threo-(+)- and threo-(-)-1-Phenyl-2-dimethylaminopropanethiol and erythro-(-)-1-phenyl-2-dimethylaminopropanethiol were synthesized and asymmetric synthesis of methyl mandelate from phenylglyoxal in methanol was attempted with the foregoing compounds as a catalyst. Yield of the product was the best when using the compound of erythro system. Examinations were made on the configuration of (+)- and (-)-1-phenyl-2-dimethylaminoethanethiol, reported in a previous paper, and it was found that methyl mandelate of L-system was obtained formed from D-system catalyst, and D-system esters from L-system catalyst.
Compounds I to (VI) were synthesized by the diazotization of aniline, p-thiocyanatoaniline, 3-chloro-4-thiocyanatoaniline, p-chloroanilne, p-nitroaniline, and o-chloroaniline, and application of 8-quinolinol to the diazonium salts in ethanol. The compound (VIII) was prepared by the diazotization of p-chloroaniline and application of 6-aminoquinoline to its salt. Antibacterial action in vitro of these compounds and those prepared earlier (IX to XXXIII), *3 was tested with Aspergillus niger, Trichophyton mentagrophytes Wachsman 640, Saccharomyces cerevisiae ATCC 9763, Trichophyton rubrum, Ophyobolus miyabeanus, Piricularia oryzae, and Cladosporium herbarum.
Various derivatives of cotarnine, substituted with amino, acylamino, or hydroxyl in the benzene ring of the benzyl group in 1-position of cotarnine (I) were synthesized V to XI, and XVI. Of these derivatives, 1-[2, 4-bis(benzamido)benzyl]-2-methyl-8-methoxy-6, 7-methylenedioxy-1, 2, 3, 4-tetrahydroisoquinoline (Xa) was found to undergo selective demonobenzoylation by hydrolysis with 10% sulfuric acid to form 1-(4-amino-2-benzamidobenzyl)-2-methyl-8-methoxy-6, 7-methylenedioxy-1, 2, 3, 4-tetrahydroisoquinoline (Xb). This product was identified with an authentic sample obtained by catalytic reduction of 1-(2-benzamido-4-nitrobenzyl)-2-methyl-8-methoxy-6, 7-metheylenedioxy-1, 2, 3, 4-tetrahydroisoquinoline (XVIb) obtained by condensation of I and 2-benzamido-4-nitrotoluene.
Various derivatives of shionone were examined. Since epi-dihydroshionol (II), obtained by catalytic reduction of shionone (I) in acetic acid over platinum, does not submit to retropinacoline rearrangement by phosphorus pentachloride, the carbonyl group in I is not present in its partial structure (A). Catalytic reduction of I in acetic acid over palladium-carbon afforded dihydroshionene (VI) and from the fact that methyl ketocarboxylate (VII) and dimethyl dicarboxylate (VIII) are obtained by the route shown in Chart 1, the carbonyl group in I must be present in the partial structure of the ring, -CH2-CO-CH(CH3)- (C). Skeletal structure of the ring part of I was assumed to be Ia or Ib from the product obtained by selenium dehydrogenation of the dehydrated product (III) of II.
Reaction product of shionone (I) and dihydroshionone (II) by various reduction agents were examined and two pairs of epimers, epi-shionol (V) and shionol (VI) from I, and epi-dihydroshionol (III) and dihydroshionol (IV) from II, were found to be formed. Yield of these products is shown in Tables I and II. IV and VI, mainly obtained by reduction with sodium in amyl alcohol, have equatorial hydroxyl. Oxidation of equimolar mixture of III and IV with 0.5 equivalent of chromium trioxide and examination of the recovery rate of unreacted alcohol revealed that III has an axial hydroxyl group since III is more easily oxidized by chromium trioxide than IV, as shown in Table III. From these and previously obtained results, it was assumed that the carbonyl group in I and II was subject to steric hindrance, i.e. presence or methyl or alkyl group of axial orientation in the β-carbon of the carbonyl group.
Two kinds of bromine derivatives, α- and α′-bromodihydroshionone, were prepared from dihydroshionone by the respective action of N-bromosuccinimide and pyridinium bromide perbromide. These monobromo compounds were shown to have the respective partial structures (B) and (C). UV and NMR spectra of the compound IX, obtained by dehydrobromination of α′-bromodihydroshionone (VIII) were measured (Fig. 7) and this confirmed the partial structure (D) for IX, which in turn suggested the partial structure (E) for Shionone. NMR spectra of shionone and its various derivatives were examined (Figs. 1-6) and it was assumed that there are eight methyl groups in shionone.
N-(5-Benzyloxy-3, 4-dimethoxyphenethyl)-2-(p-methoxyphenyl)acetamide (I) and N-(5-acetoxy-3, 4-dimethoxyphenethyl)-2-(p-methoxyphenyl)acetamide (II) were synthesized and the direction of cyclization of I and II by the Bischler-Napieralski reaction was examined. Cyclization was found to take place in the position para to benzyloxyl group in I and to acetoxyl group in II, respectively forming VI and IX.
N-(3, 4-Dimethoxy-5-phenoxyphenethyl)formamide (I) and N-(3, 4-dimethoxy-5-phenoxyphenethyl)-2-(p-methoxyphenyl)acetamide (II) were synthesized and the direction of cyclization of I and II by the Bischler-Napieralski reaction was examined. Cyclization was found to occur in the position ortho to the phenoxyl group in both I and II, respectively forming IX and XIII.
Chimaphilin (I) and a glycoside (II) of m.p. 170-173° (decomp.), considered to be identical with monotropein, were isolated from Chimaphila japonica MIQ., together with a new glycoside (III) of m.p. 175-176°, [α]D12-64° (c=1.0, EtOH), which was found to be 2-methyl-4-hydroxyphenyl β-glucopyranoside and was named isohomoarbutin.
Antitumor activity of a large number of nitrofuran derivatives of quinoline was tested with mice bearing Ehrlich ascites tumor EY-33. Pure strain healthy ddN mice, weighing 18-22g., were intraperitoneally inoculated with this Ehrlich ascites tumor. After 24 hours, 0.2ml. of 5% glucose solution of the test compound was injected intraperitoneally, once a day for 7 days, to test antitumor activity. Normal mice inoculated with this ascites tumor generally died from accumulation of the ascites after about 10-19 days. Compounds were considered effective when the mice survived 50 days after the inoculation of the ascites. The compounds found to be effective by this test were sodium 2-[2-(5-nitro-2-furyl)vinyl]-4-quinolinecarboxylate (I), 2-[2-(5-nitro-2-furyl)-vinyl]-4-aminoquinoline lactate (II), and 4-[2-(5-nitro-2-furyl)vinyl]-2-aminoquinoline lactate (III). For the sake of comparison, panfuran hydrochloride and mitomycin-C were tested at the same time. The data obtained with these compounds were as follows (given in the order of the name of compound, LD50 in mg./kg., ED60 in mg.×kg., and C. I.): I, 240, 20, 12; II, 23.8, 1, 23.8; III, 26.3, 5, 5.2; panfuran hydrochloride, 72.5, 0, 0; mitomycin-C, 5.2, 0.5, 12.4. In order to clarify the action mechanism of these compounds, their action in suppressing the dehydronase of Ehrlich ascites tumor, and syntheses of nucleic acid and protein by coli bacilli was examined. It was presumed from its results that the antitumor action of I was due mainly to the suppression of dehydrogenase action, and that of II and III to the suppression of dehydrogenase action and DNA synthesis.
The electrical conductivities of sodium alginate, sodium carboxymethylcellulose, and sodium polyacrylate in 0, 10, 20, and 30% aqueous sucrose solutions were measured at the polymer concentration between 0.0002 and 0.04M. The equivalent electrical conductivity Λ of these polyelectrolytes decreased with the increase of sucrose concentration. This is considered to be due to the decrease of the mobility of ions, mainly because of the increase of the viscosity of the medium, aqueous sucrose solution. This is confirmed by the fact that the Λη0 value is almost independent of the sucrose concentration. In a more detailed observation, however, the Λη0 value showed a tendency to increase with the increase of sucrose concentration at the polyelectrolyte concentration of more than 0.002M, while the tendency was reversed at the concentration of less than 0.002M.
The Malpress method for the microdetermination of lactose in the presence of glucose, which is said to be simple in procedure, was examined and further improvement was made by the modification of heating temperature and time. Stability of coloration due to reaction of the liquid was examined and the coloration was found to become stable, without formation of a precipitate, by the addition of hydrochloric acid and ascorbic-acid. This procedure also eliminated interference of glucose with this reaction and increased accuracy of determination. The procedure follows. A sample solution of pH 6-8 (4ml.) is placed in a graduated test tube, 0.2ml. of 10% methylamine reagent is added, and the mixture is warmed in a water bath of 80° for 10 minutes. After addition of 0.2ml. of 18% sodium hydroxide solution, the mixture is warmed for 5 minutes, cooled in a water bath of 20° for 4 minutes, and 0.4ml. of 15% hydrochloric acid and then 0.2ml. of 10% ascorbic acid solution are added. This mixture is heated in a boiling water bath for 5 minutes, cooled in a water bath of 20° for 10 minutes, and the whole volume is brought to 5ml. Absorbance of this solution is measured at 487 and 425mμ to estimate the quantity of lactose and glucose at the same time.
19-Nortestosterone phenylpropionate was found to color yellow when heated with sulfuric acid, and addition of acetone changed this color to reddish violet, which had absorption maximum at 585mμ. This color reaction was tested with various kinds of steroid and Δ4-3-ketosteroids all showed good coloration of reddish violet to blue, having absorption maxima in the range of 580-610mμ. Limit of detection of 19-nortestosterone phenylpropionate by this method was 0.4μg./0.05ml. Examinations were made on the colorimetric determination using this color reaction and a method was established for quantitative determination of 19-nortestosterone phenylpropionate. At the same time, application of this method for oily injections was examined. It was found that solution of this sample in isooctane and extraction with 90% methanol resulted in elimination of interference by vegetable oils, giving a good result. Recovery of synthetic sample by this method was 100.3% (n=8) and precision of measurement was σ=0.61% (n=8). Colorimetric Procedure: To 1ml. of the test solution (chloroform solution containing about 40μg./ml. of 19-nortestosterone phenylpropionate) placed in a 10ml. volumetric flask, 0.8ml. of sulfuric acid is added, shaken vigorously for 1 minute, and heated in a boiling water bath for 10 minutes. The flask is cooled in ice, while adding 25ml. of acetic acid with shaking, and 4ml. of acetone is added with shaking. The whole volume is brought exactly to 10ml. with chloroform and allowed to stand for 5 minutes. Absorbance of this solution is measured at 585mμ. A blank test is carried out with the same amount of the same reagent and in the same manner, using 1ml. of chloroform in place of the test solution. In the case of oily injection, the sample is dissolved in isooctane, extracted with 90% (v/v) methanol, and methanol is evaporated from the extract. Benzene is added to its residue, the solvent is evaporated, and the residue is dissolved in chloroform. This chloroform solution is submitted to the same procedure as above.
Quercitrin and afzelin were isolated from the leaves of Acer carpinifolium SIEBOLD et ZUCCARINI, A. diabolicum BLUME, and A. marmoratum HARA form. dissectum REHDER. Besides flavonoid compounds, methyl gallate was isolated from the leaves of A. diabolicum BLUME. Trifolin and a mixture of isoquercitrin (predominant) and hyperin were obtained from the leaves of A. Negundo LINNAEUS.
dl-N-Norarmepavine (III) and L-(-)-N-norarmepavine (II) were isolated and identified from the root of domestic Lauraceae plant, Machilus Thunbergii SIEB. et ZUCC. (Japanese name “Tabuno-ki”). dl-N-Norarmepavine (III) and reticuline (VI) were isolated and identified from commercial Siamese “Tabuko” (Joss powder).
Examinations were made on the structure of sanguisorbigenin, the genin of sanguisorbin, a saponin contained in Sanguisorba officinalis L. The formula (I) derived from this examination was found to be identical with that of tomentosolic acid, whose structure had been determined as 19-dehydro-20-epi-ursolic acid (XVII), obtained from Vangueria tomentosa.
Optically active N2-phthaloylaspartimide was synthesized from pharmacological interest. The optically active N2-phthaloylasparagine, obtained by resolution of racemic compound with brucine, was found to undergo dehydrative cyclization by the action of acetyl chloride under a mild condition to form the optically active N2-phthaloylaspartimide.