Ferric chloride oxidative coupling of 1, 2, 3, 4-tetrahydro-7-hydroxy-1-(2-hydroxybenzyl)-6-methoxyisoquinoline (IIb) afforded two dimeric benzylisoquinolines, III in 1.6% yield and V in 1.1% yield, respectively. Eschweiler-Clarke reaction of III gave the corresponding N-methyl derivative (IV), which was identified with authentic sample. Ferricyanide oxidative coupling of 1, 2, 3, 4-tetrahydro-7-hydroxy-1-(3-hydroxybenzyl)-6-methoxy-2-methylisoquinoline (IId) also gave the dimeric benzylisoquinoline (VI) in 0.4% yield, which was characterized by microanalysis and spectral data.

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The reaction between benzoyl peroxide and hydrazones follows second-order kinetics, first-order in respect to peroxide and hydrazone. The reaction is accelerated by electron donation groups in hydrazone, and the electronic effect follows Brown-Okamoto's ρσ⁺ relationship. Radical inhibitors and polymerizable monomers have no effect. It was concluded that the reaction is not a radical chain process, but involves an ionic process without radical formation, and a possible reaction mechanism is proposed.

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Oxidation of 2-benzoyl-6-acetoxymethyl-3, 6-dihydro-1, 2-oxazine (7) with osmium tetroxide afforded a mixture of 4, 5-cis-glycols which were separated and characterized as benzoyl derivatives (8a and 9a). Similarly 7 was oxidized with potassium permanganate, yielding a 4α, 5α-dihydroxyl derivative (8b) as the major product along with its 4β, 5β-isomer (9b). On the other hand, treatment of 7 with pertrifluoroacetic acid gave a crystalline 4β, 5β-epoxide (12) and a syrupy 4α, 5α-epoxide (13) in a good yield. Further, 12 was treated with sodium azide in dimethylformamide to give a 5β-hydroxy-4α-azide (14a) and a 4β-hydroxy-5α-azide (15a). Conformational analysis of these synthesized compounds was carried out by nuclear magnetic resonance spectrometry. Attempted conversion of 8b or 14a into a 4, 5-epimine was not successful.

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Diuretic and natriuretic activities and duration of the diuretic action in rats were studied with 22 sulfonamide derivatives. In order to clarify the active form of the sulfonamides, the effect of pH of the rat body fluid on the diuretic activity was studied. 1) The diuretic and natriuretic activities of the sulfonamides increased with an increase of their carbonic anhydrase inhibitory activity except for o-substituted benzenesulfonamides, disubstituted benzenesulfonamides and 2-amino-1, 3, 4-thiadiazole-5-sulfonamide. 2) A close correlationship of diuretic and natriuretic activities with the electronic characteristics of the sulfamoyl group, such as Hammett's σ factor, pK_a, NMR chemical shift of the sulfamoyl protons and S=O valence-force constant, was observed for the derivatives with some exceptions. 3) A compound having a large partition coefficient and strong albumin binding ability showed long duration of the diuretic action 4) The diuretic and natriuretic activities of sulfonamides were enhanced with an increase of their dissociation constants. The diuretic activity was enhanced under alkalotic conditions. Thus, it was concluded that active form of the sulfonamide carbonic anhydrase inhibitors was the ionized form.

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Critical micelle concentrations (CMC) of acylcholines were measured by surface tension, colorimetry of Sky blue FF, fluorophotometry of Eosin and solubilization of Sudan III. Formation of micelle was not observed on acetylcholine chloride, propionylcholine iodide, butyrylcholine iodide and hexanoylcholine iodide, but observed on octanoylcholine iodide, decanoylcholine iodide, dodecanoylcholine iodide and hexadecanoylcholine iodide. Relationship between log CMC of octanoylcholine iodide, decanoylcholine iodide and dodecanoylcholine iodide by solubilization of Sudan III at 45° and the number (N) of carbon atoms in the hydrocarbon chain was written in the following manner. log CMC(M)=1.040-0.295n

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Hydrolysis of acylcholines in 0.1N hydrochloric acid solution and that in borate buffer solution [Na₂B₄O₇ (0.01M)+H₃BO₃ (0.16M)+NaCl (0.04M)] at 60° were studied. Hydrolysis in Acidic Solution-Octanoylcholine iodide, decanoylcholine iodide, dodecanoylcholine iodide and hexadecanoylcholine iodide (micellar acylcholines) were less stable below their critical micelle concentrations (CMC) and more stable above their CMC. Acylcholine with longer hydrocarbon chain was more stable than shorter chain. Hydrolysis in Basic Solution-Linear relationship was found between concentration (log scale) of acylcholine and time on hydrolysis at its low concentration (below CMC) but was not found at its high concentration (above CMC). But it might be considered that initial stage was linear. The linear portion at initial stage and the gradually curved portion with course of time were discussed. (1) The linear portion at initial stage Hydrolysis was accelerated by formation of micelle and it was observed that the longer the hydrocarbon chain was, the less the stability became. (2) The gradually curved portion with course of time It was considered that fatty acid produced by hydrolysis of acylcholine in borate buffer solution was ionic type and it formed complex with cationic acylcholine, and repression of hydrolysis was ascribed to solubilization of this complex into micelle of acylcholine.

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The degradation reaction to identify the individual carbon atoms of itaconitin were established as shown in Chart 1.

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The biosynthetical studies of itaconitin were carried out with labelled compounds. C₁₀-chain (C-1-9, 13) and methyl carbon (C-14) were found to be derived from acetatemalonate and C₁-unit. C₃-unit (C-10-12) was most probably introduced from Phosphoenolpyruvate (PEP) or oxaloacetate which is formed by the carboxylation of PEP.

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Microbial oxidation of diosgenin with Cunninghamella blakesleeana gave 7β-hydroxydiosgenin, 7β, 12β-dihydroxydiosgenin, and 7β, 11α-dihydroxydisogenin. The former two compounds were confirmed by their synthesis from 7-oxodiosgenin and 7, 12-dioxodiosgenin (=7-oxogentrogenin) respectively with lithium aluminum hydride.

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Structures of oxidation products of grayanotoxins are determined by chemical and spectroscopic methods. The IR spectra of numerous derivatives of triketo-G-II and diketo-G-I derived from grayanotoxins by chromium trioxide oxidation showed that the triketone and diketone compounds should be represented such as XXVII and XXII, respectively.

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A new anti-inflammatory proteinase designated as kinonase BI has been isolated from the mixture of kinonases produced by Streptomyces kinoluteus. Kinonase BI is purified by gradient column chromatography on DEAE-cellulose and gel filtration on a column of Sephadex G-75. Kinonase BI is considered to be a neutral proteinase of microbial origin. Kinonase BI is of acidic protein nature having pH optimum at 6.5 and optimum temperature at 55° against casein. Kinonase BI is rather stable in a solution of pH 5-9, but labile specially of acidic pH or by heating at 70° for 10 min. The proteolytic activity of kinonase BI is almost lost by addition of 10^-3M of a heavy metal ion, Cu²⁺ or Hg²⁺, and ethylenediaminetetraacetic acid, but not by addition of ω-chloroacetophenone, p-chloromercuribenzoate diisopropylfluorophosphate and potato trypsin inhibitor at the same concentration. Kinonase BI hydrolyzes bradykinin to arginylprolylprolylglycine, phenyalanylserylproline and phenylalanylarginine. The anti-inflammatory activity on carrageenin-induced edema is observed in kinonase BI at the same level as in kinonase AI or AIII. Kinonase AII containing a trace of kinonase AI is recovered also from the mixture of kinonases. Kinonase AII is presumed to be a kind of leucine amino peptidases. Bradykinin is not hydrolyzed by kinonase AII and the anti-inflammatory activity is not observed in kinonase AII.

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α-¹H chemical shift of alkyl derivatives is dependent mainly on the sigma- and π-electronic contributions, and the detailed discussions have proved that the former is conformed to the so-called inductive effect and the latter is substantiated from an electric field effect provided by the substituent group. And, the same result is also reliable in the ¹³C chemical shift of above series.

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Methylphloroacetophenone was proved to be an intermediate in usnic acid biosynthesis by the tracer experiments. The origin of methylphloroacetophenone was also shown to be derived from acetate-malonate and C₁-unit.

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The incorporation of sodium acetate (2-¹⁴C) and ¹⁴CO₂ had been investigated in every two to four months to prove seasonal variation in usnic acid biosynthesis. In Parmelia caperata and Usnea diffracta, collected in different places, the highest incorporation was observed in February and the lowest in July. The alteration of experimental conditions gave no effect upon the results and it was concluded that the activity of usnic acid biosynthesis is effected by the seasonal condition.

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A series of thirty-one sulfonamidopropionamidine derivatives have been synthesized and evaluated for antiviral activity. The synthesis of the sulfonamidopropionamidine series was prepared from the corresponding nitriles via ethyl imidates. The compounds synthesized were tested as to their inhibitory effect on polio virus in membrance culture and influenza virus in mice. The results of testing these compounds were found ineffective on the polio virus. However, among the intermediate nitrile derivatives, three compounds, 11, 12 and 22, exerted slight effect and final amidine derivatives, five compounds, 7, 8, 11, 18 and 19, showed marked effects on the influenza virus in mice. Especially, 3-(4-ethylbenzenesulfonamido) propionamidine hydrochloride (7) was found comparable to that of Adamantanamine Hydrochloride.

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The stereochemistry of isopropylidenedihydrotaxinolactone, a novel autooxidation product of dihydrotaxinol derivatives (e.g. III and IV), was proposed as represented by (V) (cf. IX). Furthermore, some additional findings relating to the stereochemistry of taxinine derivatives were described.

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For the selective reduction of carboxyl groups in peptides, diborane and sodium borohydride were examined. Because of accompanying reductive side reaction, the reduction of carboxyl groups with diborane in tetrahydrofuran was unsatisfactory. On the other hand, by the use of sodium borohydride in aqueous solution, certain model peptide esters were easily reduced to corresponding alcohols without any appreciable side reaction.

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In the course of preparing 4-hydroxycarbostyril by potassium hydroxide-fusion of 4-chlorocarbostyril, a novel reaction was found. This reaction was explained by the formation of aryne intermediate. This prediction was confirmed by investigating reactions of other haloquinolones with molten potassium hydroxide.

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The nature and strength of the complexation of polyvinylpyrrolidone (PVP) with iodine were investigated by spectroscopic method. The complex included combined triiodide anion in the structure, and was considered to be an "inner complex" reported by Mulliken. This was supported from the fact that triethylamine, a strong electron-donor, exhibited spectroscopically same behavior as PVP and 2-pyrrolidone toward tetracyanoethylene as well as iodine in a polar medium. The apparent complexation constant was evaluated by utilizing the Langmuir isotherm equation at 30° in ethanol. The complexation constant appeared generally dependent on the size of PVP and 2-pyrrolidone molecules, and therefore the complexation between PVP and iodine may be attributed to van der Waals-type forces or the like as well as charge-transfer forces.

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Treatment of ethyl 4, 5-dimethoxy-2-nitrobenzylidenemalonate (III), ethyl 4-benzyloxy-5-methoxy-2-nitrobenzylidenemalonate (IV), and ethyl 4, 5-methylenedioxy-2-nitrobenzylidenemalonate (V) with triethyl phosphite at 160-170° for 20 hr afforded 2-ethoxy-3-ethoxycarbonyl-6, 7-dimethoxyquinoline (VI), 7-benzyloxy-2-ethoxy-3-ethoxycarbonyl-6-methoxyquinoline (VII), and 2-ethoxy-3-ethoxycarbonyl-6, 7-methylenedioxyquinoline (VIII), respectively, in 53-68% yield. On the other hand, the 6-benzyloxy-2-ethoxycarbonyl-5-methoxyindole (XIII) was obtained with the same treatment of ethyl 4-benzyloxy-3-methoxy-2-nitrocinnamate (XII).

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The disappearance of ethoxybenzamide from a rabbit plasma after an intravenous injection was studied. 1. The distribute phase after the injection could not be neglected, and the two compartmental model was applied to analize the time course of plasma concentration. 2. The iterative least square method with a digital computer was proposed to obtain pharmacokinetic constants and their statistical values. 3. The present method gave the unique parameters independent of personal error for drawing straight lines in the semilogarithmic plots of plasma concentration vs. time, and it could test the adoptability of data for the model.

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With two equivalents of diazomethane, 3-(5-nitro-2-furyl) acryloyl chloride (Ia) gave 3-diazoacetyl-4-(5-nitro-2-furyl)-1-[3-(5-nitro-2-furyl) acryloyl]-2-pyrazoline (Va) in good yield, which was converted to the corresponding bromide (VIa (X=Br)), chloride (VIa (X=Cl)) and thiocyanate (VIIIa) in the usual methods. To confirm the results described above, cinnamoyl chloride (Ib) was treated with various amounts of diazomethane. With excess, two equivalents of, and an equimolar amount of diazomethane Ib gave 3-diazoacetyl-4-phenyl-2-pyrazoline (IVb), 1-cinnamoyl-3-diazoacetyl-4-phenyl-2-pyrazoline (Vb) and the mixture of Vb and 3-chloroacetyl-1-cinnamoyl-4-phenyl-2-pyrazoline (VIb) respectively. Furthermore, the same mixture of Vb and VIb was obtained by the treatment of IVb with an equimolar amount of Ib. Antimicrobial activities of nitrofuran derivatives are listed in the table.

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Each epimers of 2, 3-episulfides of 5β, 25D-spirostane and 17β-hydroxy-5α-androstanes having a methyl group at C-1α, C₂, or C₃ were synthesized via the corresponding vicinal diaxial thiocyanatohydrins. In addition the formation of both episulfides and oxides from the vicinal diaxial thiocyanatohydrin acetates was discussed on the basis of the natures of the substituents.

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The NMR spectra and ORD curves of berbamunine, magnoline and two corresponding diastereoisomers and O, O, O-tribenzyl derivatives were investigated, in the latter of which an interesting change was observed on being set aside at room temperature for a long time.

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Linear conjugated diynones, capillin (Ia), and the ethyl analogue, 1-phenyl-2, 4-heptadiyn-1-one (Ib), were applied to the synthesis of the corresponding β-triketones, 1-phenyl-1, 3, 5-hexanetrione (IIIa) and 1-phenyl-1, 3, 5-heptanetrione (IIIb), respectively. Acid catalyzed hydration of Ia and Ib afforded 2-methyl-6-phenyl-4H-pyran-4-one (IIa), and 2-ethyl-6-phenyl-4H-pyran-4-one (IIb), which were converted to IIIa and IIIb by alkaline hydrolysis, respectively. On the other hand, treatment of Ia and Ib with pyrrolidine gave novel biphenyl derivatives, 3, 5-di-N-pyrrolidinyl-1, 1'-biphenyl (VIIa) and 2-methyl-3, 5-di-N-pyrrolidinyl-1, 1'-biphenyl (VIIb), in addition to normal enamine products, 1-phenyl-5-N-pyrrolidinyl-4-hexen-2-yn-1-one (Va) and 1-phenyl-5-N-pyrrolidinyl-4-hepten-2-yn-1-one (Vb), respectively. Acid hydrolysis of Va and Vb also afforded the expected 4-pyrone derivatives (IIa, IIb). In order to examine the mechanistic pathway of I to VII, 1-phenyl-5-N-pyrrolidinyl-4-hexen-1, 3-dione (IX) derived from IIIa was treated with pyrrolidine to lead to VIIa, which was assumed to form the same intermediate (VI).

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Syntheses of the six intermediary peptide fragments for the synthesis of α^1-23NH₂-ACTH, carbobenzoxyseryltyrosylserine hydrazide, t-butyloxycarbonylmethionyl-γ-t-butylglutamylhistidine hydrazide, t-butyloxycarbonylphenylalanylnitroarginyltryptophanylglycine, t-butyloxycarbonyl-N^ε-carbobenzoxylysylprolylvalylglycine, t-butyloxycarbonyl-N^ε-carbobenzoxylysyl-N^ε-carbobenzoxylysylnitroarginylnitroarginylproline and valyl-N^ε-carbobenzoxylysylvalyltyrosine amide, are described.

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Several kinds of bicyclic nitrogen-containing heterocycles were synthesized by the Ritter reaction of 1, 3-glycols (IX, X, and XI) and acetonitrile. Three types of compounds, hexahydrobenzoxazoles (XII and XVIII), hexahydro-3H-indoles (XIII, XIX, and XXXII), and hexahydrobenzoxazines (XXX and XXXI), were obtained. XII and XIII were obtained from IX, XVIII and XIX from X, and XXX, XXXI, and XXXII from XI. XIX underwent facile autoxidation to form a 3-hydroxy compound (XXIII).

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Reaction of 2-(2-hydroxycyclohexyl)- and 2-(2-hydroxycyclopentyl)-ethanols (VI and XX) with nitrile in the presence of stannic chloride afforded 4, 4-pentamethylene- and tetramethylene-1, 3-oxazine (VIII, XIX, and XXI). The same reaction of α-(2-hydroxycyclopentyl)-t-butanol (II) with a nitrile gave cyclopentenodihydropyridine (III). Reaction of 1-(2-hydroxycyclohexyl) propan-2-ol (XXV) and a nitrile in the presence of sulfuric acid gave 1, 3-oxazine derivative (XXVI) and cyclohexanopyrroline (XXVII) which easily underwent oxidation to a 3-hydroxy compound (XXXI).

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2-Methyl-4, 7-dichlorofuro [2, 3-d] pyridazine (IV) was synthesized and reacted with nucleophiles such as hydroxide, alkoxide and amine to give monosubstituted isomers. The structure assignments of these isomers were described.

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