Examinations were made on the relationship between nature of hydrated water and coloration of solid drugs. It was found that if the water of hydration is that of crystallization, it had no effect on powders even if adsorption and desorption of water were reversible but if water was attached in a free state, coloration occurred whose degree was approximately proportional to the quantity of such water.
Coloration of solid pharmaceutics was assumed to proceed through the formation of a kind of solution system by the water of hydration contained in the pharmaceutics and examinations were made to see if reaction kinetics in dilute solution could be applied in this case. It was thereby found that coloring rate was proportional to the rate of hydration in simple powders, and a linear relation was found to hold between coloring rate constants and the reciprocal of absolute temperature. If conditions were selected, periodical change of such coloration could be predicted as in the case of dilute solutions. On the bases of these ideas, examinations were made also on granules and tablets, and comparison of the values calculated from the result of acceleration tests and those obtained on actual samples by standing for some period at room temperature showed fairly good agreement.
Comparative examinations were made on the antispasmodic action of a crude drug, bezoar, produced in Australia, Europe, India, North America, and South America. There was no difference in their quality. The fraction containing deoxycholic acid extracted from Indian bezoar showed the greatest anticholinergic activity but this activity was considerably weaker than that of atropine. Gas chromatographic analysis of this fraction showed the presence of cholic acid in an amount about 1/5 of the main component. Therefore, examinations were made on the complex effect of cholic acid and deoxycholic acid in various ratios on the anticholinergic activity and their synergistic effect, with deoxycholic acid as the main component, was evidenced. At the same time, the hydroxyl group attached to carbon-7 in cholic acid was found to be not necessarily required in antispasmodic action.
Previous report from this laboratory described the examination of NMR spectra of N-methyl-coclaurine alkaloids and the assignment of the protons at 5-and 8-positions of the isoquinoline nucleus and the methoxyl group in these compounds. In the present series of work, further evidences were provided for the assignment of methoxyl group and aromatic protons utilizing trideutero-O-methylation using deuterodiazo-methane and deuterium exchange reaction of aromatic protons.
Synthefic reactions of ester derivatives of ascorbic acid were investigated in various ways. Thirty two compounds were prepared and their physicochemical properties determined. 1) In general, the 6-monoester and 5, 6-diester of ascorbic acid were obtained by esteri-fication of ascorbic acid in acidic medium and the 2, 6-di-, 2, 5, 6-tri-, and 2, 3, 5, 6-tetra-esters were obtained by esterification of ascorbic acid or its ester derivatives in basic medium. 2) The results obtained by using the deuteration method indicated that the OH streching absorption band of the 3-OH in ascorbic acid and its derivatives occurred near 3000 cm-1. 3) The UV absorption maxima of the neutral molecule and anion of ascorbic acid, which appear respectively at 243 mμ and 265 mμ, decreased similarly by about 10 mμ by esterification of the 2-OH, but were scarcely affected by that of 5-OH and 6-OH. 4) The pKa' value of ascorbic acid was exceedingly decreased by esterification of the 2-OH and slightly by that of the 5-OH and 6-OH. This effect was slightly different according to the acyl group of the esters.
Twelve α-hydroxyamino compounds were synthesized to examine their biological activity. Their chemical structure was determined as 3-alkylamino-2-hydroxypropyl benzhydryl ether by means of glycol cleavage and mass spectral analysis.
Direct condensation of various secondary amines with sodium glucuronate was investigated. N-Glucuronides (sodium salt) of secondary amine such as 4-monomethylaminoazobenzene, piperidine, morpholine and diethanolamine were synthesized as a crystal or a pulver by direct condensation. Further study was carried out on the possibility of direct condensation and the stability of secondary amine N-glucuronide by examining the change of optical rotation.
For the purpose of determining the original plant of commercially available "Engosaku"(Corydalis sp.) and its quality, gas chromatography and thin-layer chromatography were emploved. The Rf values of 14 corydalis alkaloids were determined by thin-layer chromato-graphy using 5 different solvent systems, and the retention time of 5 Corydalis alkaloids in gas chromatography was estimated. According to the paterns, or these chromatograms, the commercially available crude drugs originating from different parts of Asia were divided into two group. Such a differentiation was obtained by the observation of color of drugs ; bright yellowish and dark pale dusky yellow. The former includes Chinese Corydalis which was identified as Corydalis bulbosa D.C. cultivated in China, containing much more alkaloids than the latter. The latter was identified as Korean Corydalis and Chineee Corydalis which contains smaller amount of the total alkaloid. The latter Korean and Chinese Corydalis might be considered to be of the same origin or closely related.
Behavior of alumina and silica, the principle components in sodium aluminosilicate, was examined during crystallization of this salt. The salt was prepared by the reaction of silica, sodium aluminate, and sodium hydroxide in solution. The yield became the maximum when the ratio (n0) of silica to alumina at the time of mixing was around 2 and the yield increased with crystallization when n0 was below 2. When n0 is 3.5 to 5.8, yield of silica decreased and that of alumina increased, but the total yield of silica and alumina did not vary greatly. The ratio (n) of silica to alumina in the crystals formed was almost 2 when n0 was below 2, forming an A-type zeolite, while n was 2.6∼3 when n0 was over 4, formed an X-type zeolite. Crystallization degree of these zeolites was 1.3∼1.6 times that of commercial products in A type and 1.5 to 2 times in X type.
Examination were made on gas chromatographic detection of approximately sixty kinds of nitrofuran derivatives. With the exception of a few compounds, majority of these derivatives were found to be detectable without decomposition.
The quantity T, measured by a turbidimeter with an integrating sphere, decreases slightly as absorption increases in a colored turbid system. In order to estimate the turbidity τ, the following expression between T and optical density DT or D was derived by a theoretical consideration and was supported by a theoretical calculation where the Rayleigh equation is applicable.[numerical formula] where DT is the optical density obtained from the ratio of the total quantity of transmitted light and the diffuse transmitted light, Tt and Td, respectively, according to the equation : [numerical formula] and the D obtained from ordinary method. This relation was supported by an experiment for the solution containing polymer latex and Methyl Orange, and the values of p and q were determined. The parameter q thus determined was almost constant, even though the kind of latex used and its concentration were different, but p depended upon the both. It was concluded that when a certain colored turbid solution is given, turbidity of this solution can be obtained from the measurement of T and DT or D, if the parameters p and q were determined beforehand for this turbid system.
Mass spectra of several kinds of pavine-type alkaloids (cf. Table I) were measured and fragmentation mechanism was presumed from the examination of mass shifts of metastable ions of each alkaloid and of deuterated compounds by the mass spectrometric shift technique.
As a part of work on the syntheses of compounds related to corpaverine, one of its isomers, 1-(p-hydroxybenzyl)-2-methyl-6, 7, 8-trimethoxy-1, 2, 3, 4-tetrahydroisoquinoline (XVIII), was synthesized. Condensation of 6, 7, 8-trimethoxyisoquinoline methiodide and p-nitro-toluene, in the presence of sodium hydride, gave 1-(p-nitrobenzyl) compound (XV) which was reduced to the amino compound (XVII), diazotized, and decomposed into XVIII. XVIII was also synthesized from mescaline via XIX, XX, XXI, and XXII by the usual method, and the two kinds of compounds so obtained were identified by mixed fusion and infrared absorption spectra.
Refluxing of 1-(p-methoxybenzyl)-6, 7, 8-trimethoxy-3, 4-dihydroisoquinoline (I) in 20% hydrochloric acid for 5 hours resulted in demethylation of the 7-position, with oxidation of the methylene in the benzyl group in 1-position, affording 1-(P-methoxybenzoyl)-6, 8-dimethoxy-7-hydroxy-3, 4-dihydroisoquinoline (II). Reduction of II gave III, whose methylation produced IV, confirming the structure of II. In order to prove demethylation of the 7-position in I, the amine (X) was prepared from methyl 3, 5-dimethoxy-4-benzyloxybenzoate (V) via VI, VII, VIII, and IX, Schotten-Baumann reaction of X gave the amide (XI), which was cyclized and debenzylated. The final product of this reaction was identified with II by mixed fusion.
To test their antibacterial activity, [2(5-nitro-2-furyl)vinyl)-azoles and-azines were prepared by the condensation of 5-nitro-2-furaldehyde with azoles and azines, which have active methyl or methylene group. Almost all the compounds possess antibacterial properties and some of them also have strong antifungal and antiprotozoal activities.
Forty-three pyridine derivatives have been screened for antitumor activity using the Ehrlich carcinoma cells in ascites as well as in solid form. Of these compounds, 14 are new and their synthetic procedures are also described. The compound IIIa in Table I showed an antitumor effect on the solid type of Ehrlich carcinoma cells. No other substances were found effective as shown in Table I.
The quaternary base fraction of "Engosaku"(Corydalis bulbosa D.C.) was examined. The following alkaloids were isolated from this fraction by means of alumina column chromatography ; dehydrocorydaline nitrate, m.p. 245∼247°(decomp.), dehydrocorydaline chloride, m.p. 191∼193°(decomp.), coptisine nitrate, m.p.>290°(decomp.), columbamine nitrate, m.p. 237∼238°(decomp.), l-tetrahydrocolumbamine, and the mixture consisting of dehydrocorydaline bromide and chloride.