, though it was not found in the former. By the LiAlH4 reduction of (XA) and (XB), both compounds were converted to (XIA) and (XIB), which showed the band at 2700-2800cm-1. The IR measurement of both compounds in various concentrations of carbon tetrachloride showed that, though the former showed the band at 3370 and 3600cm-1, the band at 3370cm-1 was weakend and contrary the band at 3600cm-1 was appeared to be strengthened. In the latter compound, a strong band was always found at 3430cm-1.
IR analysis of serum and total lipid separation in blood of the cancer patients showed generally a decrease of phospholipids. When the binding ratio of serine, ethanolamine and choline, as component of phospholipids, was examined, it has a tendency with cancer patient to increase serine and to decrease choline.
By the determination of using platinic iodate reagent which develops sensitive coloration against spermine, but is negative against amino acids, neither the bond type nor the free type spermine has been identified in the phospholipid separation of the blood with cancer patients.
Diphenyliodonium bromide (DIB) was reacted with various phenols either in its potassium salts or in the presence of potassium carbonate. It was found that the elevation of the reaction temperature in DME as a solvent shorten the reaction period (Table I). Even when nitro or acetyl group which may hinder sterically or form chelation at ortho position of the hydroxyl groups, the reaction was recognized to take place (Table II). The syntheses of (V) R=H and (IX) R=H were successful applying the reaction of Chart 2. Phenylation of heterocyclic aromatic compounds, such as 8-quinolinol and carbostyril (X) (Chart 3) with DIB afforded 8-phenoxyquinolinol, 2-phenoxyquinolinol, 3-phenylcarbostyril and the substance of m.p. 169-171°, whose structure was unknown. In this reaction, 1-phenylcarbostyril had not been obtained.
The isolation of both basic and neutral components of Lycopodium clavatum L. was attempted and lycopodine, L30. from basic component, as well as sucrose, α-onocerin and two kinds of new terpenes, such as lycoclavanol, m.p. 308-310°, [α]D13 -23.1°, C30H50O3, and lycoclavanin, m.p. 344-346°, (acetate: m.p. 236-237°, [α]D -32.2°), C30H48O5 from neutral component were isolated.
1-Arylsulfonyl-3-(2-bromoethyl)urea (III) was, in the presence of base, cyclized very easily to 2-arylsulfonamido-2-oxazoline (IV) and 1-arylsulfonyl-2-imidazolidinone (V), simultaneously. The ratio of the production, IV/V, decreased in the following order of water and alkaline solution, and (V) was dominantly produced in either dehydrated pyridine or NaOEt (in dehydrated EtOH), (IV) being scarcely produced. (V) is also obtainable by reacting 2-imidazolidinone with arylsulfonyl chloride in pyridine. (V) was easily hydrolyzed to arylsulfonylethylenediamine when it was kept standing at room temperature in strong alkali. A part of (IV) was converted to (V) by fusion. (III) was prepared from arylsulfonylurea and 2-bromoethylamine⋅HBr easily, and its cyclization mechanism is also reported.
In order to examine an influence upon blood sugar by cyclization of chained urea structure of the sulfonylurea compounds which possess descending action of blood sugar, the following compounds were prepared. These compounds synthesized were: 1-arylsulfonyl-2-imidazolidinone (XI), 1-arylsulfonyltetrahydro-2(1H)-pyrimidinone (IX), 1-arylsulfonyl-2-imidazolidinethione (XV), 1-aroyl-2-imidazolidinone (XIII) and N-p-chlorophenylsulfonyl derivatives of 2-iminoöxazolidine, 2-oxazolidinone, 2-pyrrolidinone, ethylenediamine and pyrrolidine. When 1-arylsulfonyl-3-(3-bromopropyl) urea (VII) was treated by alkali, it was cyclized easily to (IX) and, simultaneously, 2-arylsulfonamido-5, 6-dihydro-4H-1, 3-oxazine (VIII) was obtained.
The influence of 40 kinds of 1-arylsulfonyl-2-imidazolidinone and its related compounds, whose cyclic ureide structure were converted from the straight-chained urea structure of sulfonyl urea derivatives, having blood-sugar descending action upon normal rabbit has been studied by oral administration. Some of 1-arylsulfonyl-2-imidazolidinone and 1-arylsulfonyltetrahydro-2(1H)-pyrimidinone were found to indicate such a strong blood-sugar ascending action of having max. 300mg%. The details of 1-(p-chlorophenylsulfonyl)-2-imidazolidinone which showed the strongest action among them were examined and it was clarified that the administration of 200mg./kg. showed two ascending peaks of blood-sugar action within 48 hours and that this high blood-sugar action antagonized completely with Tolbutamide. The correlation between the structure and the action was considered and an indispensable structure for blood-sugar ascending action was suggested to be . Furthermore, the similarity of the relationship between these series of compounds and sulfonyl urea compounds having blood-sugar descending action was also interpreted by the relationship between the structure and the action.
Condensation of methyl ethyl ketone and 5-nitro-2-furfural diacetate afforded 1, 5-bis(5-nitro-2-furyl)-2-methyl-3-pentadienone (I) and 3-methyl-4-(5-nitro-2-furyl)-3-buten-2-one (II). By the reaction of these compounds with aminoguanidine, their amidinohydrazone hydrochlorides were purified. Heating of the amidinohydrazone of (I) in organic solvent, in the presence of alkaline substance, gave 3-amino-6-[1-methyl-2-(5-nitro-2-furyl)vinyl]-as-triazine. Antibacterial activity of these compounds was examined and interesting results were obtained.
Experimental evidences suggest that the bases contained in Thalictrum thunbergii DC. (Japanese name “Akikaramatsu”) differs slightly by its habitat. In order to elucidate this point, the root of this plant collected in Nagano Prefecture was processed and a comparatively large amount of magnoflorine (I) was obtained, while its leaves and stems yielded takatonine (II). The leaves and stems of the same plant collected in Kochi Prefecture yielded magnoflorine (I) and berberine (III). These results are summarized in Table I.
Reaction of glucuronolactone and aliphatic amines afforded N-alkyl-α-D-glucuronamide or N-alkyl-1-alkylamino-1-deoxy-D-glucuronamide. In this reaction, interesting correlation was found to exist between the number of carbon atoms in the aliphatic amine, and reaction solvent and product.
Stability constants of the complexes formed between alkaline earth metals and three types of citric acid were determined by the ion exchange method using 45Ca, 90Sr and 133Ba. Results obtained were listed in Tables I and II. Comparing these results with those of biological studies, it was suggested that the values of KSr/KCa were more important than the stability constants themselves for the effective excretion of radioactive strontium from living body.
As the color reaction between hexestrol and α-nitroso-β-naphthol is unstable in its reaction solution by itself, colorimetric determination is impossible but when 70% ethanol was employed as a dilutant, a superior result was obtained in stabilizing color solution, reproducibility of the reaction and also monochromatic property of the coloration. This improved method is applicable to the colorimetric quantitative method, which may be superior to the other colorimetry, not only from the stability of the reagent and simplicity of manipulation of the sample, but also from the specific coloration to hexestrol. 5-50μg. of hexestrol was added to 2ml. of water and to it both 0.4ml. of 0.1% ethanol solution and 0.4ml. of conc. nitric acid were added. The mixture was heated on a water bath for 2min. and 2ml. of 70% ethanol was added after cooling. The absorption was measured at 520mμ, using a standard without nitric acid. In this reaction, if the ethanol containing solvent is used instead of water initially, the coloration will develop with difficulty.
It was reported by T. H. Yang that liriodenine (VI) was obtained by the oxidation of ushinsunine (I) and roemerine (II), aporphine type alkaloid with CrO3-pyridine complex. A similar oxidation was carried out with nucif erine (III), glaucine (IV) and O, O-dimethylcorytuberine (V.) of the aporphine type alkaloid and the oxidized products (VII), (VIII) and (IX) possessing 7H-dibenzo[de, g]quinolin-7-one skeleton were obtained.
In continuation to the previous paper, by the Ullmann reaction of D-(-)-1-(p-methoxybenzyl)-2-methyl-6-methoxy-1, 2, 3, 4-tetrahydroisoquinolinol-7 (I), as a starting material, with bromobenzene to the corresponding phenoxy derivative (II), an opening reaction of the structure with metal-Na in liq. ammonia was carried out, and derived to l-1-(p-methoxybenzyl)-2-methyl-6-methoxy-1, 2, 3, 4-tetrahydroisoquinolinol (III). It has been chemically identified to be D-type.