Pyridazine-thiol derivatives were synthesized through the reaction between chloropyridazine and thiourea. The reaction of thiol derivatives with aniline and sulfanilamide was attempted to examine the reactivities. The antibacterial properties of these thiol derivatives were also studied.
Pyrroline and tetrahydropyridine derivatives (IV) were synthesized by the Bischler-Napieralski cyclization with 1, 1-diphenyl-ω-acylamino-1-alkene (III). The synthesis of (IIIa, c) were carried out in the reaction of 2, 2-diphenyltetrahydrofuran (IX) by hydrobromic acid to 4-bromo-1, 1-diphenyl-1-butene (X), which gave the amine (XI) by the Gabriel reaction, followed by acylation. (IIIb, d) were obtained from acylation of the amine (XIII) which was prepared by the reduction over Raney Co from the nitrile (XII), which was derived from (X).
As the chemical properties of 2-phenylquinoxaline 4-oxide, various following reactions were examined in detail. Results of these reactions and considerations on them are given with the reaction formulae in the text. (1) Catalytic reduction over Raney nickel at ordinary temperature and pressure, and reaction with phosphorus trichloride. (2) Oxidation with hydrogen peroxide. (3) Reaction with acetic anhydride. (4) Reaction with sulfuryl chloride. (5) Reaction with tosyl chloride and alkali. (6) Reaction with benzyl chloride and potassium cyanide. (7) Reaction with phenyl isocyanate. (8) Reaction with phenyllithium. (9) Reaction with phenylmagnesium bromide. (10) Reaction with hydrogen cyanide. (11) Reaction with sulfurous acid. (12) Reaction with hydrazine.
Seven kinds of N1-4-pyridazinylsulfanilamides and N1-(3-oxo-2, 3-dihydro-4-pyridazinyl) sulfanilamides were synthesized from 3, 4, 6-trichloropyridazine. Further, by the condensation of 4-aminopyridazine derivatives and N-acetylsulfanilyl chloride, followed by hydrolysis, N1-(3-methoxy-6-methyl-, N1-(3, 6-dimethyl-, N1-(6-methyl-, and N1-(3-oxo-6-methyl-2, 3-dihydro-4-pyridazinyl) sulfanilamides were prepared. Antibacterial action of these compounds in vitro was tested with thirteen kinds of bacteria.
Metabolism of codeine N-oxide (I) was examined using an albino rat. Codeine (II′) and norcodeine (IV′) were identified as the metabolic products by paper chromatography and an unidentified spot (V′), whose Rf value agreed with that of acetylcodeine (V), was also detected. Further, codeine (II′) was extracted from the urine as the metabolite, isolated as colorless prismatic crystals, and confirmed by its derivation to the picrate and acetate. The amount of metabolites excreted after administration of (I) by various methods, and the blood level and excretion into bile after intravenous injection were determined. Liver perfusion test revealed the formation of codeine. Finally, some considerations were made on the relationship between the metabolism of codeine N-oxide and its pharmacological activity.
The Perkin-Oglialoro reaction was carried out on phenylacetic acid, 2-nitro-4, 5-methylenedioxybenzaldehyde, and 2-nitro-4, 5-dimethoxybenzaldehyde and α-phenyl-2-nitromethylenedioxycinnamic acid (I and II) and α-phenyl-2-nitro-4, 5-dimethoxy-cinnamic acid (V and VI) were obtained, by which the presence of hitherto unknown stereoisomers was clarified. The effect of Perkin-Oglialoro reaction on the formation of stereoisomers under various conditions was examined and the formation ratio was found to be affected approximately by the following conditions: 1) Formation ratio of the trans type increased when inorganic salt of phenylacetic acids was used. 2) Formation ratio of the cis type increased by the use of an organic base as the condensation agent rather than inorganic salt of phenylacetic acids. 3) Under the use of a same agent, the higher reaction temperature resulted in higher formation of the cis type and the lower temperature increased the formation of the trans type. The ultraviolet absorption spectra of the stereoisomers were compared.
Perkin-Oglialoro reaction was carried out on (3, 4-dimethoxyphenyl) acetic acid, o-nitrobenzaldehyde, (3, 4-methylenedioxyphenyl) acetic acid, and 2-nitro-4, 5-methylenedioxybenzaldehyde, and α-(3, 4-dimethoxyphenyl)-2-nitrocinnamic acid (I and II) and α-(3, 4-methylenedioxyphenyl)-2-nitro-4, 5-methylenedioxycinnamic acid (V and VI) were obtained. Effect of reaction conditions of this condensation on the formation ratio of the cis and trans isomers was examined.
Permselective collodion and ion exchanger-collodion membranes were prepared and these were used as the membrane electrode to carry out potentiometric titration of potassium sulfate-barium chloride, potassium sulfate-barium acetate, and aniline sulfate-barium chloride systems to examine the membrane permeability of these ions. The collodion membrane, and cation and anion membranes used for the experiment selectively passed anions and cations when potassium chloride in the concentration range of 10-2 to 10-1M was used as the standard solution. Model curve of potentiometric titration was drawn from Henderson′s characteristic membrane potential formula and compared with the titration curve drawn from the experimental data. It was thereby found that the aniline H+ is more difficultly permeable than Ba2+ through the cation membrane, and that AcO- is more difficultly permeable than SO42- through the anion membrane. Cation selectivity of the collodion membrane is weak and the experimental result indicated higher permeability of aniline H+ than Ba2+. The anion selectivity of the collodion membrane varied in aniline sulfate.
Determination of bromovalerylurea in biological sample was devised. Plasma or urea is extracted with ether, the extract solution is washed with water, dried, and ether is evaporated. The residual extract is dissolved in dehyd. ethanol, 0.2M acetate buffer (pH 4.0) is added, and this solution is submitted to polarography between 0.0V and -1.6V. From its diffusion current, 5γ/cc. of bromovalerylurea can be determined. Recovery, 95-5%. This determination was carried out on the urea and blood of narcotism patients and observations were gained which would be of interest from the point of therapeutic diagnosis and forensic chemistry.
In order to investigate the behavior of phenoxazine compounds in living body from the standpoint of biophysical chemistry, the measurements of diffusion constants, as well as the degree of association are described in this report with 4 kinds of phenoxazine compounds such as xanthommatin, extracted from eyes of Musca domestica and the synthesized pigments, such as catalin, A-catalin and C-catalin. The value of the diffusion constants increased as the temperature rose and, under the same condition of temperature, the value was inclined to be smaller, as the molecular weight become larger. The value of A-cataline was observed to be smaller than that was expected from the molecular weight. The degree of association calculated from the diffusion constant of each pigment at the respective temperature showed that catalin was not almost associated at 37°, but the other pigments associated into 2 to 3 molecules, at the same time the degree of association increased as the temperature became lower. With A-catalin and xanthommatin, this phenomenon was remarkable and the degree of association of C-catalin has undergo any influence by temperature.
In order to elucidate the mechanism of penetration of phenoxazone compounds through a membrane, its permeability was examined by the use of Visking cellulose as the nonbiological membrane. In any of the pigments, permeability constant (P) of the pigment increased with increasing temperature and the order of the permeability of the pigments at a given temperature was in an increasing order of A-catalin, xanthommatin, C-catalin, and catalin at any of the temperature tested. The permeability constant, P, is thought to be represented as P=fD*, where D* is the diffusion coefficient of the pigment and f is the membrane constant that shows porosity of the membrane. Using the constant f=0.0473, measured with the use of sodium and potassium chlorides, diffusion constant, D*, of each pigment through the Visking cellulose membrane was calculated. The ratio of this diffusion constant to the diffusion constant in water, D, as reported in the preceding paper, was calculated and approximately constant ratio of D*/D was obtained. Diffusion constant through the membrane was found to give values about 1/3 that in water.
It was found that dl-canadine, dl-magnoflorine iodide, or dl-β-canadine methiodide and its methochloride could be optically resolved by paper chromatography using a buffer solution as the developing solvent. A large-scale paper chromatography was therefore carried out and dextro- or levo-rotatory compounds were isolated. It was also proved by isolation of optically active compounds as crystals that the same resolution could be effected by cellulose column chromatography.
Analgesic and antitussive actions were examined with 1-phenethyl-3-methyl-4-phenyl-4-propionyloxypiperidine hydrochloride (I), 1-[2-(methylphenylamino)ethyl]-3-methyl-4-phenyl-4-propionyloxypiperidine dihydrochloride (II), and 1-[2-(ethyl-phenylamino)ethyl]-3-methyl-4-phenyl-4-propionyloxypiperidine dihydrochloride (III). These compounds had strong activities in both and the action of (II), with the strongest analgesic action, was seven times that of morphine hydrochloride and 14 times that of pethidine hydrochloride by the pressure method in mice. Antitussive action of (II) and (III) by the mechanical stimulation in guinea pigs was 6 times that of morphine hydrochloride and 9.5 times that of pethidine hydrochloride. Antispasmodic test with isolated small intestine of rat and tracheal chain preparation of guinea pig, and acute toxicity in mice were also tested.
Tetrandrine (V) was synthesized by the Ullmann condensation of L-N-methylcoclaurine (II), obtained by cleavage of isotetrandrine (I) with sodium in liquid ammonia, and L-3′, 8-dibromo-N, O, O-trimethylcoclaurine (IV), obtained by bromination of (II) followed by methylation. (V) was obtained as its crystalline picrate and identified with natural L, L-tetrandrine picrate. In this reaction, O, O-dimethyl-bebeerine (VI) should have been formed at the same time and this is now under investigation.
In an earlier work with Tomita, the absolute configuration of the coclaurine-type bases was established by derivation of D-(-)- and L-(+)-laudanosine, whose absolute configuration had been established by Corrodi and others, to D-(-)- or L-(+)-N, O, O-trimethylcoclaurine (IIa and IIb). As a result of these experiments, the absolute configuration of the two asymmetric centers was confirmed in majority of biscoclaurine-type bases which produce two kinds of optically active coclaurine-type bases by cleavage with metallic sodium in liquid ammonia. In continuation of this work, the absolute configuration of the two asymmetric centers in cepharanthine (IV), which has methylenedioxy group as the characteristic atom group in the molecule, was also established. Cleavage reaction with sodium in liquid ammonia carried out on insularine (VIIa) and insulanoline (VIIb), having a depsidane ring as the characteristic atom group in the molecule, produces l-homoarmepavine (VIII), besides coclaurine-type base (IX) as the cleaved bases. One (in A) of the two asymmetric centers in insularine (VIIa) and insulanoline (VIIb) had not been established as yet. In the present series work, in order to solve this problem, L-(+)-armepavine (X), whose absolute configuration had already been established, and dimethylamine were submitted to the Mannich reaction and its reaction product was reduced at a high pressure, affording L-(+)-homoarmepavine (VIIIa). Comparison of this product with l-homoarmepavine (VIII), obtained by the cleavage of insularine (VIIa) with metallic sodium in liquid ammonia, revealed that the absolute configuration of (VIII) was a D type. Consequently, the absolute configuration of the two asymmetric centers in insularine (VIIa) and insulanoline (VIIb) was completely established as (D, D).
Ordinary α-type crystals of thiamine hydrochloride irradiated with 4×107 to 1×108 r of 60Co γ-ray was found to be more stable than the control, non-irradiated thiamine hydrochloride when compounded in a powder with calcium carbonate. The irradiated thiamine hydrochloride was found to have higher density and lower hygroscopicity than the non-irradiated salt, and a fairly great difference was found between them in relative intensity in their X-ray diffraction powder pattern.
When maleic anhydride derivatives (IV), containing alkyl group, was condensed with phenylhydrazine in acetic acid, (IVa) affoded N-anilino derivative (V) mainly, besides minor amount of pyridazine derivative (VI) as a by-product. However, (IVb) afforded (Vb) only, without producing (VIb). In the case of 3, 4, 5, 6-tetrahydrophthalic anhydride (IVc) whose alkyl groups increased, the cyclization was so difficult that neither (V) nor (VIc) could be produced, but only (VIc) was obtained, when 20% sulfuric acid was employed instead of acetic acid. (Va) and (Vb) rearranged to (VIa) and (VIb) when they were boiled in dilute sulfuric acid (or hydrochloric acid). Though the derivatives (Type E in Table V) of having VI-type structure provided the ketonic group at a fixed region, on IR-spectra its intensity was so weak that monoketo-monoenol structure have been presumed from both UV-spectra (EtOH) and IR-spectra. The resembling derivatives of Type B, C and D, having C=O group did not show any characteristic absorption of νc=o that was observed with Type E and gave an usual ketonic absorption.
Non-ionic surfactant of polyoxyethylene derivatives was dissolved in 0.9% sodium chloride solution and this solution was injected into the femoral region of a rabbit to observe its local irritating action to the muscle by naked eyes. The appearance of the muscle at 24 hours after the injection would enable compare the local action of surfactants. The higher the concentration of the surfactant and the more number of injections, the severer the action was. From the structure of the surfactants, the local action became weaker as the degree of polymerization of oxyethylenes was increased or hydrophilic property is raised Moreover, in respect to the shape of the surfactant molecules, the broad molecules caused the weaker local action than the narrow and long molecules. Microscopic observation of the cross-sections of muscles under such a local action showed that in portions with drastic local action degeneration of cytoplasm occured by destruction on the other hand, of cell membrane of muscle fiber cells in the portions with weak action healthy cells remained. The local action of the surfactants was found to be in parallel with their hemolytic action and it was assumed that the mechanism of this local action was similar to that of their hemolytic acition, that is, penetration of the surfactant into cholesterol of the cell membrane. Therefore, penetration of surfactants into monomolecular layer of cholesterol was measured and this was found to agree with the above tendency.
Chelate formation between l-ephedrine and copper salt in alkali hydroxide solution was examined. Reddish violet crystals (I) was isolated from hexane extract and pale violet-blue crystals (II) from the aqueous solution. The structure of these two kinds of substances and their mutual relationship were examined. (I) and (II) were found to have the same fundamental molecular structure and thermal balance examination and infrared spectra suggested that (II) had a sexted structure with two moles of coördination water. Considerations were also made on the structure of (I) and (II) in aqueous solution and changes of that structure by alkali hydroxide. The visible absoption spectra of (I) showed the solvolysis phenomenon between (I) and ethanol, and the mechanism of chelate formation was clarified through potentiometric titration.
For the X-ray contrastmedium, particles of barium sulfate are required to be fine and homogeneous. Therefore, the grain size distribution of the particles, prepared by the EDTA method which had been known as one of the monodispersion barium sulfate preparations, was measured by the sedimentation velocity method. The particle distribution observed has been recognized to accord with the Gauss distribution, except some of the gross particles. There was an inclination to decrease average particle diameter, and to become narrow in distribution width, as days passed, after sodium hexa-metaphosphate was added as dispension medium in the case of sedimentation velocity measurement. Average diameter of the particles thus obtained was 1.0-2.9μ which corresponded well with the value measured optico-microscopically. This is supposed to be the diameter of the secondary formed particles which aggregate into masses of the particles, recognized electron-microscopically. The value of the particle diameter decreased when concentration increased. This phenomenon quite agreed with the Weimarn Law.
Coumarin derivatives, such as 3-(3, 4-methylenedioxyphenyl)-6, 7-methylenedioxycoumarine (III) and 3-phenylcoumarine (VI) were synthesized by heating quinoline with either cis-α-(3, 4-methylenedioxyphenyl)-2-nitro-4, 5-methylenedioxycinnamic acid (I) or cis-α-phenyl-2-nitrocinnamic acid (V). These new reactions which have never been described, may be applicable to the synthesis of coumarin derivatives. The investigation on the reaction conditions of (V), showed that (VI) was afforded in about 80% yield, when heated at 260° in the presence of copper powder (Table I).
In the continuation of the previous report, an attempt of synthesizing coumarin derivatives from α-phenylcinnamic acid derivatives was described. When several α-phenyl-2-nitrocinnamic acid derivatives were heated with Gattermann copper in quinoline, the corresponding 3-phenylcoumarin derivatives were obtained respectively.
7-Chloro-3-methyl-1, 2, 4-benzothiadiazine-1, 1-dioxide which was reported by Rubin et al. as a substance having low blood pressure effect, without having saluric effect among benzothiadiazine derivatives was synthesized through the other route. 7-Chloro-3-substituted-3, 4-dihydro-2, 4-benzothiadiazine-1, 1-dioxide (3-methyl and 3-benzyl) were newly synthesized.
Benzoylation of 1, 9-dibromo-5-aminononane to form 1, 9-dibromo-5-benzaminononane, its reaction with amines, and debenzoylation by heating with phosphoric acid gave 1, 9-bis (dialkylamino)-5-aminononane. Using this compound, 1, 9-bis (dialkylamino)-5-dimethylaminononane and its methobromide were synthesized.
Bases contained in the fresh wood, cortex, and leaves of domestic Liriodendron tulipifera L. (Japanese name “Yuri-no-ki”) were examined. Non-phenolic bases, liriodenine (I) and d-glaucine (III), were isolated from the wood and a non-phenolic base, considered to be an aporphine type, was isolated from the cortex, as its oxalate of m.p. 198-200°(decomp.), C20H21O4N⋅C2H2O4. The presence of a non-phenolic base, possibly d-glaucine, in the leaves was assumed from the result of paper chromatography but it was not isolated. Phenolic bases contained in the wood, cortex and leaves were easily decomposed and the quantity was so minute that they could not be examined in detail. Water-soluble quaternary base was not found in any of these parts. A neutral substance, aesculetin dimethyl ether (IV), was isolated from the cortex.
Thiamine disulfide was obtained by reacting chlorosulfonic acid ester to sodium salt of thiamine in thiol-form. When chlorosulfonic acid ester was treated to thiamine in alkaline solution to which mercaptan was existed prior to the treatment, it was found that thiamine alkyl disulfides (IX) were produced easily. The same reaction proceeded by the sulfonyl chloride, instead of chloro sulfonic acid ester.
Methylation of 6-methyl-3-pyridazinol 1-oxide (V) with dimethyl sulfate and dilute alkali hydroxide or with dimethyl sulfate and sodium methoxide in methanol afforded 2, 6-dimethyl-3(2H)-pyridazinone 1-oxide (VII) as the chief product and 3-methoxy-6-methylpyridazine 1-oxide (III) as the by-product. The structure of (VII) was confirmed by its derivation to 2, 6-dimethyl-3 (2H)-pyridazinone (VIII) by catalytic reduction, which indicated that the N-oxide group in (V) is in the position adjacent to the methyl group.