Some discussions were made on the presence of a long-range I-I coupling of C4-H in the NMR spectra of Δ4-3-keto-steroids substituted with chlorine at 6α-, 6β-, 2α-, and/or 2β-positions, and stereochemical significance of the width of their half-values. Comparative examinations were made on the maximum absorptions and absorbance of various derivatives in their ultraviolet spectra. It was suggested from the results of NMR and ultraviolet spectra that the size of the long-range I-I coupling was correlated to the steric state of A and B rings.
Galanthamine (I) and lycoramine (II), the substances that inhibit cholinesterase activity, have a fundamental skeleton of 1, 2, 3, 4-tetrahydrospiro [5H-2-benzazepine-5, 1′-cyclohexane] (III). In order to examine the pharmacological action of the derivatives of III, the title compound (IV) was synthesized through the route shown in Chart 2 and its pharmacological action is now being tested.
As to the reaction of amines with thioacetals (I) and their derivatives, following findings have been obtained. 1) When morpholine. and piperidine were reacted with I, respective ethyl 2-methylthio-2-morpholino-1-cyanoacrylate (II) and ethyl 2-methylthio-2-piperidino-1-cyanoacrylate (III) were obtained. 2) The reaction between ethanolamine and I afforded oxazolidine compounds, IV and V. VIa and XIb of ketene-S⋅N-acetal derivative gave VII and VIII of ketene-N⋅N-acetal derivatives easily. 3) By reacting methanolic ammonia, methyl 2-carboethoxymethylamino-2-methylthio-1-cyanoacrylate (X) afforded 2-(cyanocarbomethoxymethylene) imidazolidone-(4) (XI). 4) When methanolic ammonia, of XIIa and XIIb, reaction products between I and active methylene compound, dimethyl 2-cyano-3-amino-glutaconate (XIII) and 2-cyano-3-methylthio-3-carbomethoxy-glutaconimide (XIV) were produced and the reaction of 47% hydrobromide with XIIa gave 2-carbomethoxy-3-methylthioglutaconimide (XV).
N-Bis (methylthio) methylenebenzenesulfonamides (I), para-substituted in the benzene ring, were prepared by the condensation of para-substituted benzenesulfonamide with carbon disulfide in alkaline medium and methylated with dimethyl sulfate (Table I). Application of amines and active methylene compounds to I afforded para-substituted 1-(phenylsulfonyl)-S-methylisothioureas (Va-h) (Table II), phenylsulfonylguanidines (III) (Table III), and N-(2-imidazolidinylidene) sulfonamides (IV) (Table IV). Treatment of I with sodium ethoxide gave pare-substituted benzenesulfonylcarbamates (V).
It had been found that oxidation of 4′-hydroxyacetanilide with potassium ferricyanide in sodium hydroxide alkalinity under ice-cooling and addition of phenol resulted in blue (λmax 635mμ) coloration. Application of this color reaction for quantitative determination was examined for conditions, effect of co-existing substances, and specificity of this reaction, and a method for determination of 4′-hydroxyacetanilide in various preparations was established. Determination of prepared samples (Table V) by this method gave an accuracy of 1.19% (n=6) and recovery rate of 98.6-102.2%. Determination of 4′-hydroxyacetanilide in marketed tablets, capsules, syrups, and liquids gave satisfactory result. The color product, obtained as crystals, was assumed to be N-(p-hydroxyphenyl)-p-benzoquinone imine from its analytical data, absorption spectra, Rf value, and melting point.
Sulfonamides containing gulcosamine or N-methylglucamine residue were synthesized, in expectation of increasing water solubility. These compounds had very low toxicity (LD50>5g./kg.). Their antibacterial activities tested on E. coli and Staph. aureus were low, but some of them were found to show considerable blood-sugar depressing action in normal rabbits. Additionally their physical and chemical nature, e.g. solubility, optical rotation, and ultraviolet and infrared spectra were examined.
In continuation of the previous paper, the structure of taxinine is discussed. The moieties A, B, and C are expanded and taxinine is shown to be represented by the partial structure L. In combination with the fact that taxinine can be converted into anhydrotaxininol, which on selenium dehydrogenation yields 1, 2, 3, 8-tetramethylanthracene, the above finding strongly supports formula XXXIII for taxinine.
4, 6-Disubstituted 2-benzylidenehydrazinopyrimidines gave the corresponding 4, 6-disubstituted 2-(5-nitro-2-furfurylidenehydrazino) pyrimidines upon treatment with 5-nitro-2-furaldehyde in acidic condition. Several other 5-nitro-2-furfurylidenehydrazinopyrimidines were prepared by condensation of the corresponding substituted pyrimidinylhydrazines with 5-nitro-2-furaldehyde. Most of these nitrofuran compounds were found to be active against Trichomonas vaginalis in vitro.
Syntheses of 5-substituted 3-(5-nitro-2-furfurylideneamino) rhodanines, 3-[2-substituted-3-(5-nitro-2-furyl)-allylideneamino]-5-substitutedrhodanines, 3-[2-substituted 3-(5-nitro-2-furyl) allylideneamino]-5-morpholinomethyl-2-oxazolidinones and 5-substituted 2-[2-(5-nitro-2-furyl) vinyl]-1, 3, 4-oxadiazoles are described. 5-Substituted 2-methyl-1, 3, 4-oxadiazoles yielded 5-substituted 2-[2-(5-nitro-2-furyl)-vinyl]-1, 3, 4-oxadiazoles and 2-[2-(2-furyl)vinyl]-5-methyl-1, 3, 4-oxadiazole (XII) by condensation of 5-nitro-2-furaldehyde or 2-furaldehyde, respectively. 2-[2-(5-Nitro-2-furyl) vinyl]-5-methyl-1, 3, 4-oxadiazole (IX) was also obtained by direct nitration of XII, and exhibited significant activity against Trichomonas vaginalis in vivo and no toxicity.
In the course of investigation of Smiles rearrangement on 2-(o-aminophenylthio)-3-nitro-5-chloropyridine (I) and its acetate (II), the following findings were obtained: 1) Hydrolysis of N-acetyl group was facilitated by the participation of thiol anion and B-ring nitrogen in the intermediate stage of rearrangement of the acetate (II). 2) I was easily rearranged to the corresponding disulfide (V) by ethanolic hydrochloric acid. Additionally, it was assumed that ring closure to pyridobenzothiazine (VII) taking place after rearrangement depends upon the conformation of the rearrangement products.
For the purpose of obtaining the compound (V) containing a seven-membered heterocyclic ring by cyclization of the amino-alcohol (VIII), either the nitroalcohol (VII) or the cyanohydrin (X) was first treated with lithium aluminum hydride. The product thus obtained was found, however, to be the diol (IX) and not the expected aminoalcohol (VIII) which was finally obtained by catalytic hydrogenation of X, but could not be cyclized to the 2-benzazepine (XIII) by the Pictet-Spengler or the Bischler-Napieralski method. Next, we turned to the synthesis of the tetralone (XV), which was expected to be converted into a 2-benzazepine derivative by the Schmidt reaction. For this purpose the nitrile (XVI) was treated with methyl magnesium iodide to give the methyl ketone (XVIII) which underwent smooth condensation with ethyl formate, yielding XX. Acetalization of XX with ethylene glycol, followed by treatment with sodium borohydride, and acetylation, afforded XXII which on treatment with acetic acid-hydrochloric acid gave, as a result of cyclization by the acid used to the dihydronaphthalene (XXIII) and simultaneous Wagner-Meerwein rearrangement, the cycloheptanaphthalene (XXIV), as shown by the infrared, ultraviolet, and NMR spectra, together with its analytical values.
Ethyl [(5-pyrazolyl) aminoalkylidene] cyanoacetates were obtained by heating ethyl (1-ethoxyalkylidene) cyanoacetates with 5-aminopyrazoles. In the cyclization reaction of these compounds, ethylidene-(XI-XIII) and propylidene-cyanoacetates (XIV to XV) tended undergo cyclization at the ester group to form 6-cyanopyrazolo [1, 5-a] pyrimidin-7(4H)-one compounds (XXIV to XXIX). When heated with sodium ethoxide catalyst in ethanol, they formed only the 7-one compounds, while heating with hydrochloric acid catalyst gave, besides the 7-one compound, ethyl 7-aminopyrazolo [1, 5-a] pyrimidine-6-carboxylates (XVII to XXII) formed by cyclization at the nitrile group. Methylenecyanoacetates (XVI and XXXII) tended to form the 7-amino compounds by cyclization at the nitrile group. When heated in ethanol with the hydrochloric acid catalyst or a large excess of sodium ethoxide catalyst, 7-amino compounds (XXIII and XXXIII) are almost the only product, while the use of about 2 molar equivalents of sodium ethoxide as a catalyst gives the 7-one compounds (XXX and XXXIV) at the same time. Heating of (1-ethoxyethylidene) malononitrile (IV) and 5-aminopyrazoles (V to VIII) in ethanol without a catalyst results in condensation and cyclization to form 7-aminopyrazolo [1, 5-a] pyrimidine-6-carbonitriles (XXXV to XXXVIII).
Nitrosation reaction of ethylpyridine, phenethylpyridine, and benzylpyridine, and their N-oxides, making a total of 12 kinds of compound, was examined. All these compounds reacted with amyl nitrite in liquid ammonia, in the presence of potassium amide, and formed the corresponding ketoximes; methyl 2-pyridyl ketone oxime (26%) from 2-ethylpyridine, methyl 4-pyridyl ketone oxime (35%) from 4-ethylpyridine, anti-methyl (2%) and syn-methyl (77%) types of methyl 2-pyridyl ketone 1-oxide oxime from 2-ethylpyridine 1-oxide, methyl 2-pyridyl ketone 1-oxide oxime (57%) from 4-ethylpyridine 1-oxide, benzyl 2-pyridyl ketone oxime (29%) from 2-phenethylpyridine, benzyl 4-pyridyl ketone oxime (45%) from 4-phenethylpyridine, benzyl 2-pyridyl ketone 1-oxide oxime (54%) from 2-phenethylpyridine 1-oxide, benzyl 4-pyridyl ketone 1-oxide oxime (32%) from 4-phenethylpyridine 1-oxide, phenyl 2-pyridyl ketone oxime (anti-phenyl type) (73%) from 2-benzylpyridine, phenyl 4-pyridyl ketone oxime (93%) from 4-benzylpyridine, phenyl 2-pyridyl ketone 1-oxide oxime (86%) from 2-benzylpyridine 1-oxide, and phenyl 4-pyridyl ketone 1-oxide oxime (94%) from 4-benzylpyridine 1-oxide. It was found from these reactions that N-oxygenation markedly increased the activity of the methylene group.
A small amount of a new, tertiary phenolic base of biscoclaurine type was isolated, besides dauricine (I), from Menispermum dauricum DC. (Japanese name “Kohmori-kazura”). This base, designated as daurinoline, was obtained as non-crystallizable, pale yellow powder and its analytical values corresponded to C37H42O6N2⋅H2O. Methylation with diazomethane gave the known O-methyldauricine (IV), and ethylation with diazoethane gave O, O-diethyldaurinoline (V), whose cleavage reaction with metallic sodium in liquid ammonia afforded D-(-)-O-ethylarmepavine (VI) as a non-phenolic base and D-(-)-1-(p-hydroxybenzyl)-2-methyl-6-ethoxy-7-methoxy-1, 2, 3, 4-tetrahydroisoquinoline (VII) as a phenolic base. These experimental facts indicated that the structure of daurinoline should be represented by the formula III.
Comparative examinations were made on the biological activity of α-lipoic acid and newly synthesized α-lipoic acid derivatives, using Streptococcus faecalis 1 OCI by the modified methodof Uehara. Of the newly synthesized derivatives, biological activity of N-methyl-DL-α-lipamide and 4-(DL-α-lipamido) butyric acid was higher than that of the authentic sample of DL-α-lipoic acid, especially the latter showed almost twice the activity of DL-α-lipoic acid. Other compounds which had lower activity than α-lipoic acid were N-DL-α-lipoyl-L-tryptophan, N-DL-α-lipoyl-L-phenylalanine, N-DL-α-lipoyl-L-leucine, and N-DL-α-lipoyl-L-isoleucine.
Pharmacological action of 4-(DL-α-lipamido) butyric acid was examined. The compound was found to have a marked detoxicating activity against mercury and arsenic poisoning, especially the latter, when tested in mice. This effect was better than that of a mixture of α-lipoic acid and 4-aminobutyric acid so that it is unlikely that the lipamidobutyric acid is degraded into its components to show its effect. Liver dysfunction of a rabbit caused by carbon tetrachloride was improved by the lipamidobutyric acid in the same degree as that of α-lipoic acid. Acute toxicity of the lipamidobutyric acid in mice was weaker than that of α-lipoic acid, either by intravenous, intraperitoneal, subcutaneous, or oral route. This is true on the molar basis and must be the characteristic of the α-lipamidobutyric acid.
Systematic examinations were made on the aqueous methanolic extract of the tubers of Aconitum japonicum THUNB, except the basic fraction. Lead salt and ion-exchange resin methods were used. The first isolation of β-sitosterol-β-D-glucoside (daucosterin) from Aconitum sp. is reported. Sucrose was obtained in a high yield (9%) from the neutral fraction and that fraction contained meso-inositol (0.05%). The main constituent of the acid fraction was trans-aconitic acid (0.7-0.9%), just as in A. napellus. The other isolated acids were benzoic, p-hydroxybenzoic, fumalic, and citric acid. Myristic, palmitic, stearic, oleic, and linoleic acids were detected by gas chromatography.
A new, water-soluble, quaternary base was isolated from a Formosan lotus embryo (Nelumbo nucifera GAERTN.) (Nymphaeaceae), besides the earlier reported isoliensinine (I). This base, named lotusine, formed a chloride of m.p. 213-215°, [α]D-15.0° (methanol), picrate of m.p. 212-214°, and an iodide of m.p. 202-204°, [α]D-19.2° (methanol). From its NMR spectrum (D2O) a formula VII was presumed. The iodide of lotusine was identified by infrared spectrum (Nujol) with D-N-methylisococlaurine (VI) methiodide (Table I).