By boiling kainic acid (α-I) or N-acetylkainic acid (α-II) with acetic anhydride, N-acetylkainic anhydride (β-VIII) is obtained. Hydrolysis of (β-VIII) gives N-acetylkainic acid (β-II) which is different from (α-II) and hydrolysis of (β-II) with potassium hydroxide yields the isomer of (α-I). In order to differentiate these compounds, the hitherto known kainic acid obtained from the natural product will be designated as α-kainic acid (α-I) and the isomer obtained in the present experiments as β-kainic acid (β-I). Many derivatives of the β-kainic acid were prepared in order to examine the properties of (β-I) and it was found that (β-I) possessed one double bond, two carboxyl groups, and a secondary amino group, and that it was very similar to (α-I).
Ozonization of β-kainic acid (β-I) yields formaldehyde and β-methyl ketone compound (β-VI) which is an isomer of α-methyl ketone compound (α-VI) obtained by the ozonolysis of α-kainic acid (α-I). It follows, therefore, that (β-I) also possesses an isopropenyl side chain, as in (α-I), and the two are assumed to be steric isomers.
Reduction of α-kainic acid (α-I) gives α-dihydrokainic acid (α-X) which, on boiling with acetic anhydride, yields β-N-acetyldihydrokainic anhydride (β-XIV) and this is hydrolysed by water to β-N-acetyldihydrokainic acid (β-XI). Further hydrolysis of (β-XI) with diluted sulfuric acid yields β-dihydrokainic acid (β-X), a stereoisomer of (α-X). Such isomerization of α-dihydrokainic acid (α-X) by treatment with acetic anhydride suggests that the double bond in the kainic acid molecule does not take part in the isomerization.
Treatment of an aqueous solution of β-kainic acid (β-I) in a sealed tube, at a high temperature, results in its isomerization to α-kainic acid (α-I). The same treatment of an aqueous solution of β-N-acetylkainic acid (β-II) results in concurrent hydrolysis and isomerization to (α-I), and the same treatment of β-dihydrokainic acid (β-X) gives its isomer, α-dihydrokainic acid (α-X). In the case of β-N-acetyldihydrokainic acid (β-XI) and monomethyl β-N-acetyldihydrokainate (β-XIII), this reaction effects concurrent hydrolysis and isomerization to (α-X). The reaction whereby the compounds of α-series are isomerized to those of the β-series through acid anhydride will hereafter be designated as kainic inversion, and its reverse, from β- to α-series, retrokainic inversion. It is assumed that these inversions occur in the one and only asymmetric carbon present in the kainic acid molecule.
Treatment of α-kainic acid (α-I) with mineral acids results in the formation of a δ-lactone ring between one of the carboxyls and the tertiary carbon in the isopropenyl group, forming α-kainic acid lactone (α-XV). Its acetylation yields α-N-acetylkainic acid lactone (α-XVI), whose methylation yields methyl α-N-acetylkainate lactone (α-XVII). (α-XVI) is also obtained by the lactonization of N-acetylkainic acid (α-II) and its hydrolysis gives (α-XV). The reaction mother liquor left after lactonization of (α-I) yielded α-isokainic acid (α-XVIII), probably an isomer of (α-I).
Treatment of β-kainic acid (β-I) with mineral acids results in the formation of a δ-lactone ring between one of the carboxyls and the tertiary carbon in the isopropenyl group and gives β-kainic acid lactone (β-XV). Its acetylation yields β-N-acetylkainic acid lactone (β-XVI), whose methylation yields methyl β-N-acetylkainate lactone (β-XVII). (β-XVI) is also obtained by the lactonization of N-acetylkainic acid (β-II) and its hydrolysis gives (β-XV).
Since α-kainic acid lactone (α-XV) does not undergo kainic inversion on being boiled with acetic anhydride, it is assumed that this inversion occurs through the formation of an acid anhydride by the compounds of α-series. Treatment of an aqueous solution of β-kainic acid lactone (β-XV) at a high temperature results in retrokainic inversion to form (α-XV) that such inversion is found to occur at the asymmetric carbon bonded to the carboxyl group indifferent to the lactonization. Comparative examination of the pK′ of β-kainic acid (β-I), monomethyl β-N-acetylkainate (β-V), β-kainic acid lactone (β-XV), and β-N-acetylkainic acid lactone (β-XVI) and of various amino acids showed that the acid group taking part in lactonization is the acetic acid group and that not participating in it is the carboxyl group bonded to the asymmetric carbon at 2-position of the pyrrolidine ring, so that the inversion occurs with this asymmetric carbon.
Hydrolysis of the lactone ring in α-kainic acid lactone (α-XV) with 2% methanolic potassium hydroxide or 2% sodium methoxide results in the formation of hydroxy-dicarboxylic acid. The hydroxy diester obtained by its esterification liberates the hydroxyl group as water by vacuum distillation to form dimethyl α-isokainate (α-XIX), whose hydrolysis gives α-isokainic acid (α-XVIII). This compound is identical with the substance obtained as a by-product by the lactonization of α-kainic acid (α-I) with mineral acids, together with its chief reaction product, α-kainic acid lactone (α-XV).
Ozonolysis of α-isokainic acid (α-XVIII) produces acetone from which (α-XVIII) is found to possess an isopropylidene group. The fact that the treatment of α-kainic acid (α-I), possessing an isopropenyl side chain, yields α-kainic acid lactone (α-XV) and α-isokainic acid (α-XVIII) with an isopropylidene side chain suggests that the steric configuration of the carboxyl and the acetic acid groups in (α-XVIII) is the same as those in (α-I) but that the position of the double bond alone differs in the two compounds, forming structural isomers. Catalytic reduction of (α-XVIII) gives α-dihydrokainic acid (α-X) and a dihydro compound with an isopropyl side chain of different steric configuration in good yields.
Hydrolysis of the lactone in β-kainic acid lactone (β-XV) with 2% methanolic potassium hydroxide yields a hydroxy-dicarboxylic acid whose ester, on vacuum distillation, liberates the hydroxyl as water to form dimethyl β-isokainate (β-XIX). Hydrolysis of (β-XIX) yields β-isokainic acid (β-XVIII). (β-XIX) easily undergoes retrokainine inversion on distillation at a somewhat higher temperature and isomerizes to (α-XIX).
A new effective component, T acid (α-allo-I), isolated from Digenea simplex Ag. together with α-kainic acid (α-I), yielded formaldehyde as the volatile componet by ozonolysis so that T acid is also known to contain an isopropenyl side chain. The reaction mother liquor yielded methyl ketone compound, C9H13O5N, identical with (α-VI) obtained by the ozonolysis of (α-I). This fact suggests that the configuration, of the carboxyl and acetic acid groups in the T acid is identical with those in (α-I) but with the configuration of the isopropenyl group different from that in (α-I), and that the two are stereoisomers. The dihydro compound (α-allo-X), obtained by the catalytic reduction of the T acid, is identical with the dihydro compound obtained by the catalytic reduction of α-isokainic acid (α-XVIII). Therefore, the T acid was designated α-allokainic acid.
1) The specific rotation curves of α-kainic acid (α-I), β-kainic acid (β-I), and α-allokainic acid (α-allo-I) suggest that (α-I) and (α-allo-I) are L-series substance peculiar to natural amino acids, while (β-I) is a compound of D-series. It therefore follows that α-isokainic acid (α-XVIII) is the L-series and β-isokainic acid (β-XVIII), D-series substance. 2) Since in general when a five-membered and six-membered rings are bonded in hydrindane-type, the cis-bonding is more stable than the trans-bonding, it is known that β-N-acetylkainic anhydride (β-VIII) is an acid anhydride of the β-series compounds in which the carboxyl and the acetic acid groups take the cis-configuration and that the compounds of the β-series derived from it possess the cis-configuration of the two acid groups, while they are in the trans-configuration in the compounds of the α-series.
Lactonization of α-isokainic acid (α-XVIII) yields only α-allokainic acid lactone (α-allo-XV) from which the latter was assumed to be the cis-lactone and further that the acetic acid and isopropenyl groups is α-allokainic acid (α-allo-I) are in cis-configuration. It is thereby known that they are in trans-configuration in α-kainic acid (α-I). Since the relationship between acetic acid and isopropenyl groups in β-kainic acid (β-I) is the same as in (α-I), they must be in trans-configuration. Summarizing the facts described in this and the preceding paper, the steric structures indicated in Fig. 2 and Table I are proposed for kainic acid and the isomers.
The so-called B-series glycosides, with gitoxigenin as the parent ring, are contained in the leaves of Digitalis purpurea. The present series of experiments were carried out in order to make a separatory determination of these B-series glycosides. The glycosides of B-series in the Digitalis leaves known to date are purpurea glycoside-B, digitalinum verum, gitorin, gitoxin, strospeside, and gitoxigenin. The extract of the dried leaves of Digitalis purpurea contains, besides the foregoing, six new substances which show fluorescence peculiar to the B-series glycosides. In order to make separatory determination of these 12 substances, conditions which would offer sufficient differece in Rf values were examined. It has been possible to effect sufficient difference of Rf values between the known glycoside of A-series, with digitoxigenin as the parent ring, and non-cardiac glycoside, diginin, and this suggests that separatory determination can be effected on a mixture of the glycosides of these two series by the concurrent use of the methods for the separatory determination of A-and B-series glycosides
Methylpropamine and Propamine are easily and quantitatively nitrated by potassium nitrate and conc. sulfuric acid. The conditions of such nitration, conditions of extraction from the nitration solution, and conditions of determination of such nitrated compounds by polarography were examined. Such determination was effected by the following procedures. In a test tube containing 0.1-3mg. of Methylpropamine, 1cc. of the nitration agent (a solution of 1g. of potassium nitrate dissolved in 10cc. of conc. sulfuric acid) is added, warmed for 5 minutes in a water bath, cooled, 10cc. of water added while cooling, and followed by 10cc. of 30% ammonia water. After shaking this mixture well, the mixture is allowed to cool, and extracted three times with 20-cc. portion of chloroform. The chloroform layer is filtered through a dry filter, the filter is washed thoroughly with chloroform, and the combined filtrate and washings evaporated. This residue is dissolved in 2cc. of acetone, 0.5cc. of N potassium chloride and 2.5cc. of the Mcllvaine buffer of pH 5 are added, and this solution is submitted to polarography by the usual method. By automatic recording between 0 and -1.2 volts, the amount is relatively determined.
It was experimentally proved that the basic aluminum salts in solution is extremely unstable and undergoes rapid condensation of hydroxoaluminum ion by the passage of time or at higher temperatures, its composition changes, and finally reaches the stable polynuclear aluminum complex ion. The structure of this polynuclear aluminum comlex ion [Alx(OH)y(OH2)z]+(3x-y) and the reaction mechanism whereby this returns to the original mononuclear ion by acids was presumed from experimental results.
Reaction of acetonitrile and benzonirile with sodium hydroxide in the presence or absence of liquid ammonia yielded acetamide, diacetonitrile, and 2, 4-dimethyl-6-amino-pyrimidine from acetonitrile, and benzamide and 2, 4, 6-triphenyl-1, 3, 5-triazine from benzonitrile.
Amount of eosine adsorbed on the surface of coli bacilli was colorimetrically determined by the use of the dispersion method. It was found that tannin and gallic acid inhibited adsorption from which those were assumed to undergo bonding with basic portion on the bacillary surface.
The condensate obtained by the reaction of formaldehyde and urea in hydrochloric acid solution quantitatively adsorbs gallotannin in the presence of sodium chloride solution, but not gallic acid. This was utilized in fractional colorimetry of gallotannin and gallic acid by coloration with ammonium molybdate and satisfactory results were obtained.
Introduction of a substituent in the 4-position of 3 (2 H) -pyridazone ring by direct substitution reactions has been made by many workers but the substitution of the 4-position in pyridazine ring has not been attempted as yet. Taking lessons from the chemistry of pyridine 1-oxides developed by Prof. Ochiai and his school, introduction of a substituent in 4-position of 3, 6-dimethoxypyridazine was successfuly concluded. The mono-oxide (I) was obtained by oxidation with hydrogen peroxide in glacial acetic acid. Owing to the mesomeric effect of the N-oxide group, the 4-position in (I) is reactive and easily reacted with electrophilic reagents such as nitric acid to yield the 4-nitro compound (II). The 4-nitro group, as in the case of pyridine and quinoline 1-oxides, easily underwent substitution with sodium methoxide to form 3, 4, 6-trimeth-oxypyridazine 1-oxide (IV) and with acetyl chloride to form 3, 6-dimethoxy-4-chloro-pyridazine 1-oxide (III). Reduction of (IV) with phosphorus trichloride yields 3, 4, 6-trimethoxypyridazine (V). Catalytic reduction of (II) in hydrochloric acid solution or in neutral medium yields 3, 6-dimethoxy-4-aminopyridazine 1-oxide (VI), and in acetic anhydride, 3, 6-dimethoxy-4-acetaminopyridazine (VII). (VII) is easily hydrolyzed so that its recrystallization from water gives 3, 6-dimethoxy-4-aminopyridazine (VIII).
Colorimetric determination of tetracycline was carried but by utilizing the coloration developed when tetracycline hydrochloride and ammonium molybdate are reacted in an acetic acid buffer of pH 4.0 at 60° for 15 minutes. By calculating E430-E548, tetracycline alone can be determined, completely removing the effect of oxytetracycline. The values obtained by this method agree with those by bioassay.
Determination of tetracycline was carried out utilizing the fact that when sodium carbonate, sodium tungstate, and a minute amount of hydrogen peroxide are added to the aqueous soluion of tetracycline hydrochloride and warmed at 40° for 25 minutes in a water bath, a reddish violet color develops and by measuring the optical density of this coloration at 530mμ. Chlorotetracycline colors faintly yellowish orange by this method and its optical density at 530mμ is smaller than that of tetracycline. Therefore, the presence of less than 50% of chloroteracycline allows determination of tetracycline within an error of less than 2%. The results of this method agree well with those by the ammonium molybdate and bioassay, described in early papers.
Phthalic acid monoesters of sugars and polyhydric alcohols were prepared and they were used as the coating agent on potassium chloride tablets. The monoesters of phthalic acid of dextrin, lactose, sucrose, mannitol, and glucose are unchanged by immersion in artificial gastric juice for 4 hours but crumble when immersed in artificial intestinal juice for 20 minutes that they are extremely good as the enteric coating agent.
1) The derivatives of β-phenylethyl alcohol possess only a weak antispasmodic action while those of α-aminophenylacetic acid esters are strong antispasmodics. 2) The compounds of the 1st and 5th groups possess excellent antiacetylcholinic and antibarium actions and the esters are more powerful when the ester group is not lower alkyls but isoamyl or more especially, cyclohexyl group. The compounds are also powerful when the tertiary amino group is a lower one, such as dimethylamino and diethylamino, the action decreasing with the increase of the number of carbons in the allyl group. 3) With the exception of No. 16, the compounds of 2nd and 3rd groups showed only a weak antispasmodic acitivity. 4) The compounds of the 4th group possess antibarium and antihistaminic actions similar to those of 1st group but their antiacetylcholinic action is much weaker. 5) Contrary to expectations, the acitivity was not increased in compounds of the 6th group, only their antihistaminic action alone being better than the compounds of other groups.
Microchemical detection and determination of hydroxyanthraquinone and hydroxyanthrone derivatives were made by paper chromatography using the fresh and stored products of Cascara barks. It was thereby found that these components varied in accordance with the passage of time since collection. In the fresh bark, the presence of a minute amount of free emodin and small amounts of glycosides of chrysophanol, emodin, and aloe-emodin are detected while in the stored product, marked presence of the free and glycosides of emodin and aloe-emodin, and a small amount of chrysophanol were found. The presence of hydroxyanthrone derivatives in the fresh product was found only in a minute quantity in the stored goods. Drying of the fresh product with application of heat failed to show much change except that the presence of an unknown substance A became marked. Rhein and rhein-anthrone were not detected but some observations were made on four kinds of unknown substances. Anthrones of chrysophanol, emodin and aloe-emodine were isolated and identified, and were confirmed to be the 1, 8-dihydroxy-9-anthrone derivatives.
The aqueous solution of diphenylhydantoin sodium does not easily precipitate out the crystals even in the state of supersaturation at temperatures below solid-liquid equilibrium. In a sealed tube, it was difficult to find the temperature at which the crystals precipitate out from the state of supersaturation. When such a solution is cooled under agitation in an unsealed vessel, reproducible results were obtained as to the temperature of crystal precipitation. The curve obtained by plotting such a temperature against the concentration of a solution was designated as the supersolubility curve, which was approximately parallel to the solubility curve.
The aconite plants (species undetermined) collected in seven localities on the Shimokita Peninsula, Aomori Prefecture, were extracted as before, and the alkaloids isolated are indicated in Table II. All the plants contained aconitine and mesaconitine, and the characteristic feature of these plants is that the amount of aconitine is larger than that of mesaconitine, as in the aconite plant from Shiriya. Besides the above, crystalline alkaloids of m.p. 325° (decomp.) and m.p. 295-297° (decomp.) were isolated. Both gave the same Rf values but their identity has not been established as yet.
1) 2-Arylidenehydrazono-4-thiazolidone and its 5-methyl derivative, corresponding to 2-salicylidenehydrazono-4-thiazolidone and its 5-methyl derivative but the hydroxyl in the ortho-position substituted with methoxyl, amino, nitro, or chloro group, and their meta- and para-isomers were synthesized for use in antibacterial test. It was thereby found that the antibacterial action against tubercle bacilli markedly decreased in those possessing functional groups other than the hydroxyl. 2) Over 20 of these samples were prepared by the addition of ethyl chloroacetate or α-bromopropionate to the thiosemicarbazones of aromatic aldehydes, in the presence of N-ethylpiperidine or sodium acetate as the neutralization agent, or by the hydrolysis of 2-α-methylbenzylidenehydrazono-4-thiazolidone or its 5-methyl derivative with 2N hydrochloric acid to obtaine crude 2-hydrazono-4-thiazolidone hydrochloride which is condensed with the foregoing aromatic aldehydes to 2-arylidenehydrazono-4-thiazolidone and its 5-methyl derivative.
It was actually proved that vitamin A palmitate is solubilized not only by nonionic but also by ionic surface active agents. Of homologous agents of the same hydrophilic groups, the solubilization power is stronger, the larger the lipophilic groups.
Antipyrine which does not possess any group bonded to the C4 of the pyrazolone ring was nitrosated with a nitrite in acid solution to obtain 4-nitrosoantipyrine and the quantitative determination of antipyrine and its salts was examined. Results of examination of the conditions for such nitrosation and for polarographic determination revealed that the nitrosation by the application of 1cc. of 0.1N sulfuric acid and 1cc. of 0.1M sodium nitrite to 1cc. of 10-2 mole solution of antipyrine or its salts and warming the mixture for 12 minutes at 23-28°, resulted in a quantitative formation of 4-nitrosoantipyrine. Excess nitrous acid was neutralized by the addition of 1cc. 0.1N sodium hydroxide, 0.5cc. of 1% gelatine solution was added to suppress specific waves, and the solution was submitted to polarography by the relative method, recording the waves between -0.3 and -1.3V., to give satisfactory results.
The oxidation products of morphine in which the 9-position has been derived to the carbonyl group, such as morphinone, codeinone, and thebainone, easily undergo reduction by mercury drop electrode. Quantitative determination of sinomenine the optical isomer of 7-methoxythebainone, and dihydroxycodeinone, which are on the market, was studied. The relation of Id=cK is established in a range of 5×10-3 to 10-5 molar concentration of sinomenine and dihyroxycodeinone, in McIlvaine's buffer of pH 5 containing 0.1N potassium chloride. This method was applied to the quantitative determination of various preparations.
The benzylisoquinoline-type morphine alkaloids can be divided into the following two classifications of structures from the point of polarographically active functions, and both are based on the carbonyl group conjugated to the double bond. One group possesses the aldehyde group in 1-position, such as cotarnine, and the other possesses the carbonyl group in 9-position, such as narceine and papaveraldine. The former group is subdivided into three types, the aldehyde, carbinol, and ammonium types, such as will be seen in the structures of berberine and hydrastinine. Various experiments have failed to discriminate the three structures by polarography but it was found that all three showed the aldehyde type in the electrolytic solution, using either the free base or the salts, and were reduced in all the pH ranges. In the case of the latter group, the carbonyl group at 9-posion was reduced in all the pH ranges. In other words, cotarnine, narceine, and papaveraldine are reduced but not narcotine, gnoscopine, hydrocotarnine, codamine, cryptopine, laudanidine, laudanine, laudanosine, and papaverine.
In order to synthesize fusaric acid and its homologous compounds and to examine their pharmacological actions, β-propionylpyridine was prepared from nicotinamide by the usual method and its Grignard reaction afforded β-pyridylmethylethylcarbinol, which was reduced with hydriodic acid and phosphorus to 3-sec-butylpyridine.
Using the comparatively easily available 2-methyl-5-ethylpyridine (I) as the starting material, 2-methyl-5-butylpyridine (VII) was obtained by the usual method. Before deriving it to 2-styryl-5-butylpyridine (VIII), the reaction of (I) to 2-styryl-5-ethylpyridine was effected by using either zinc chloride or acetic anhydride as a dehydration agent, though the latter substance was found to be better. Therefore, benzaldehyde and acetic anhydride were applied to (VII) to introduce the styryl group and (VIII) thereby obtained was oxidized with potassium permanganate in acetone solution to the objective 5-butylpicolinic acid (fusaric acid).
Ether solution (25cc.) of butyllithium (containing 12.5mM of butyllithium), prepared in the preparation flask (PF) shown in Fig. 1, was led into the carbonation flask (CF) and reacted there with 2g. of xanthene to form the lithium salt of xanthene. This was then reacted with 14CO2, generated from 1.037g. (1.091mc) of Ba14CO3, in the generator (G) in vacuo, and 1.354g. of xanthene-9-[14C] carboxylic acid (III) with specific activity of 0.407μc/mg., with 14C-utilization rate of 50.5%. A mixture of 1.043g. of (III) and 0.63g. of β-diethylaminoethyl chloride in 6cc. of isopropanol was refluxed and 1.032g. of β-diethylaminoethyl xanthene-9-[14C] carboxylate hydrochloride (IV), 0.247μc/mg., was obtained. By reacting 0.856g. of (IV), with 2.76cc. of 0.862N ethanolic potassium hydroxide and 10cc. of 20% ethanolic solution of methyl bromide in pressurized bottle, 0.759g. of β-diethylaminoethyl xanthene-9-[14C] carboxylate methobromide (V), 0.210μc/mg., was obtained.
1) Starting with 2, 4- and 2, 5-dichlorobenzoic acid, through chloroxanthone, 2- and 3-monochloroxanthydrol were prepared and their properties as the estimation reagent for amides (amides, sulfonamides, urethan, substituted barbituric acid) were compared with xanthydrol. 2) It was thereby found that these compounds did not react with amides as easily as xanthydrol but were more stable and it was possible to use them as a supplement for the qualitative reagent for the foregoing amides. The melting point of the condensation products was examined.
Following the extraction of a sterol as the non-saponifiable matter from the ether extract of the root of Oenothera lamarckiana Ser., which was assumed to be β-sitosterol, the presence of sterol was examined in four kinds of Oenothera spp., O. odorata Jacp., O. parviflora L., O. lacimata Hill., and O. tetraptera Cav. These plants all yielded the same sterol as that obtained from O. lamarckiana Ser.
Using the method of McFadyn-Stevens for the synthesis of aromatic aldehydes by the decomposition of tosylates of aromatic carboxylic acid hydrazides with alkali, 2-, 3-, and 4-formyldiphenyl ethers were obtained from 2-, 3-, and 4-carboxydiphenyl ethers.