Ethyl p-(2-dialkylaminoacylamino)benzoate and α-(2-dialkylaminoacylamino)benzamide derivatives were systematically prepared and examinations were made on the relationship between their chemical structure and local anesthetic activity. Of the 24 kinds of these compounds, the ester derivatives (XIV to XX) had almost equal to or better local anesthetic activity than procaine, with less toxicity.
Addition of quinone moöxime methyl ether into the insulinase extract and subcutaneous injection of this solution after allowing to stand for 24 hours resulted in strong inhibition of hyperglycemic action of the insulinase extract. Insulin-decomposing action of this extract was also inhibited by quinone monoöxime methyl ether. It was assumed that the following two actions worked synergetically as the action mechanism of quinone monoöxime methyl ether: (1) The quinone compound protected the insuline molecule to prevent its decomposition by the insulinase, and (2) the quinone compound acted directly on the insulinase enzyme to inhibit the decomposition of insulin.
Infrared absorption spectra of 14 kinds of glucuronolactone derivatives were measured and four characteristic absorption bands of the γ-lactone are described, two for νc=o and νc-c. The absorption of νc=o in 5-acetylated compound shifts to higher wave-number side than that in 5-hydroxyl compound and this was assumed to be due to the interaction of 1, 4-dicarbonyl group.
Alkaloids contained in Michelia compressa MAXIM. var. formosana KANEHIRA (Japanes name “Taiwan-Ogatamanoki”), a plant of the Magnoliaceae family indigenous to Formosa, were examined. From the heartwood of this tree, tertiary non-phenolic beses were isolated as colorless prisms, m.p. 180-181°, and pale yellow needles, m.p. 279-281°(decomp.). The main alkaloid of m.p. 180-181° was named “ushinsunine.” This base corresponds to the molcular formula of C18H17O3N, [α]D -113.6° (EtOH), it is positive to the Gaebel and Labat's color reaction for methylenedioxy group, and does not contain methoxyl group. It easily forms a basic monoacetate of colorless prisms, m.p. 202-203°, C18H16O2N(OCOCH3). Infrared spectrum of ushinsunine revealed the presence of alcoholic hydroxyl and methylenedioxy groups (Chart 1) and its ultraviolet spectrum suggested the structure of an aporphine-type base (Fig. 1). It was thereby assumed that ushinsunine is an aporphine-type base represented by the experimental formula of C18H17O3N=C16H11(OH)(O2CH2)(NCH3). The other base of m.p. 279-281° (decomp.) was proved to be the identical with oxoushinsunine, m.p. 280-281°(decomp.), obtained by oxidation of ushinsunine with pyridine and chromium trioxide, as will be described in a later report. Water-soluble quaternary bases were obtained in the form of magnoflorine (I) and a minute amount of a new base as a picrate.
Hofmann degradation of ushinsunine (I) gives an optically inactive methine base of m.p. 108-109°, whose composition agrees with the formula C19H17O2N. The ultraviolet and infrared spectra of this substance indicated new formation of a double bond conjugated to the benzene ring, disappearance of a hydroxyl group, and new formation of a terminal vinyl group. From these evidences, formula (III) was assumed for this methine base. Treatment of ushinsunine (I) with phosphoryl chloride in pyridine solution produces optically inactive anhydroushinsunine (VI), m.p. 88-89°, C18H15O2N. This fact suggests the presence of alcoholic hydroxyl in the 6a- or 7-position of the aporphine ring. It had been found in the previous work that ushinsunine is easily acetylated and quantitatively forms a basic monoacetate. This fact endorses the presence of a secondary hydroxyl in 7-position in ushinsunine molecule. The Clemmensen reduction of (I) afforded an optically inactive dehydroxyushinsunine, m.p. 87-88°, C18H17O2N, which was identified with dl-roemerine (VIII). It follows, therefore, that the methylenedioxy group in ushinsunine is in the 1-2 position of the aporphine ring. Oxidation of ushinsunine (I) with chromium trioxide-pyridine afforded oxoushinsunine, C17H9O3N, as pale yellow needles, m.p. 280-282°(decomp.), which was found to be entirely identical with liriodenine (XIII), synthesized by Taylor independently. It had already been reported that this oxoushinsunine is contained in the heartwood of this plant, together with ushinsunine. The same oxoushinsunine is obtained on oxidation of ushinsunine with manganese oxide in chloroform but Oppenauer oxidation of (I) results in the recovery of the starting base. Oxidation of l-roemerine (VIII) with chromium trioxide-pyridine also affords oxoushinsunine. All these facts may be explained by the formation of (XV) to (XVI) to (XIII), during the oxidation of ushinsunine (XII) or roemerine (VIII) to oxoushinsunine (liriodenine) (XIII), and ushinsunine may be considered as the initial oxidation product of roemerine.
The structure (II) of oxoushinsunine (liriodenine) was confirmed by Taylor independently and the reduction of (II) was carried out under various conditions in the present series of experiments. The Clemmensen reduction of oxoushinsunine (II) afforded a secondary base corresponding to dl-anonaine (III) which was proved by its derivation to dl-roemerine (IV) by its N-methylation with formic acid·formaldehyde. Reduction of (II) with sodium borohydride or lithium aluminium hydride resulted in recovery of unchanged (II). The behavior of (II) in these reduction reactions proves the correctness of this formula (II) for oxoushinsunine. Buchanan and Dickey had isolated liriodenine from the heartwood of Liriodendron tulipifera L., an American Magnoliaceous tree, and gave the formula (VI) to it from several oxidation reaction of liriodenine. On the other hand, Taylor had proved its structure to be (II) by its synthesis. Oxidation reaction of (II) in the present series of experiment proved that (II) is decomposed through the route of (VII) to (VIII). Measurement of the NMR spectra of ushinsunine and roemerine revealed that the steric structure of ushinsunine would be represented by the formula (XIII) or its antipode.
Alkaloids contained in Michelia alba DC. (Japanese name “Ginkoboku”), a plant of the Magnoliaceae family growing in Formosa, was examined. Ushinsunine (I) and oxoushinsunine (II) were isolated as the tertiary, non-phenolic bases, salicifoline (III) as the water-soluble quaternary base of phenethylamine type, and a new secondary base of m.p. 205-207°. The new secondary base was named michelalbine. Michelalbine, m.p. 205-207°, [α]D-105.2°(CHCl3), corresponds to the formula of C17H15O3N, does not possess methoxyl or N-methyl group, gives positive methylenedioxy reaction, and forms an N-nitroso compound. Its infrared and ultraviolet spectra suggested that it is an aporphine-type base, indicated by the rational formula of C17H15O3N=C16H11(OH)(O2CH2)(NH). N-Methylmichelalbine, obtained by N-methylation of michelalbine with formic acid-formaldehyde, was found to be identical with ushinsunine (I) and this has revealed that the structure of michelalbine is N-nor-ushinsunine represented by formula (IV).
Alkaloids contained in Magnolia coco (LOUR.) DC. (Japanese name “Tokiwarenge”) and Magnolia kachirachirai DANDY (Japanese name “Kachirachirai-no-ki”), the plants of Magnoliaceae family growing in Formosa, were examined. Magnolia coco yielded oxoushinunine (liriodenine) and a minute amount of a base of mp 237-240° (decomp), as the tertiary bases, and salicifoline, the phenethylaminetype base, and magnoflorine, the aporphine-type base, as the water-soluble, quaternary bases. Magnolia kachirachirai afforded glaucine (I) as the tertiary, non-phenolic base, a minute amount of a base of mp 131-132°, and magnoflorine as the quaternary base. Alkaloids isolated during the present series of work from two kinds of Michelia genus and two kinds on Magnolia genus plants are summarized in Table I.
Aluminium distearate was obtained by double decomposition of potassium stearate and aluminium chloride in water and by hydrolysis of aluminium isopropoxydistearate, obtained from aluminium isopropoxide in nonaqueous solvent. Viscosity of four kinds of these soaps and commercial products in benzene solution was measured and intrinsic viscosity immediately after solution was calculated. It was thereby found that (1n ηγ)/C of aluminium stearate in benzene solution is linear with concentration, that the value of [η] and, accordingly, degree of polymerization, are independent of melting point and stearate aluminium ratio found by chemical analysis, and that degree of polymerization of aluminium soap can be represented well by the intrinsic viscosity measured immediately after solution. The degree of polymerization of aluminium stearate is the greatest in di-soaps with a hydroxyl but it was found that di-soaps with impurities also had greater degree of polymerization immediately after solution and that some of the commercial products were of fairly low degree of polymerization.
The reaction of 2-benzylideneamino-3-phenyl-1-propanol (III) and acid anhydrides was examined. The reaction with acetic anhydride or chloroacetic anhydride afforded N-acyloxazolidine derivative (IV or V), while the reaction with dichloroacetic anhydride gave a β-lactam derivative (VI). The reaction of N-benzylidene-α-methylphenethylamine (IX) and dichloroacetic anhydride also gave a β-lactam derivative. This β-lactam cyclization by the reaction of the Schiff base and dichloroacetic anhydride is a new reaction not reported in existing literature. The structure of the product was confirmed by various reactions such as reductive cleavage with lithium aluminium hydride, dehalogenation reaction, and alkaline decomposition. It was thereby revealed that the structure of (X) would be represented by 1-(α-methylphenethyl)-3, 3-dichloro-4-phenyl-2-azetidinone and that of (VI) as 1-[α-(dichloroacetoxymethyl)phenethyl]-3, 3-dichloro-4-phenyl-2-azetidinone.
The reaction of the Schiff bases of β-amino alcohols with dichloroacetic anhydride was examined. While the Schiff base of alkanolamines underwent oxazolidine cyclization reaction, the Schiff base of aralkanolamines, having phenyl, benzyl, or phenethyl group in the 2-position of ethanolamine, underwent β-lactam cyclization. On the other hand, the Schiff base (VIII) of aralkanolamines, with a phenyl group in 1-position underwent oxazolidine cyclization, and the Schiff base (XXII) of that with a phenyl group in 1-position and methyl group in 2-position underwent β-lactam cyclization. D-threo-1-(p-Nitrophenyl)-2-benzylideneamino-1, 3-propanediol (XXVII) underwent neither oxazolidine nor β-lactam cyclization by reaction with dichloroacetic anhydride but formed chloramphenicol (XXX) and its bis (dichloroacetate) (XXIX).
Reaction between the Schiff bases of various amino acid esters and dichloroacetic anhydride was examined and it was found that, while the Schiff base of aliphatic α-amino acid esters underwent addition of the acid anhydride to their >C=N- double bond, the Schiff base of phenyl-α(or β)-alanine esters, having a phenyl group in α-or β-position of the amino group, underwent β-lactam cyclization reaction. Further, it was found that the Schiff base (XV) of phenylserine ester, the ester of a hydroxyamino acid, underwent oxazolidine cyclization reaction, while its methoxylated Schiff base (XVII) underwent β-lactam cyclization.
The reaction of the Schiff base of various amines with dichloroacetic anhydride was examined. The Schiff base of benzylamine or phenethylamine derivatives without a side chain in the α-position underwent addition reaction of the acid anhydride to the >C=N- double bond, while the Schiff base of amines with a side chain in the α-position undergoes β-lactam cyclization. N-Benzylidene-1, 3, 3-trimethylbutylamine (XXII) and N-(p-nitrobenzylidene)-1, 2, 2-trimethylpropylamine (XXIV), which possess tert-butyl instead of phenyl group, undergo β-lactam cyclization reaction with dichloroacetic anhydride. It was assumed from these experimental results that the presence of a bulky group, such as the phenyl or tert-butyl, in the α- or β-position of nitrogen is necessary in order that the Schiff base undergoes β-lactam cyclization and that the reaction is affected greatly by the steric effect. Finally, some considerations were made on the mechanism of these β-lactam cyclization reactions.
Kojibiose, obtained by synthesis, was recrystallized and three kinds of crystals, (A), (B), and (C), were obtained, which had different solubility, melting point, and crystal form. From the infrared spectra, molecular rotation, elemental analyses, and mutual relation of these crystals, it was found that (A) is an anhydrous β-kojibiose, (B) is an anhydrous α-kojibiose, and (C) is a monohydrate of α-kojibiose.
N1-[6-Methoxy (or Ethoxy Butoxy)-4-pyridazinyl] sulfanilamide (XIV) was synthesized from 4-amino-6-pyridazinol (I), 4-amino-3, 6-dichloropyridazine (VI), or 4-amino-5, 6-dichloropyridazine (XVIII). Reaction of 4 (or 5)-ethoxy-6-chloropyridazine (XVIII) with ammonia only gave 4 (or 5)-amino-6-chloropyridazine (XIX).
The use of soybean lecithin in the culture of Serratia plymuthicum resulted in good yield of the fungus. The use of soybean cephalin was also found to give good growth of the fungus, but the constituent components of cephallin did not effect growth. The fungus was found to utilize cephalin itself in the same way as lecithin. Examination of enzyme activity of the fungal extract showed the presence of strong lysolecithinase and glycerophosphorylcholine-diesterase actions, with hardly any lecithinase-A activity. Determination of lysolecithinase and measurement of snake venom lecithinase-A activity were carried out with the crude enzyme solution.
Reaction of benzoyl chloride and sodium thiosulfate in hydrous ethanol gave sodium benzoylthiosulfate. Other aromatic and heterocyclic sodium acylthiosulfates were prepared by the use of this reaction. Aliphatic sodium acylthiosulfates were obtained by the reaction of acid chloride and sodium thiosulfate without the use of a solvent.
Sodium benzoylthiosulfate undergoes thermal decomposition to form benzoyl disulfide and benzoic acid, quantitatively in alkaline solution, and benzoyl disulfide and benzoic acid in acid solution. Sodium benzoylthiosulfate acts as a good benzoylation agent for phenols, thiophenols, and aniline, but does not react well with alcohols. It is more reactive than benzoyl chloride.
Comparative examinations were made on the application of benzoyl chloride and sodium benzoylthiosulfate on aminophenol, o-aminothiophenol, and L-cysteine, which have hydroxyl, mercapto, and amino groups in the molecule. In the alkaline reaction, application of benzoyl chloride gave N, O- or N, S-dibenzoyl compounds alone or a mixture of that and N-benzoyl compounds, whereas that of sodium benzoylthiosulfate gave only the O- or S-benzoylated compounds. In acid reaction, application of benzoyl chloride gave only the N-benzoylated compound alone or N, S-dibenzoylated compound, while that of sodium benzoylthiosulfate gave N-benzoylated compound alone.
S-Acylthiamines were synthesized in a good yield by the application of sodium acylthiosulfate to thiol-type thiamine. S-Acylthiamine O-phosphates were prepared by application of sodium acylthiosulfate to thiol-type thiamine phosphate.
Alkaline decomposition of bilobanone (I) afforded 2 moles of acetone and a fragment of C9H14O (II), bp5 61-63° (semicarbazone, mp 157°; 2, 4-dinitrophenylhydrazone, m.p. 143°). From its N. M. R. spectrum and various reactions, (II) was identified as 1-methyl-4-acetyl-1-cyclohexene. Application of iodine and alkali on (II) gave methyl iodide and 4-methylcyclohexanecarboxylic acid (III). The catalytic reduction product (V) of (II) was proved to be cis-1-acetyl-4-methylcyclohexane and the product (VI) formed by reaction of (V) with iodoform was identified as 4-methylcyclohexanecarboxylic acid.
Reaction of 2-amino-3-bromotropone (I) with phenylacetonitrile resulted in rearrangement to a six-membered ring to form 2-amino-3-phenyl-8-quinolinol (II). The by-products obtained in the reaction of (I) and malononitrile and of (I) and diethyl malonate, reported in the previous paper, were found respectively to be 2-amino-8-hydroxy-3-quinolinecarbonitrile (VI) and ethyl 2, 8-dihydroxy-3-quinolinecarboxylate (X).
Reaction of 2-amino-3-bromotropone (I) with active methylene compounds having a ketone group was examined. It was found that (I) undergoes condensation with the methylene and ketone groups in the active methylene compound and forms a cyclohepta[b] pyrrol-8(1H)-one derivative. It was also revealed that if an ester group is also present in the active methylene compound, ketone group undergoes preferential condensation. From 2-methylcyclohepta[b] pyrrol-8(1H)-one (IV) obtained by this reaction, a seven-membered compound having similar structure similar to tryptophan, 3-(2-methyl-8-oxo-1, 8-dihydrocyclohepta[b] pyrrol-3-yl) alanine (XV), was prepared by a method same as in the preparation of indoles.
Permeability of caffeine and ephedrine through the cation-exchange membrane was examined by the use of five-compartment cell and heterogeneous ion-exchange membrane prepared in the laboratory. Each compartment of the cell contained stock solution of various compositions, concentration chamber was fixed, and the dilution chamber in the center was flown with the stock solution, from the bottom to the top. Electrodialysis was carried out for 1 hour and the amount of each ion in the sample solution in the concentration chamber was determined by the conventional method. Some noteworthy results of this experiment are given below. 1) Ephedrine and caffeine can be concentrated to over 3 times and 1.7 times, respectively, of the original concentration, ephedrine by the use of a weak acid resin membrane, at a strong acidity and high current density, and caffeine by the use of a strong acid resin membrane, at pH 3, and a high current density. 2) Permselectivity coefficients of ephedrine and caffeine, when using sodium ion as the reference standard, both become over 20 times and 5 times, respectively, higher by the use of a weak acid resin membrane, in a region below pH 1, and a low current density. 3) The use of a high current density at a neutral solution results in markedly small parmselectivity coefficient and this makes it possible to remove contaminating inorganic ions. 4) The ease of permeability is greater in caffeine than in ephedrine through a strong acid resin membrane but this order is reversed with a weak acid resin membrane.
3-Methoxy-17β-methyl-estra-1, 3, 5(10)-trien-17α-ol (VI) was prepared by dehydration of 3-methoxy-17α-methyl-estra-1, 3, 5(10)-trien-17β-ol (I) with phosphoryl chloride in pyridine, followed by epoxidation with perbenzoic acid, and reduction of its product with lithium aluminium hydride.
A number of 3-substituted 2-piperazinones were synthesized. Usually 3-substituted 4-methyl-2-piperazinone hydriodides were obtained by their methylation with methyl iodide, but 3, 3-diphenyl-4-methyl-2-piperazinone crystallized out in free form. These compounds have substantially no antispasmodic activity.
A number of 1-(2-alklaminoethyl)-5-phenylhydantoins were synthesized by the amination of 1-(2-bromoethyl)-5-phenylhydantoins. Some new N-substituted 2-phenylglycines were obtained by their hydrolysis with barium hydroxide solution under high pressure.
[(2-Diethylaminoethyl) amino] phenylacetonitrile was prepared and isolated as its hydrochloride, but its analogs could not be isolated in pure form. ω-Substituted 1-(aminoalkyl)-5-phenylhydantoin hydrochlorides were obtained from these crude α-substituted phenylacetonitriles, potassium cyanate, and hydrochloric acid. In another runs, anisaldehyde, 1-naphthaldehyde, and 2-thiophenecarboxaldehyde were used instead of benzaldehyde to prepare crude substituted acetonitriles. Of these hydantoins, 1-(3-diethylaminopropyl)-5-phenylhydantoin hydrochloride and 1-(2-dimethylaminoethyl)-5-thienylhydantoin hydrochloride were the most promising as an anticonvulsive substance.
Dyes of sulfonphthalein series undergo combination with various organic bases to form salts soluble in organic solvents and are utilized for colorimetric determination of organic bases. Some modifications were made in the existing method to simplify the procedure and make the method more practicable. In this modified method, the Bromocresol Green salt of the organic bases formed in aqueous phase is extracted with chloroform, the chloroform layer, which is colored yellow, is separated, and addition of ethanolic solution of triethanolamine to it changes its color to blue. This blue chloroform solution is submitted to the measurement of absorbance at 630mμ.
From one of the acid substances isolated from the Aristolochia genus plants, aristolochic acid (I), 3, 4-methylenedioxy-8-methoxyphenanthrene (IV) was formed and its picrate was identified with an authentic synthesized specimen. The unknown acid substance, acid C, isolated at the same time, was led to various derivatives and its structure was assumed as (XVIII) from the results of elemental analysis, infrared spectrum, and various chemical properties.
Basic components in the heart wood of Michelia compressa MAXIM. (Japanese name “Ogatama-no-ki”) growing in Japan was examined and the presence of ushinsunine (I) and oxoushinsunine (II) was proved by their isolation. Ito had earlier isolated from the trunk bark of domestic Michelia compressa, the tertiary, phenolic biscoclaurine-type base oxyacanthine, the quaternary, berberine-type bases berberine, palmatine, and jatrorrhizine, and the aporphine-type bases magnoflorine and michepressine. Yang had isolated ushinsunine (I) and oxoushinsunine (liriodenine) (II) from the heart wood of Formosan Michelia compressa MAXIM. var. Formosana KANEHIRA (Japanese name “Taiwan-Ogatama-no-ki”).
Complete benzyl ether of phenol can be obtained easily and in a good yield by boiling for 1hour a mixture of benzyl chloride, anhydrous potassium carbonate, and dimethylformamide with phenol compounds (including polyhydric phenols and phenol compounds possessing a hydroxyl adjacent to electron-attracting group).
p-Trimethylsilylbenzaldehyde (I) was prepared by the reduction of p-trimethylsilylbenzonitrile. Various reactions for aromatic aldehydes were carried out on (I). The Cannizzaro reaction and Cross-Cannizzaro reaction with formaldehyde afforded p-trimethylsilylbenzyl alcohol, benzoin condensation of (I) afforded 4, 4′-bis (trimethylsilyl) benzoin, the Perkin reaction afforded 4-trimethylsilylcinnamic acid, and the reaction of (I) with acetophenone afforded phenyl 4-trimethylsilylstyryl ketone. It was thereby confirmed that (I) undergoes almost the same reaction as benzaldehyde.
p-Trimethylsilylbenzonitrile (II) was synthesized by two different ways. Several reactions of the cyano group in (II) were carried out and 4-trimethylsilylbenzamide, p-trimethylsilylbenzyl alcohol, ethyl p-trimethylsilylbenzoate, 4-trimethylsilylbenz-amidine, three kinds of alkyl p-trimethylsilylphenyl ketone, and 4-trimethylsilyl-benzophenone were obtained. These experimental results proved that the cyano group in (II) has the same reactivity as that in benzonitrile.
Examinations were made on the urinary elimination of boron and its distribution in some organs by its oral administration to rabbits and guinea pigs in a single dose. It was found that majority of boron administered was excreted into the urine in a period of 48 hours but a part of it accumulated in the brain and the liver, the level of B being higher in the former organ.