A new and comparatively simple method for the synthesis of α-amino acids from diketene was tried. This is a simultaneous Hofmann reaction and haloform reaction to α-substituted acetacetamide with KOBr solution. DL-Leucine was synthesised from 2-isobutylacetacetamide (IV), in about 50% yield. In this reaction, molar ratio of KOH, KOBr, and 2-isobutylacetacetamide, and the reaction temperature were important.

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3-[2-(5-Nitro-2-furyl)vinyl]-5-amino-1, 2, 4-thiadiazoles (IV), 3-[2-(5-nitro-2-furyl)vinyl]-1, 2, 4-oxadiazoles (XI and XII), and 3-[2-(5-nitro-2-furyl)vinyl]-Δ²-1, 2, 4-oxadiazolines (XIII) were synthesized by the known method using 5-nitro-2-furanacrylamidine hydrochloride (II) and 5-nitro-2-furanacrylamidoxime (IX) as the starting materials. Antibacterial activity of these new compounds against four kinds of bacteria was compared with that of 1, 3, 4-oxa (or thia) diazole ring and its result is summarized in Tables I to III.

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As part of a series of work dealing with the syntheses of water-soluble compounds allied with papaverine, 1-benzyl-2-methyl-6-methoxy-1, 2, 3, 4-tetrahydroisoquinoline-7-ol (XI) was prepared. Phenylacetyl chloride and 3-methoxy-4-benzyloxyphenethylamine were derived to the amide (VI) by the usual method, cyclized to 3, 4-dihydroisoquinoline compound (VII), and led to the objective XI via the methiodide (IX) or 1, 2, 3, 4-tetrahydroisoquinoline compound (X). Methylation of XI afforded II whose identification was established by the synthesis of II in the following manner. Homoveratrylamine and diazo ketone (IV) were submitted to the Arndt-Eistert reaction to form the amide (V), which was cyclized by the usual method, derived to the methiodide (VIII), and submitted to reduction.

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In connection with the syntheses of water-soluble compounds related to papaverine, 1-phenyl-2-methyl-6-methoxy-1, 2, 3, 4-tetrahydroisoquinolin-7-ol (VI), unknown in past literature, was synthesized. 3-Methoxy-4-benzyloxyphenethylamine (I) and benzyl chloride were reacted to form the amide (II), cyclized to III by the usual method, derived to the methiodide (IV), and reduced with zinc dust and hydrochloric acid to VI. Reduction of IV with sodium borohydride and hydrolysis of its product (V) also afforded VI. The structure of VI was proved by its methylation to form the 1, 2, 3, 4-tetrahydroisoquinoline compound (VII).

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1-[2-(tert-Amino) ethyl]-2-(arylthio) benzimidazoles were obtained by the condensation of para-substituted benzenethiol with 2-chlorobenzimidazole in the presence of alkali and its product reacted with 2-(tert-amino) ethyl chloride. Analgesic potency of these benzimidazoles was tested by the D'Amour-Smith and pressure methods, and eight of these compounds showed activities comparable to or better than morphine sulfate or codeine phosphate. Correlation between analgesic effect and chemical structure of 1-[2-(diethylamino) ethyl]-2-(p-R-phenylthio) benzimidazoles showed the presence of bioisosterism in R. The same examinations were made on 1-[2-(diethylamino) ethyl]-2-(aryloxy) benzimidazoles.

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3-Diphenylmethyleneproline (XIII) was synthesized by the following two methods.
(i) Diethyl formamido (3, 3-diphenylallyl) malonate (X) was cyclized by the Bischler-Napieralski reaction to diethyl 3-diphenylmethylene-1-pyrroline-5, 5-dicarboxylate (XII), which was reduced, saponified, and decarboxylated to XIII.
(ii) XIII was obtained directly by the Pictet-Spengler reaction of 2-amino-5, 5-diphenyl-4-pentenoic acid and formaldehyde.
The cyclization in method (i) was of low yield while that of (ii) gave a high yield. The structure of XIII was established by its esterification, N-ethoxycarbonylation, and ozone oxidation to diethyl 4-oxo-1, 2-pyrrolidinecarboxylate (XX), and identified with XX synthesized by the method of Kuhn and others. The present work proved that the Pictet-Spengler reaction can be utilized also for the cyclization of monocyclic compounds.

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Reaction of triethyl phosphonoacetate (I) and 2-methyl-1-indanone (II) in the presence of an excess of sodium hydride afforded, besides ethyl cis- and trans-2-methyl-Δ^{1, α}-indaneacetate (III′), ethyl 2-methyl-indene-3-acetate (IV′). It was found that IV′ was formed directly from I and II, and not through III′.
Similarly, in the case of 1-indanone (V), cyclohexanone (VI), and propiophenone (VII), β, γ-unsaturated ethyl carboxylates are formed together with α, β-unsaturated esters, and it is considered that a part of the former was formed by isomerization of the latter.

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Comparative examinations were made on 2, 5-furandicarboxaldehyde, 5, 5′-methylenedi-(2-furaldehyde), 5, 5′-ethylenedi-(2-furaldehyde), and 5, 5′-oxydimethyldi-(2-furaldehyde) as a coloring agent. 5, 5′-Methylenedi-(2-furaldehyde) reacted with aromatic primary amines to show a characteristic coloration and the colored solution exhibited absorption maximum at 700-750mμ in acetic acid solution. The compound did not react easily with aliphatic amines. Amino acids like glycine, valine, leucine, methionine, cysteine, cystine, glutamic acid, lysine, histidine, proline, tyrosine, and phenylalanine did not undergo coloration with this compound, but tryptophan reacted with it to form a stable reddish violet color with absorption maximum at 510mμ when heated in butanol-acetic acid mixture at 60° for 3 hours. Consequently, the compound can be used for selective coloration of tryptophan in the presence of these amino acids. This coloration is interfered by the presence of indole, 2-methylindole, 3-methylindole, and tryptamine. This method of determination is accurate to within ±3%.

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Syntheses of 5, 6, 8-trimethoxy-7-dimethylaminoquinoline (XI) and 7-amino-6-hydroxy-5, 8-quinolinedione (XVIIa) were attempted in order to use them as the starting material for the synthesis of hexamethyldihydrostreptonigrin (VI), derived from streptonigrin (V). Guaiacol was derived to 5-bromo-4, 6-dinitroguaiacol (VII), by a four-step procedure according to Robinson's method, treated with sodium hydroxide to change the bromine into hydroxyl, and dimethylated with dimethyl sulfate in nitrobenzene. Reduction of the nitro group with iron and hydrochloric acid led the product to a diamino derivative (X) which was submitted to the Skraup reaction, and 5, 6, 8-trimethoxy-7-aminoquinoline (XI) thereby formed was treated to the Eschweiler-Clarke reaction of heating with formic acid and formaldehyde in a sealed tube, finally giving the N-dimethylated derivative (XII). Its identification was established as a perchlorate after purification by alumina chromatography. Treatment of XI with 48% hydrobromic acid gave the demethylated compound (XVI) which was derived to XVIIa by air oxidation in alkaline solution.

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Effect of several monoguanidino compounds on neuromuscular transmission was examined, using frog sciatic nerve sartorius muscle preparation and following results were obtained. Monoguanidino compounds were classified into three groups; curare antagonists, curare potentiators, and muscle relaxants. In the anti-curare activity of these compounds, maximal point existed at methylguanidine or N, N-dimethylguanidine, and guanidino compounds with bulky substituents possessed a muscle-relaxing action. As to the mode of action, curare antagonists (guanidine, methylguanidine, and ethylguanidine) antagonized any of the muscle relaxants tested such as d-tubocurarine, succinylcholine, and magnesium ion. On the other hand, muscle relaxants (hexylguanidine) blocked neuromuscular transmission in concentrations which did not prevent nerve conduction and muscle response to direct stimulation. This neuromuscular block was antagonized by potassium ion and guanidine, but not by neostigmine.

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An infrared spectrophotometric method is offered for rapid simultaneous determination of Methylparafynol and Anergen in oil capsules. The key bands used for Methylparafynol and Anergen are 10.94μ and 13.40μ, respectively, and these two components can be determined without any interference of the common components in commercial samples by the use of suitable base lines. This method gave good results both in standard mixed samples and in commercial samples.

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Determination of all-trans-, 2-cis-, and 6-cis-vitamin A acid in their mixture has been developed by using infrared absorption spectroscopy, for a manufacturing process control.
All-trans-vitamin A acid can be determined with a key band at 8.65μ without the interference of 2-cis- and 6-cis-isomers by the use of an available base line. The key bands used for 2-cis- and 6-cis-vitamin A acid are at 10.31 and 10.43μ, respectively, and these two components can be determined by the use of compensation method.
The results obtained by analysis of standard mixed samples by this method indicated that the standard deviations are 0.47% for all-trans compound, 0.47% for 2-cis compound, and 0.56% for 6-cis compound. This method can be applied to a wide variety of samples and is useful as an industrial method with simple operations.

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A rapid method for the determination of sulpyrine in injection solutions has been devised by using infrared spectroscopy. Aqueous sample solutions can be used directly for the measurement without any treatment. The key band used is at 8.54μ and sulpyrine can be determined without interference of N-methylaminoantipyrine, which is formed by the decomposition of sulpyrine. The results obtained by analysis of standard mixed samples indicated that the method gave a good recovery.

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A rapid method for simultaneous determination of aminopyrine and isopropylantipyrine in their pharmaceutical preparations has been devised by using infrared absorption spectroscopy.
These two compounds are separated from phenacetine and caffeine by the use of carbon disulfide as a solvent. The key bands used for aminopyrine and isopropylantipyrine are 10.48 and 9.95μ, respectively, and these two components can be determined without interference of other components by the use of two available base lines. The results obtained by analysing standard mixed samples indicated that the method gave satisfactory results.

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A method for semimicrodetermination of terephthalic acid reported previously is suitable for its assay in urine or tissues. Muscle and other organs might contain terephthalic acid in smaller quantity and a method was developed for its determination in tissues.
The procedure is as follows: One g. of tissue is placed in a Waring blender containing 1ml. of 0.3M perchloric acid-ethanol and 9ml. of ethanol, and homogenized for 5 minutes (20, 000r.p.m.). After standing for 5 minutes the mixture is centrifuged for 5 minutes (3, 500r.p.m.). The supernatant is poured into a polypropylene test tube and the precipitate is re-extracted with 5ml. of ethanol by the same procedure as above. These extracts are combined in one test tube and neutralized to pH 5.5 with a small amount of 20% sodium hydroxide solution. After standing overnight with a stopper, at -20° in a refrigerator, the extract is centrifuged and charged on 2ml. of ethanolic Permutit column at 0.4ml./min. flow rate.
After washing the column with 5ml. of ethanol, terephthalic acid is eluted with three 10ml. portions of 0.93M perchloric acid in ethanol at the same flow rate. The UV absorbance of the eluate is measured at 240mμ and their values are converted into μg. terephthalic acid from the following equation:
terephthalic acid content (μg./g. of tissue)=E₂₄₀/g. of tissue (treated)-E₂₄₀/g. of tissue (control)/0.110
E_1cm^1%=1, 100 (240mμ)

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Subacute toxicity of decanohydroxamic acid was examined for 3 months by forced oral administration in rats. No marked changes from the controls were observed in the growth (weight change), death rate, incidence of disease, effect on blood (number of erythrocytes and leucocytes, hemoglobin, reticulocytes, platelets, and blood picture), renal functions (urinary pH, glycosuria, proteinuria), liver functions (urobilinogen, bilirubin), macroscopic observations on internal organs, their weight and weight ratio, and pathohistological observations (heart, liver, adrenal, kidney, lung, spleen, bone marrow, and testis or ovary), indicating that the compound has no subacute toxicity by oral administration.

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Examinations were made on dermal absorption, physical distribution, and subacute toxicity through the skin (11 weeks) of decanohydroxamic acid, using rats. Absorption through the skin was found to give a definite blood level 1 hour after the application and comparatively large amount was distributed in the kidney and spleen 6 hours after the application, but only a small amount in the lung and heart.
Subacute toxicity of decanohydroxamic acid by skin application in rabbits (11 weeks) was examined but no marked difference from the control was observed in the growth (weight change), death rate, incidence of disease, effect on blood (erythrocytes, leucocytes, hemoglobin, reticulocytes, platelets, and blood picture), renal functions (urinary pH, prote inuria, glycosuria), liver functions (urobilinogen, bilirubin), macroscopic observations on internal organs, weight of organs and their weight ratio, and pathohistological observations (heart, liver, adrenal, kidney, lung, spleen, bone marrow, testis or ovary, skin, and thyroid), indicating that the compound has no subacute toxicity by skin application.

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