When the oxidation of thiocarbanilide (Ia) with sodium peroxide was carried out in aqueous ethanol under refluxing for the purpose of preparing carbanilide (IIa), unexpected 1-phenyl-2-benzimidazolinone (IIIa) was obtained besides IIa, the former being identified with the authentic sample by mixed mp and infrared spectra. Similar cyclization was confirmed with several other symmetric and asymmetric thiocarbanilides.

View full abstract

Oxidation of thiocarbanilide (Ia) with sodium peroxide in aqueous ethanol was investigated at room temperature in connection with the previous work in which the same reaction was carried out in boiling water bath to afford carbanilide (IIa) and 1-phenyl-2-benzimidazolinone (IIIa), and N, N'-diphenylformamidine (IVa) was obtained in addition to IIa and (IIIa). In the same manner, starting from 4, 4'-diethoxythiocarbanilide (Ib), N, N'-bis (p-ethoxyphenyl) formamidine (IVb) was obtained, together with 4, 4'-diethoxycarbanilide (IIb) and 1-(p-ethoxyphenyl)-6-ethoxy-2-benzimidazolinone (IIIb).

View full abstract

A total of 48 derivatives of 2-(alkylaminomethyl)-2, 3-dihydrobenzofuran (VII) and 5- or 7-substituted 2-(3-alkoxypropylaminomethyl)-2, 3-dihydrobenzofuran (VI) were synthesized and their pharmacological behavior was examined. VI showed analgesic, sedative, antipyretic, antiadrenaline, and coronary vascular dilating action. 2-(Monoalkylaminomethyl)-2, 3-dihydrobenzofuran showed an especially strong analgesic action.

View full abstract

A new coumarin, peuformosin (I), C₂₄H₂₆O₇, mp 155-156°, [α] ²⁷_D+67.3°, was isolated from ether extract of the root of Peucedanum formosanum HAYATA, in addition to (+)-anomalin, upon silica gel column chromatography, and was elucidated as 3'-angeloyloxy-4'-senecioyloxy-3', 4'-dihydroseselin from the fact that treatment of I with ethanolic sodium hydroxide under mild condition led to the formation of senecioic acid and 3'-angeloyloxy-4'-ethylkhellactone (VI) which yielded angelic acid and (+)-trans-ethylkhellactone (IIIc) upon further saponification. The ether extract of the root of Peucedanum japonicum THUNB. afforded a new coumarin, peucedanol (VII), C₁₄H₁₆O₅, mp 174-175°, [α]²⁰_D+31.2°, and a crystalline compound (XI), C₂₁H₂₂O₇, mp 90-96°. Peucedanol has three hydroxyl groups, one of which is phenolic. Oxidation of mono-O-methyl peucedanol (VIII) with sodium periodate yielded 6-formylmethyl-7-methoxycoumarin (X) with the formation of acetone, indicating that the structure of VII must be presented as 6-(2, 3-dihydroxy-3-methylbutyl)-7-hydroxycoumarin. The compound XI was presumed to be a mixture of acetyl-angeloylkhellactone (XIa) and acetyl- tigloylkhellactone (XIb) from NMR spectrum and the compsition of XI, and from the fact that treatment of XI with ethanolic sodium hydroxide yielded (±)-cis- (XIIb) and (±)-trans-ethylkhellactone (XIIa), and angelic, tiglic, and acetic acids.

View full abstract

Nine kinds of quaternary salts of phthalazines, possessing a substituent (C₆H₅, C₆H₅-CH₂, CH₃, RO) in 1-position, were synthesized, and it was clarified that the nitrogen in 3-position had been quaternized in these compounds. Since the methiodide of 1-methyl-4-ethoxyphthalazine formed a trimethinecyanine dye, the quaternization had taken place at the nitrogen in 2-position in this case. Structure of main products was determined when these quaternary salts were (a) heated above their decomposition temperature and (b) when they were reacted with silver oxide in the cold.

View full abstract

Mutarotation of 2-(D-gluco-1, 2, 3, 4, 5-pentahydroxypentyl) thiazolidine (I) in alkaline solution and the change of chromatogram on thin-layer chromatography are described. Reaction of I with acetone containing hydrogen chloride afforded crystals and the structure of this product was assigned as 2-(D-gluco-1, 2 : 4, 5-di-O-isopropylidene-1, 2, 3, 4, 5-pentahydroxypentyl) thiazolidine hydrochloride (VII). Some derivatives of VII were also prepared. 2-(D-Gluco-1, 2 : 4, 5-di-O-isopropylidene-3-O-mesyl-pentahydroxypentyl)-3-acetylthiazolidine (XV) was converted into D-galacto derivative (XVII) by sodium azide in hot dimethyl formamide containing 0.5% water. 2 (D-Gluco-1, 2, 3, 4, 5-pentahydroxypentyl)-3-ethylthiazolidine (XXIII) was synthesized from D-glucose and 2-(ethylamino)-ethanethiol. The acetate (XXIV) and benzoate (XXV) of XXIII were prepapred and their structures were elucidated.

View full abstract

Effect of the use of 4-hydroxyantipyrine, the metabolite of aminopyrine and antipyrine, with aminopyrine, antipyrine, and 4-iso-propylantipyrine, the antifebrile-analgesic of the pyrazolone system, on the metabolsim of these principal agents was examined by the measurement of the metabolic rate and rabbit blood level of the principal agents, using rat liver specimens, 9000xg supernatant fraction of the liver, and rabbit liver specimen. 1) Metabolism with rabbit and rat liver rspecimens showed the inhibitive effect of 4-hydroxyantipyrine against aminopyrine and antipyrine, but only slight on 4-iso-propylantipyrine. 2) Metabolism of principal agents by the 9000xg supernatant fraction from rat liver was inhibited by 4-hydroxyantipyrine. 3) Continued administration of 4-hydroxyantipyrine and antipyrine failed to show any phenomena for induction of drug metabolizing enzyme. 4) Blood level of principal agents in rabbit was maintained when 4-hydroxyantipyrine was administered orally in combination rather than when those were administered alone. These results indicated that 4-hydroxyantipyrine possessed the effect of inhibiting the metabolism of pyrazolone series agents.

View full abstract

Effect of p-hydroxyacetanilide, the metabolite of acetophenetidine and acetanilide, when used in combination with aminopyrine, antipyrine, and isopropylantipyrine, the antifebrile-analgesic of pyrazolone system, on the metabolism of these agents was examined by measuring the metabolic rate with rat and rabbit liver specimens and in 9000xg supernatant fraction from rat liver, and blood level in rabbit. 1) p-Hydroxyacetanilide hardly affects the metabolism of aminopyrine and 4-isopropylantipyrine in rat and rabbit liver enzyme system, or blood level in rabbit. 2) Metabolism of antipyrine is inhibited by p-hydroxyacetanilide and blood level of antipyrine is maintained longer. 3) Metabolism of p-hydroxyacetanilide is inhibited by antipyrine and its blood level is maintained longer by antipyrine. 4) Penetration of antipyrine and p-hydroxyacetanilide through the excised intestine is mutually inhibited by the other agent. These results show that p-hydroxyacetanilide affects the metabolism of antipyrine but not that of other agents.

View full abstract

Effect of the combined use of 4-hydroxyantipyrine and p-hydroxyacetanilide with acetophenetidine, acetanilide, and N-(p-ethoxyphenyl)-β-hydroxybutyramide on the metabolism of these agents was examined by measuring the metabloic rate of these principal agents using rat and rabbit liver specimens, and the blood level in rabbits. 1) p-Hydroxyacetanilide hardly affects the metabolism of the principal agents by liver slices but 4-hydroxyantipyrine inhibits their metabolism. 2) Blood level of these principal agents in rabbit is maintained by the combined use of 4-hydroxyantipyrine but is hardly affected by p-hydroxyacetanilide. These results indicate that both 4-hydroxyantipyrine and p-hydroxyacetanilide inhibit, though weakly, the metabolism of these principal agents and this effect is much higher in 4-hydroxyantipyrine.

View full abstract

Although sulpyrine (I) can be quantitatively determined by iodometric titration in cold strong acidic solution, decrease of titration value is observed by allowing to stand it as aqueous solution. The rate of this decrease is more rapid in acidic solution than in neutral or alkaline solution. From the studies of proton magnetic resonance spectra of I in deuteroxide and D₂SO₄, the cause of this decrease was found to be based on the dissociation of I to 4-(methylamino) antipyrine (III) and sodium hydroxymethanesulfonate (IV), which does not react with iodine. In this connection, it has also been found that N-methanesulfonic acid is reactive to iodine, whereas O-methanesulfonic acid is not. pH dependency of dissociation and formation rate of I were studied from the curve of this decrease. In the reaction of sulpyrine (I) &rlarr^^^(k₁)___(k₂) 4-(methylamino) antipyrine (III)+HOCH₂SO₃Na (IV) dissociation and formation rate constants of I are calculated as follows : k₁=2.30×10^-1h^-1, in aqueous solution, 1.11×10^-1h^-1 in 1N hydrochloric acid, k₂=1.19×10²M^-1·h^-1 in aqueous solution, and 6.35×10^-1M^-1·h^-1 in 1N hydrochloric acid. In view of these results, pH dependency of dissociation rate is found to be small, while that the formation rate is much affected by pH. It is supposed that formation of 4-(methylamino) antipyrine cation in acidic medium prevents the condensation of III with IV and therefore, formation rate of I becomes slow. This might be the causue of pH dependency of titration value decrease. Proton magnetic resonance spectra of I in D₂SO₄ and the solution obtained from the reaction of I with iodine have shown that sodium hydrogen sulfite, formaldehyde, and/or 4-(N-hydroxymethyl-N-methyl) aminoantipyrine (II) were not formed in the former solution, but that II and/or formaldehyde was formed in the latter solution immediately after the addition of iodine. In consideration of these facts, mechanism of this reaction might be concluded that iodine attacks I directly and quantitatively oxidized it to yield sulturic acid, hydrogen iodide, and II, which dissociates rapidly to formaldehyde and III.

View full abstract

A reinvestigation of the structure of bilobanone, a sesquiterpene isolated from the heartwood extracts of Ginkgo biloba was undertaken in view of the discrepancy between its NMR spectrum and that expected for the structure (I) provisionally assigned to it. Mass spectrometry showed that bilobanone has the formula C₁₅H₂₀O₂ rather than C₁₅H₂₂O₂ previously assigned. Bilobanone contains an α, β'-disubstituted furan, an α, β-unsaturated α-methylketone, and an isobutyl side chain as inferred from its spectrometric data. Ozonolysis of dihydrobilobanone (VI) afforded isovaleric acid and 4-methyl-3-oxocyclohexanecarboxylic acid (XIII) and the Alder-Rickert reaction of dihydrobilobanone gave α-isobutyl-β, β'-furandicarboxylic acid (XIV) and 2-methyl-5-vinylcyclohexanone (XX), the latter of which was oxidized to XIII. The acid (XIV) and the racemic modification of XIII were prepared synthetically and were found to be identical with the respective compounds from natural sources. These results led to the revised structure (V) for bilobanone. Autoxidation of bilobanone gave an α, β-unsaturated γ-lactone (XXI) and peracid oxidation of dihydrobilobanol p-nitrobenzoate (XXIII) gave β, γ-unsaturated γ-lactone (XXIV) which was readily converted into the α, β-unsaturated γ-lactone (XXV). The spectral properties of these compounds confirmed the assignment of structure (V) to bilobanone. The absolute configuration (XXVI) of bilobanone was also established based on the ORD curve of the acid (XIII). Biogenesis of this terpene is discussed.

View full abstract

Reduction of 3-(methoxycarbonylmethyl)-2-methyl-3, 4-dihydroisocarbostyril (VIII) with lithium aluminum hydride gave the anticipated cyclization product, 4-oxa-9-aza-9-methyl-6, 7-benzobicyclo [3. 3. 1] nonane (X), with by-product formation of 2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-3-ethanol (XII) and 3-(2-hydroxyethyl)-2-methyl-3, 4-dihydroisocarbostyril (IX). Reduction of IX with lithium aluminum hydride also gave the cyclized reduction products, X and XII, while the sme reduction of X gave the ringcleaved product, XII. It is interesting that 2H-tetrahydro-1, 3-oxazine ring is formed by the reduction of VIII or IX. Application of this reaction to nine kinds of new piperidone compounds (XVI to XXIV) failed to afford the anticipated cyclized products (XXXII to XXXVI) and only the ringcleaved products (XXVII to XXXI) were obtained.

View full abstract

Reaction of phenethylamine (XVII) and a carboxylic acid (XVIII) afforded the amide (XIX) which was converted to the amide (XX) and submitted to the Bischler-Napieralski reaction to prepare the 3, 4-dihydroisoquinoline compound (XXI). XXI was converted, via its methiodide (XXII) and 3'-hydroxyisoquinoline compound (XXIV), into 1-(3-hydroxy-4-methoxyphenethyl)-7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-6-ol (VIII). Another reaction of the amine (XXVII) and a carboxylic acid (XXVIII) afforded the amide (XXIX) whose Bischler-Napieralski reaction gave the 3, 4-dihydroisoquinoline compound (XXX), which was converted via its methiodide (XXXI) and the 2-methyl compound (XXXII) into 1-(3-hyrdoxy-4-methoxybenzyl)-7-methoxy-2-methyl-1, 2, 3, 4-tetrahydroisoquinoline-6, 8-diol (XI). The amide (XIX) was derived to the secondary amine (XXVI) via the amide (XXV) and debenzylation of XXVI afforded 3, 3'-dihydroxyamine (XV). Phenolic oxidative coupling was examined with the compounds so obtained, VIII, XI, and XV, but the reaction did not materialize.

View full abstract

5-Nitrofuraldehyde (V) was reacted with 3-oxo-2, 3-dihydrobenzofuran (IV : X=O) and 3-oxo-2, 3-dihydrobenzothiophene (IV : X=S) derivative (s) by refluxing in acetic acid or with sulfuric acid in acetic acid at room temperature, and derivatives of 2-(5-nitro-2-furfurylidene)-3-oxo-2, 3-dihydrobenzofuran (VI : X=O) and 2-(5-nitro-2-furfurylidene)-3-oxo-2, 3-dihydrobenzothiophene (VI : X=S) were obtained (cf. Table I). Antibacterial activities of these derivatives in vitro were examined and its result is summarized in Table II.

View full abstract

Reaction between 4-(methylsulfonyl) cinnoline (I) and ketones, in the presence of sodium amide as a basic catalyst, was examined. The compounds listed used as the ketones were acetophenone (IIa), propiophenone (IIb), butyrophenone (IIc), valerophenone (IId), isovalerophenone (IIe), isobutyrophenone (IIf), acetone (IIg), diethyl ketone (IIh), methyl ethyl ketone (IIi), methyl propyl ketone (IIj), methyl isobutyl ketone (IIk), methyl isopropyl ketone (III), cyclohexanone (IIm), l-p-menthan-3-one (IIn), and cyclopentanone (IIo). The reaction with aromatic ketones (IIa to IIf) afforded the corresponding compounds (IIIa to IIIf), whose hydrolysis in alkaline reaction resulted in their decomposition to the corresponding 4-alkylcinnolines (IVa to IVf) and benzoic acid (Charts 1 and 2; Tables I and II). Symmetric, straight-chain ketones (IIg and IIh) gave the corresponding IIIg and IIIh, while the reaction with asymmetric IIi afforded two kinds of product, IIIi and IIIi'. In the case of other asymmetric ketones, IIj to IIl, only one kind of the corresponding products (IIIi to IIIl) were obtained (Chart 3 and Table I). Among the products obtained by this reaction (IIIa, IIIg, IIIi-l), the products obtained by the reaction of the methyl-carbon adjacent to the carbonyl group may show tautomerism in alcoholic solvent, as indicated by (1) in Chart 4 but they should be present in the keto form in solids or in chloroform solution. Finally, the reaction with cyclic ketone (Im) gave a product (IIIm') which was assumed to have been formed by the decomposition of the primary product, IIIm. The reaction with IIn should afford IIIn, and the product IIIo' from IIIo is assumed to have been formed via IIIo (Chart 6 and Table I).

View full abstract

For the determination of dehydroacetic acid or its sodium salt, the fluorescence reaction of aromatic o-hydroxycarbonyl compounds with boric acid reported previosly was successfully applied. A solution (9.0ml), 2-100ng/ml of dehydroacetic acid or its sodium salt in a mixture of equal volumes of acetic acid and acetic anhydride was mixed with 1.0ml of 6% w/v solution of boric acid in acetic anhydride in a stoppered test tube and was kept for 30 min at 45°. The relative intensity of fluorerscence of the solution was measured. The maximum wave length of the corrected excitation spectrum of the fluorescent solution was 330 mμ and that of the corrected emission spectrum was 362 mμ. The calibration cruve was linear in the range of 1-1000ng/ml of dehydroacetic acid or its sodium salt. This method was not interfered by the presence of various compounds except a large amount of AF-II, salicylic acid, and ferric chloride. Sodium dehydroacetate in butter was almost quantitatively determined by this method without any pretreatment other than extraction.

View full abstract

Examinations were made on the analgesic effect of 10 kinds of antifebrile-analgesic now in common use and their combinations, and the effect of a combined use of several kinds of other compounds. The most effective among the pharmaceutics used was aminopyrine, and a mixture of 2-4 kinds of antifebrile-analgesics showed the same/or weaker analgesic action than aminopyrine. Analgesic action of a mixture of aminopyrine, ethoxybenzamide, and p-acetamidophenol was clearly augmented by the combined use of caffeine or a alimemazine, but not by scopolamine or oxolamine. Some pharmacological activity of an analgesic mixture prepared according to the result of these experiments was compared with those of the known analgesic mixtures.

View full abstract

Lithium aluminium hydride reduction of 4-oxoquinolizidine (I) afforded a dimeric compound (V), C₁₈H₃₀N₂, which was also obtained by mercuric acetate oxidation of quinolizidine (III). The dihydro compound (VI) derived from V was newly synthesized, as shown in Chart 2.

View full abstract

Effect of complex formation on the absorption of drugs was examined by perfusion with rat small intestine. Following combinations were used as the model drugs : Pyrazolone derivatives (sulpyrin, antipyrine, 4-aminoantipyrine, 4-methylaminoantipyrine, and aminopyrine)-salicylic acid, pyrazolone derivatives-benzoic acid, pyrazolone derivatives-riboflavin phosphate, and salicylamide-nicotinamide derivatives (nicotinamide and NN'-dimethyl-3, 5-pyridinedicarboxamide). It was found that (a) salicylic and benzoic acid accelerated the rate of absorption of 4-methylaminoantipyrine and reduced that of antipyrine and 4-aminoantipyrine, (b) sulpyrin reduced the absorption of saliclyic acid, (c) riboflavin phosphate reduced the absorption of sulpyrin and 4-aminoantipyrine, and (d) nicotinamide reduced the absorption of salicylamide. These facts were explained by the correlation with orgnaic solvent/isotonic buffer solution partition coefficients.

View full abstract

Methylcimigenol (II), mp 218-219°, [α] D+39.25°, C₃₁H₅₀O₅, is isolated by chromatographic treatment of the product formed by hydrolysis with 50% acetic acid of a mixture of glycosides obtained from the whole herb of Cimicifuga acerina (Japanese name Ohbashoma). Acetylation of II with acetic anhdride and pyridine gives a monoacetate (III), mp 177-178°, [α] D+42.70°, C₃₃H₅₂O₆, and a diacetate (IV), mp 206-207°, [α] D+42.65°, C₃₅H₅₄O₇. Oxidation of II with chromium trioxide and pyridine produces a monoketone (V), mp 203-204°, C₃₁H₄₈O₅, and a diketone (VI), mp 216-217°, C₃₁H₄₆O₅. Comparative examination of various properties of these derivatives with those of the derivatives of cimigenol (I) suggests the formula II for methyl cimigenol. This structure was proved chemically by derivation of I to II by treatment with methanolic sulfuric acid.

View full abstract

Glaupalol, C₁₅H₁₆O₄, isolated from the rhizomes of Glaucidium palmatum Sieb. et Zucc., and its derivatives have been degraded by a variety of methods including ozonolysis and alkaline fusion. Chemical and physical evidence of glaupalol, its derivatives, and its degradation products led to the assignment of structure I to glaupalol.

View full abstract

Methods were examined for measuring ¹⁴C and for simultaneous measuring of ³H and ¹⁴C in biological samples. A lyophilized organ material was pulverized and about 20 mg of the powder was burnt in an oxygen flask. Scintillator containing ethanolamine was used for radioactive carbon dixoide and a scintillator containg dnioxan and ethanolamine was used for simultaneous measurement of ³H and ¹⁴C. Recovery of ¹⁴C was 96.3% and its standard deviation was 1.4%. Reproducibility of the assay was further examined with the same liver of a rat given ¹⁴C-ephedrine with satisfactory results, i.e. the standard deviation was 0.8%. Recoveries of ³H and ¹⁴C were 99.8 and 99.3% respectively in the simultaneous measurement, and their standard deviation was 1.3 and 1.5%.

View full abstract

As the new salt of the Wittig reagent, 5-nitrofurylmethylenetriphenylphosphonium chloride, furylmethylenetriphenylphosphonium chloride, 5-nitrofuroylmethylenetriphenylphosphonium bromide, and furoylmethylenetriphenylphosphonium bromide were prepared. Olefination was carried out by the conventional method using these phosphonium salts with 5-nitro-, 5-methyl-, and 5-bromo-furfural, furfural, 3-(2-furyl) acrolein, 3-(5-nitro-2-furyl) acrolein, and 5-(5-nitro-2-furyl)-2, 4-pentadienal. Products from each of these reactions were submitted to elution chromatography for separation into cis and trans isomers but the separation was not effected.

View full abstract

Marmesin (I) was isolated from the root of Poncirus trifoliata RAFINESQUE (Rutaceae) and was identified with an authentic sample. This is the first example of the isolation of marmesin from Ghis plant.

View full abstract